Kåre Inge Birkeland

• Sharma, Archana; Lee-Ødegård, Sindre; Holst, Jens Juul; Hartmann, Bolette; Kvist, A. Anita S. & Qvigstad, Elisabeth [Show all 9 contributors for this article] (2026). Altered glucagon and GIP responses in South Asian versus Nordic women after gestational diabetes mellitus. Diabetologia. ISSN 0012-186X. p. 1–12. doi: 10.1007/s00125-026-06898-w. Full text in Research Archive Show summary

  Abstract Aims/hypothesis We aimed to compare ethnic differences in levels of glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) following a pregnancy complicated by gestational diabetes mellitus (GDM), and to assess whether the higher insulin levels observed in South Asian compared with Nordic women could be explained by differences in the hormone secretory responses. Methods We measured glucagon, GIP and GLP-1 in 178 South Asian and 107 Nordic women during an OGTT, and stratified participants by glycaemic status. Glucagon and total GLP-1 and GIP responses when fasting and post-OGTT were assessed by linear mixed models. Ethnic differences in incretin and glucagon levels were evaluated by linear regression analyses. Pre-hepatic insulin levels were estimated using deconvolution of C-peptide kinetics. Results Ethnic differences in glucagon and incretin levels varied by glycaemic status. In the normoglycaemic South Asian group, early (0–15 min) glucagon suppression post-OGTT was significantly attenuated compared with the Nordic group ( p =0.002). Fasting glucagon levels did not differ ( p =0.139), but total glucagon exposure (including fasting levels) was higher in South Asian women ( p =0.013). No differences in GIP and GLP responses to the OGTT were observed ( p =0.490 and p =0.802). In women with prediabetes or diabetes, fasting glucagon was higher in the South Asian group ( p =0.010), but there were no significant differences in early glucagon suppression post-OGTT ( p =0.986). GIP responses to the OGTT were lower among South Asian women ( p <0.001), despite higher insulin responses compared with the Nordic women. GLP-1 responses did not differ between the ethnic groups ( p =0.661). The higher pre-hepatic insulin levels in South Asian vs Nordic normoglycaemic women were not associated with differences in incretin levels, but were associated with lower insulin sensitivity in the regression analyses ( p <0.001). Conclusions/interpretation When examined 1–3 years post-GDM, normoglycaemic South Asian women had less early glucagon suppression and higher total glucagon exposure post-OGTT compared with Nordic women. The higher pre-hepatic insulin levels were not associated with higher incretin levels, but were associated with lower insulin sensitivity.

• Nunes, Caroline Brito; Rukins, Valentina; Cisse, Aminata H.; White, Frédérique; McBride, Nancy & Kuang, Alan [Show all 79 contributors for this article] (2026). Multi-ancestry, trans-generational GWAS meta-analysis of gestational diabetes and glycaemic traits during pregnancy reveals limited evidence of pregnancy-specific genetic effects. Nature Communications. 17. doi: 10.1038/s41467-026-73509-y. Full text in Research Archive Show summary

  Gestational diabetes mellitus (GDM) affects ~14% of pregnancies and increases maternal type 2 diabetes mellitus (T2DM) risk. The GenDiP Consortium presents trans-generational, multi-ancestry genome-wide association study meta-analyses of GDM and pregnancy glycemic traits in up to 38,305 GDM cases and 776,145 controls. We identify 37 GDM-associated loci (7 novel) and five novel loci for pregnancy glycemic traits, all operating through the maternal genome. We classify 12 GDM variants with stronger effects in GDM than T2DM into five biologically informed categories, revealing pleiotropy patterns, pregnancy-dependent effect modification, and diagnostic heterogeneity. While all these loci overlap with T2DM and/or non-pregnant glycaemic traits, four (G6PC2, CAST-PCSK1, HKDC1, FOXA2) lack genome-wide-significant T2DM associations; GCK shows distinct causal variants for GDM, and MTNR1B exhibits pregnancy-amplified effects. Our findings provide new genetic insights into GDM and highlight the need for larger, ancestrally diverse studies of GDM and glycaemic traits during pregnancy to understand potential pregnancy-specific effects.

• Sousa, Ana Rita Sequeira de; Klemsdal, Tor Ole; Ghiasvand, Reza; Svendsen, Mette; Birkeland, Kåre Inge & Sveen, Kari Anne (2026). Lifestyle modifications in individuals with blood pressure beyond treatment target despite pharmacological treatment: design and baseline characteristics of the MeDiPA randomised controlled trial. Blood Pressure. ISSN 0803-7051. 35(1). doi: 10.1080/08037051.2026.2705014. Full text in Research Archive
• Bjarkø, Vera Vik; Wolford, Brooke N.; Haug, Eirin Beate; Stene, Lars Christian Mørch; Carlsson, Sofia & Langhammer, Arnulf [Show all 13 contributors for this article] (2026). Temporal changes and genetic susceptibility to type 2 diabetes (1984-2019; HUNT): a longitudinal, population-based study. The Lancet Diabetes and Endocrinology. ISSN 2213-8587. 14(3), p. 223–232. doi: 10.1016/S2213-8587(25)00322-5. Full text in Research Archive
• Jenssen, Trond; Bodegård, Lars Johan; Sveen, Kari Anne; Thuresson, Marcus & Birkeland, Kåre Inge (2025). Prevalence, outcomes, costs, and treatments of a contemporary population with chronic kidney disease in Norway: a nationwide observational study. BMC Nephrology. 26(1). doi: 10.1186/s12882-025-04171-7. Full text in Research Archive Show summary

  Background This nation-wide study describes patients with diagnosed chronic kidney disease (CKD), with and without type 2 diabetes (T2D). Methods Prevalence, key adverse outcomes, health care costs, and use of kidney-protective treatment, up until December 31st, 2022, were described in patients aged > 18 years in Norway using register-based data. Only diagnosis codes were used to identify patients with CKD, with laboratory measurements of estimated-glomerular filtration rate and albuminuria unavailable. Utilisation of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and renin-angiotensin system [RAS] inhibitors were evaluated in new users following the first Norwegian approval of an SGLT-2 inhibitor for CKD treatment. Results Approximately 3% (125,163 patients) of adults in Norway had diagnosed CKD (average age 70 years, 42% women, 73% without T2D). When describing patients with or without T2D, history of heart failure (22% versus 22%), atherosclerotic cardiovascular disease (ASCVD; 57% versus 51%), and atrial fibrillation (24% versus 27%) were similar. Larger proportions of those with T2D received SGLT-2 inhibitors (24% versus 4%) and/or RAS inhibitors (63% versus 47%). Hospitalisations for CKD (28.1 versus 22.1 events per 100 patient years), heart failure (12.6 versus 9.8), myocardial infarction (3.9 versus 2.2), and stroke (3.2 versus 2.3) were more common in patients with CKD and T2D than those without T2D. However, mortality (10.8 versus 8.5) was higher in patients without T2D. CKD and heart failure costs were higher than those for ASCVD, and generally higher in patients with T2D. SGLT-2 inhibitor utilisation increased two-fold the year after its approval but was still low, used mostly at its highest target dose. Discontinuation rates were lower with SGLT-2 inhibitors than with RAS inhibitors, the latter mostly utilised at low doses. Conclusions A CKD diagnosis was associated with substantial morbidity and mortality, costs, and undertreatment, both in patients with and without T2D. Use of novel kidney-protective treatment has increased, but an urgent need to improve the utilisation of kidney-protective medications remains, particularly in patients without T2D.

• Teigland, Tonje; Igland, Jannicke; Blytt, Kjersti Marie; Haltbakk, Johannes; Birkeland, Kåre Inge & Østbye, Truls [Show all 8 contributors for this article] (2025). All-cause and cause-specific mortality in older people with and without diabetes in Norwegian home care services: a nationwide registry study. BMC Geriatrics. 25(1). doi: 10.1186/s12877-025-06685-z. Full text in Research Archive Show summary

  Background As the number of older people living at home increases, the role of home care services (HCS) becomes more important. Diabetes is associated with premature mortality and is common among older people in HCS, yet mortality patterns among HCS recipients are not well known. This study aimed to estimate all-cause and cause-specific mortality risk in persons with pharmacologically treated diabetes receiving HCS compared to other HCS recipients and explore whether mortality risk differed between diabetes treatment subgroups. Methods This nationwide registry study merged data from the Norwegian Information System for the Nursing and Care Sector with data from the Norwegian Prescription Database, the Norwegian Patient Registry, and the Cause of Death Registry (CDR). The study population included recipients of HCS (aged 65–90 years at baseline) in Norway between 2009 and 2014. Individuals were classified as having pharmacologically treated diabetes (hereafter referred to as diabetes) (≥ 1 prescription of glucose-lowering drugs (GLD) in the current half year or the year before), or not having diabetes. Those with diabetes were further sub-classified into “non-insulin GLD only”, “insulin and non-insulin GLD”, or “insulin only”. Time of death and the underlying cause of death were retrieved from CDR. The study population, diabetes status, covariates, and all-cause mortality were updated each half-year. Mortality risk was compared between groups using Cox proportional hazards regression, with age as time scale, and reported as hazard ratio (HR) with 95% CIs. Results Women in the “insulin only” group had a higher risk of all-cause mortality (HR 1.18 (CI 1.11–1.25)) than women without diabetes, while in the “non-insulin GLD only” and “insulin and non-insulin GLD” subgroups, both women and men with diabetes had lower mortality risks than those without diabetes. Overall, persons with diabetes had a higher risk of cardiovascular mortality (HR 1.23 (CI 1.19–1.28)) compared to persons without diabetes, and a lower risk of dying from cancer (HR 0.68 (CI 0.66–0.70)) and respiratory disease (HR 0.67 (CI 0.62–0.72)). Conclusion Mortality risk varied by diabetes status and treatment subgroups. Most diabetes subgroups had lower all-cause mortality risk than those without diabetes, except for women using “insulin only”, underscoring the need for individualized HCS.

• Suntharalingam, Anita; Sharma, Archana; Qvigstad, Elisabeth; Sattar, Naveed; Gill, Jason M. R. & Bjørnvall, Christina Dybdrodt [Show all 12 contributors for this article] (2025). Differences in tissue-specific insulin resistance between South Asian and Nordic women with prediabetes after gestational diabetes. Diabetologia. ISSN 0012-186X. 68(12), p. 2696–2708. doi: 10.1007/s00125-025-06546-9. Full text in Research Archive Show summary

  Aims/hypothesis The aim of this work was to investigate tissue-specific insulin resistance in South Asian and Nordic women with previous gestational diabetes mellitus (pGDM) and to evaluate potential ethnic differences contributing to type 2 diabetes risk. Methods A cross-sectional study using a two-step hyperinsulinaemic–euglycaemic clamp with a glucose tracer was conducted to assess insulin sensitivity in muscle, liver and adipose tissue in 19 South Asian and 16 Nordic women with pGDM and prediabetes (impaired glucose tolerance and/or impaired fasting glucose), along with 16 ethnicity-specific control women. We assessed inflammation and mitochondrial genes by mRNA sequencing of adipose tissue. Results Both South Asian and Nordic women with pGDM showed reduced total glucose disposal (mainly due to muscle insulin resistance) and hyperinsulinaemia compared with the control group. Endogenous glucose production (mainly due to hepatic insulin resistance) was elevated in Nordics with pGDM, while South Asians with pGDM showed pronounced adipose tissue insulin resistance (reduced suppression of glycerol during clamp). mRNA sequencing of adipose tissue indicated increased tissue inflammation in South Asian women compared with Nordic women with pGDM. Furthermore, we observed a differential response to hyperinsulinaemia in South Asians vs Nordics related to mitochondrial mRNA, such as thymidine kinase 2 (TK2). Correlations between adiposity markers and insulin sensitivity also differed by ethnicity, suggesting that the pathways leading to type 2 diabetes may vary across populations. Conclusions/interpretation South Asian and Nordic women with pGDM exhibited differences in insulin resistance profiles, with South Asians showing greater adipose tissue insulin resistance and inflammation.

• Waage, Christin; Jenum, Anne Karen; Mdala, Ibrahimu; Lee-Ødegård, Sindre; Brænd, Anja Maria & Sletner, Line [Show all 8 contributors for this article] (2025). Diabetes and prediabetes among women universally screened for gestational diabetes: a multi-ethnic, population-based, prospective study with eleven years follow-up. BMC Public Health. 25(1). doi: 10.1186/s12889-025-22493-x. Full text in Research Archive Show summary

  Background Gestational diabetes (GDM) is a strong risk factor for later development of diabetes. However, data are scarce on the long-term risk for diabetes or prediabetes diagnosed by HbA1c, in non-selected, multi-ethnic populations universally screened for GDM using the WHO2013 criteria. We aimed to investigate the development of diabetes or prediabetes eleven years after the index pregnancy and identify risk factors in pregnancy or shortly after. Methods A population-based cohort study of 360 women with complete eleven years follow-up data for diabetes (HbA1c≥48 mmol/mol) or prediabetesADA (HbA1c 39–47 mmol/mol). Women were enrolled in gestational week 15 and universally screened with an oral glucose tolerance test in week 28. We performed least absolute shrinkage and selection operator (LASSO) regression to identify predictors of future diabetes or prediabetesADA and constructed a nomogram to predict individual risks. Results Diabetes or prediabetesADA combined, was found in 26.9%, and the prevalence was slightly higher in previous GDM compared with non-GDM women (35.6% versus 23.5%; p=0.019). The relative risk (RR) for developing diabetes or prediabetesADA was moderately elevated in GDM compared with non-GDM women (1.4 [1.0, 1.9], p=0.035). Seven women (1.9%) had diabetes and all of these except for one, had previous GDM. Hence, the crude prevalence was 5.8% among GDM women vs. 0.4% among non-GDM women. The RR for developing diabetes was substantially higher in GDM vs. non-GDM women (14.8 [2.6, 277.1], p=0.012). PrediabetesADA was found in 25% and the RR for prediabetesADA was not significantly increased for GDM compared to non-GDM women (1.3 [0.9, 1.8], p=0.143). Among Europeans, 17.0% had diabetes or prediabetesADA, compared to 43.0% among South Asians (p<0.001) and 34.4% among other ethnicities (p=0.002). The most significant predictors identified from the LASSO were HbA1c measured in early pregnancy, ethnicity, and a family history of diabetes. Conclusions The risk for developing diabetes was low, overall and among GDM women. Still GDM represented a strong risk for diabetes, but not for prediabetesADA. HbA1c early in pregnancy, non-European ethnicity, and a family history of diabetes were the strongest risk factors for developing diabetes or prediabetesADA.

• Hauge, Jostein Wågen; Borgeraas, Heidi; Birkeland, Kåre Inge; Johnson, Line Kristin; Hertel, Jens Kristoffer & Hagen, Milada [Show all 16 contributors for this article] (2025). Effect of gastric bypass versus sleeve gastrectomy on the remission of type 2 diabetes, weight loss, and cardiovascular risk factors at 5 years (Oseberg): secondary outcomes of a single-centre, triple-blind, randomised controlled trial. The Lancet Diabetes and Endocrinology. ISSN 2213-8587. 13(5), p. 397–409. doi: 10.1016/S2213-8587(24)00396-6. Full text in Research Archive
• Rishaug, Tina; Aas, Anne-Marie; Henriksen, André; Hartvigsen, Gunnar; Birkeland, Kåre Inge & Årsand, Eirik (2025). What are end-users’ needs and preferences for a comprehensive e-health program for type 2 diabetes? – A qualitative user preference study. PLOS ONE. 20(3). doi: 10.1371/journal.pone.0318876. Full text in Research Archive Show summary

  Introduction - Type 2 diabetes (T2D) prevalence is rising, which imposes a significant burden on individuals, healthcare systems, and economies worldwide. Lifestyle factors contribute significantly to the escalating incidence of T2D. Consequently, there is an increasing need for interventions that not only target at-risk populations for prevention but also empower individuals with T2D to achieve better self-management and possibly attain remission through sustained lifestyle modifications. Technological tools may improve health outcomes compared to traditional in-person care, and can include registration of important health parameters, provide follow-up and support, and enhance self-management. The aim of this study was to receive feedback from end-users to inform the development of a comprehensive e-health program focusing on lifestyle modification in pre-diabetes and T2D.<p> <p>Methods - During eight focus group meetings, sixteen adults with pre-diabetes or T2D from all over Norway informed the study about needs and preferences for an e-health program, including essential functionalities and design choices. A questionnaire and paper prototyping were used to complement the discussions in the focus group meetings.<p> <p>Results - Lack of necessary diabetes knowledge was common, and education was considered essential for improved self-management. Essential functionalities included registration and overview of several health parameters, long-term follow-up and coaching through communication platforms within the program, automatic data transfer from different devices such as blood glucose monitors and smartwatches, and educational courses. To ensure end-users’ satisfaction with the program and increase motivation for long-term usage, the participants rendered tailoring of desired functionalities and content as crucial.<p> <p>Conclusion - Based on the findings, a list of recommendations was created, containing the most crucial functionalities and features to include when developing e-health and/or m-health tools for people with pre-diabetes and T2D. Future work should include health care personnel to explore their needs and preferences, and ways such an e-health program may enhance patient interaction without increasing workload and resource use.

• Bargas, Nicolas Fragoso; Mcbride, Nancy S.; Lee-Ødegård, Sindre; Lawlor, Deborah A.; Yousefi, Paul D. & Moen, Gunn-Helen [Show all 14 contributors for this article] (2025). Epigenome-wide association study of objectively measured physical activity in peripheral blood leukocytes. BMC Genomics. 26. doi: 10.1186/s12864-025-11262-0. Full text in Research Archive Show summary

  Background: Few studies have explored the association between DNA methylation and physical activity. The aim of this study was to evaluate the association of objectively measured hours of sedentary behavior (SB) and moderate physical activity (MPA) with DNA methylation. We further aimed to explore the association between SB or MPA related CpG sites and cardiometabolic traits, gene expression, and genetic variation. Results: For discovery, we performed cross sectional analyses in pregnant women from the Epigenetics in pregnancy (EPIPREG) sample with both DNA methylation (Illumina MethylationEPIC BeadChip) and objectively measured physical activity data (SenseWear™ Pro 3 armband) (European = 244, South Asian = 109). For EWAS of SB and MPA, two main models were designed: model (1) a linear mixed model adjusted for age, smoking, blood cell composition, including ancestry as random intercept, and model (2) which was additionally adjusted for the total number of steps per day. In model 1, we did not identify any CpG sites associated with neither SB nor MPA. In model 2, SB was positively associated (false discovery rate, FDR < 0.05) with two CpG sites within the VSX1 gene. Both CpG sites were positively associated with BMI and were associated with several genetic variants in cis. MPA was associated with 122 significant CpG sites at FDR < 0.05 (model 2). We further analyzed the ten most statistically significant MPA related CpG sites and found that they presented opposite associations with sedentary behavior and BMI. We were not able to replicate the SB and MPA-related CpG sites in the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC had available objectively measured physical activity data from Actigraph (without steps/day available) and leucocyte DNA methylation data collected during adolescence (n = 408, European). Conclusion: This study suggests associations of objectively measured SB and MPA with maternal DNA methylation in peripheral blood leukocytes, that needs to be confirmed in larger samples of similar study design.

• Carlsen, Rasmus Kirkeskov; Åsberg, Anders; Svensson, My Hanna Sofia; Birkeland, Kåre Inge; Jørgensen, Hanne Skou & Bressendorff, Iain [Show all 10 contributors for this article] (2025). Hypomagnesemia, insulin secretion and action in patients without diabetes, 1 year after kidney transplantation. Frontiers in Medicine. 12. doi: 10.3389/fmed.2025.1492871. Full text in Research Archive
• Opsahl, Julia Onsrud; Bargas, Nicolas Fragoso; Lee, Y.; Carlsen, E. Ø.; Kiryushchenko, Nadezhda & Qvigstad, E. [Show all 13 contributors for this article] (2024). Epigenome-wide association study of DNA methylation in maternal blood leukocytes with BMI in pregnancy and gestational weight gain. International Journal of Obesity. ISSN 0307-0565. 48(4), p. 584–593. doi: 10.1038/s41366-024-01458-x. Full text in Research Archive Show summary

  Objectives We aimed to discover CpG sites with differential DNA methylation in peripheral blood leukocytes associated with body mass index (BMI) in pregnancy and gestational weight gain (GWG) in women of European and South Asian ancestry. Furthermore, we aimed to investigate how the identified sites were associated with methylation quantitative trait loci, gene ontology, and cardiometabolic parameters. Methods In the Epigenetics in pregnancy (EPIPREG) sample we quantified maternal DNA methylation in peripheral blood leukocytes in gestational week 28 with Illumina’s MethylationEPIC BeadChip. In women with European (n = 303) and South Asian (n = 164) ancestry, we performed an epigenome-wide association study of BMI in gestational week 28 and GWG between gestational weeks 15 and 28 using a meta-analysis approach. Replication was performed in the Norwegian Mother, Father, and Child Cohort Study, the Study of Assisted Reproductive Technologies (MoBa-START) (n = 877, mainly European/Norwegian). Results We identified one CpG site significantly associated with GWG (p 5.8 × 10−8) and five CpG sites associated with BMI at gestational week 28 (p from 4.0 × 10–8 to 2.1 × 10–10). Of these, we were able to replicate three in MoBa-START; cg02786370, cg19758958 and cg10472537. Two sites are located in genes previously associated with blood pressure and BMI. DNA methylation at the three replicated CpG sites were associated with levels of blood pressure, lipids and glucose in EPIPREG (p from 1.2 × 10−8 to 0.04). Conclusions We identified five CpG sites associated with BMI at gestational week 28, and one with GWG. Three of the sites were replicated in an independent cohort. Several genetic variants were associated with DNA methylation at cg02786379 and cg16733643 suggesting a genetic component influencing differential methylation. The identified CpG sites were associated with cardiometabolic traits.

• Myrmel, Lene Secher; Øyen, Jannike; Brantsæter, Anne Lise; Fjære, Even; Haugvaldstad, Karen & Birkeland, Kåre Inge [Show all 10 contributors for this article] (2024). Intake of different types of seafood and meat and risk of type 2 diabetes in women: a prospective study supported by a dietary intervention in mice. Scientific Reports. 14. doi: 10.1038/s41598-024-59491-9. Full text in Research Archive Show summary

  Detailed knowledge regarding the associations between intake of different types of seafood and meat and the risk of type 2 diabetes (T2D), and insight into possible mechanisms are warranted. In this study we aimed to evaluate the associations between intake of different types of seafood and meat and the subsequent risk of T2D using the Norwegian Mother, Father, and Child Cohort Study (MoBa), and furthermore, by using a mouse model to gain further insight into possible molecular mechanisms contributing to the associated metabolic changes. Women in MoBa who were free of pharmacologically treated diabetes at baseline (n = 60,777) were prospectively evaluated for incident T2D, identified on the basis of medication usages > 90 days after delivery, ascertained by the Norwegian Prescription Database. Dietary intake was obtained with a validated 255-item food frequency questionnaire which assessed habitual diet during the first 4–5 months of pregnancy. Metabolic phenotypes and plasma metabolome were investigated in female mice fed isocaloric diets with different types of seafood and meat mimicking the dietary intake in the human cohort. During maximum 10-year and mean (SD) 7.2 (1.6) years follow-up time, 681 (1.1%) women developed pharmacologically treated T2D. All statistical models identified a higher risk of T2D with increased shellfish intake, whereas no associations were observed for total seafood, fatty fish, total meat and red meat in the adjusted models. In mice, the shellfish-based western diet induced reduced glucose tolerance and insulin secretion compared to the diet based on lean fish, and we identified a number of metabolites elevated in plasma from shellfish-fed mice that correlated with glucose intolerance. Mice fed a western diet based on meat also exhibited reduced glucose tolerance in comparison to lean fish fed mice, whereas mice fed fatty fish, total seafood or red meat did not differ from lean fish fed mice. We observed a diet-specific metabolic signature in plasma demonstrating five distinct metabolite profiles in mice fed shellfish, fatty fish, total seafood/lean fish, a mixed diet and meat. In conclusion, these findings demonstrate that different types of seafood have different outcome on T2D risk. In women, intake of shellfish was associated with higher risk of T2D. In female mice, a shellfish enriched diet reduced glucose tolerance and altered the abundance of several distinct plasma metabolites correlating with glucose tolerance.

• Lee-Ødegård, Sindre; Hjorth, Marit; Olsen, Thomas; Moen, Gunn-Helen Øiseth; Daubny, Emily & Evans, David M [Show all 17 contributors for this article] (2024). Serum proteomic profiling of physical activity reveals CD300LG as a novel exerkine with a potential causal link to glucose homeostasis. eLIFE. 13, p. 1–25. doi: 10.7554/ELIFE.96535. Full text in Research Archive Show summary

  Background: Physical activity has been associated with preventing the development of type 2 diabetes and atherosclerotic cardiovascular disease. However, our understanding of the precise molecular mechanisms underlying these effects remains incomplete and good biomarkers to objectively assess physical activity are lacking. Methods: We analyzed 3072 serum proteins in 26 men, normal weight or overweight, undergoing 12 weeks of a combined strength and endurance exercise intervention. We estimated insulin sensitivity with hyperinsulinemic euglycemic clamp, maximum oxygen uptake, muscle strength, and used MRI/MRS to evaluate body composition and organ fat depots. Muscle and subcutaneous adipose tissue biopsies were used for mRNA sequencing. Additional association analyses were performed in samples from up to 47,747 individuals in the UK Biobank, as well as using two-sample Mendelian randomization and mice models. Results: Following 12 weeks of exercise intervention, we observed significant changes in 283 serum proteins. Notably, 66 of these proteins were elevated in overweight men and positively associated with liver fat before the exercise regimen, but were normalized after exercise. Furthermore, for 19.7 and 12.1% of the exercise-responsive proteins, corresponding changes in mRNA expression levels in muscle and fat, respectively, were shown. The protein CD300LG displayed consistent alterations in blood, muscle, and fat. Serum CD300LG exhibited positive associations with insulin sensitivity, and to angiogenesis-related gene expression in both muscle and fat. Furthermore, serum CD300LG was positively associated with physical activity and negatively associated with glucose levels in the UK Biobank. In this sample, the association between serum CD300LG and physical activity was significantly stronger in men than in women. Mendelian randomization analysis suggested potential causal relationships between levels of serum CD300LG and fasting glucose, 2 hr glucose after an oral glucose tolerance test, and HbA1c. Additionally, Cd300lg responded to exercise in a mouse model, and we observed signs of impaired glucose tolerance in male, but not female, Cd300lg knockout mice. Conclusions: Our study identified several novel proteins in serum whose levels change in response to prolonged exercise and were significantly associated with body composition, liver fat, and glucose homeostasis. Serum CD300LG increased with physical activity and is a potential causal link to improved glucose levels. CD300LG may be a promising exercise biomarker and a therapeutic target in type 2 diabetes.

• Viken, Jonas Krag; Olsen, Thomas; Drevon, Christian André; Hjorth, Marit; Birkeland, Kåre Inge & Norheim, Frode Amador [Show all 7 contributors for this article] (2024). Intra-Individual Variations in How Insulin Sensitivity Responds to Long-Term Exercise: Predictions by Machine Learning Based on Large-Scale Serum Proteomics. Metabolites. 14(6). doi: 10.3390/metabo14060335. Full text in Research Archive Show summary

  Physical activity is effective for preventing and treating type 2 diabetes, but some individuals do not achieve metabolic benefits from exercise (“non-responders”). We investigated non-responders in terms of insulin sensitivity changes following a 12-week supervised strength and endurance exercise program. We used a hyperinsulinaemic euglycaemic clamp to measure insulin sensitivity among 26 men aged 40–65, categorizing them into non-responders or responders based on their insulin sensitivity change scores. The exercise regimen included VO2max, muscle strength, whole-body MRI scans, muscle and fat biopsies, and serum samples. mRNA sequencing was performed on biopsies and Olink proteomics on serum samples. Non-responders showed more visceral and intramuscular fat and signs of dyslipidaemia and low-grade inflammation at baseline and did not improve in insulin sensitivity following exercise, although they showed gains in VO2max and muscle strength. Impaired IL6-JAK-STAT3 signalling in non-responders was suggested by serum proteomics analysis, and a baseline serum proteomic machine learning (ML) algorithm predicted insulin sensitivity responses with high accuracy, validated across two independent exercise cohorts. The ML model identified 30 serum proteins that could forecast exercise-induced insulin sensitivity changes.

• Carlsen, Monica H.; Totland, Torunn Holm; Kumar, Radhika; Lensnes, Therese Margrethe Lysell; Sharma, Archana & Suntharalingam, A. Anita [Show all 9 contributors for this article] (2024). Evaluation of a digital FFQ using 24 h recalls as reference method, for assessment of habitual diet in women with South Asian origin in Norway. Public Health Nutrition (PHN). ISSN 1368-9800. 27(1). doi: 10.1017/S1368980024000302. Full text in Research Archive Show summary

  Objective: Dietary assessment tools should be designed for the target population. We developed an FFQ designed to assess diet in South Asian women in Norway. The study objective was to evaluate this FFQ using 24-h dietary recalls as reference method. Design: Approximately 3 weeks after the participants (n 40) had filled in the FFQ, the first of three non-consecutive 24-h dietary recalls was completed. The recalls were telephone-based, unannounced and performed by a trained dietitian, with 2–3 weeks between each interview. Setting: The DIASA 1 study, in Oslo, Norway. Participants: Women of South Asian ethnic origin participating in the DIASA 1 study were invited to participate in the evaluation study. Results: The WebFFQasia significantly overestimated the absolute intake of energy, protein, fat and carbohydrates compared with the 24-h dietary recalls. Absolute intakes of sugar, starch and fibre did not differ significantly between the methods. For energy percentages (E%), there were no significant differences, except for monounsaturated fat. Correlations were strong for E% from sugar and saturated fat and moderate for E% from fibre, carbohydrate, total fat and protein. Fourteen food groups out of twenty three were not significantly different compared with the reference method, and sixteen groups showed strong to moderate correlations. Conclusion: The WebFFQasia may be used to assess E% from habitual diet and can adequately estimate intakes and rank participants according to nutrient intake and main food categories at group level.

• Sharma, Archana; Birkeland, Kåre Inge; Nermoen, Ingrid; Sommer, Christine; Qvigstad, Elisabeth & Lee-Ødegård, Sindre [Show all 11 contributors for this article] (2024). N-terminal pro-B-type natriuretic peptide levels vary by ethnicity and are associated with insulin sensitivity after gestational diabetes mellitus. Cardiovascular Diabetology. 23(1). doi: 10.1186/s12933-024-02349-1. Full text in Research Archive Show summary

  Background Individuals of South Asian origin have a greater risk of cardiovascular disease after gestational diabetes mellitus (GDM) than European individuals. B-type natriuretic peptide (BNP) and the amino-terminal fragment of its prohormone (NT-proBNP) are commonly used for heart failure screening and diagnosis, but biologically BNP exerts several beneficial cardiovascular effects primarily by counteracting the renin-angiotensin-aldosterone-system. We asked whether ethnic differences in circulating NT-proBNP levels could be explained by the differences in cardiometabolic and inflammatory risk markers? Methods We examined 162 South Asian and 107 Nordic women in Norway 1–3 years after GDM with a clinical examination, fasting blood samples and an oral glucose tolerance test. We measured the levels of NT-proBNP, high-sensitivity cardiac troponin T, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), leptin, adiponectin and markers of insulin sensitivity, such as the Matsuda insulin sensitivity index (ISI). Finally, we tried to identify which independent covariate best mediated the ethnic differences in NT-proBNP. Results The mean (SD) age was 35.3 (4.5) years, BMI 29.1 (6.0) kg/m2, waist-height ratio 0.60 (0.08) and 164 women (61%) had prediabetes/diabetes. Notably, South Asian women had lower levels of NT-proBNP than Nordic women in both the normoglycemic and prediabetes/diabetes groups (median (IQR) 26  (15–38)  vs. 42 (22–66) ng/L, p < 0.001). Higher NT-proBNP levels were associated with greater insulin sensitivity in both South Asian and Nordic women (p = 0.005 and p < 0.001). South Asian women had higher levels of hsCRP (median (IQR) 2.2 (1.1–4.4) vs. 1.2 (0.3–4.2) mg/L), IL-6 (2.3 (1.5–3.2) vs. 1.5 (1.5–2.5) pg/mL), leptin (1647 (1176–2480) vs. 1223 (876–2313) pmol/L), and lower adiponectin levels (7.2 (5.3–9.3) vs. 10.0 (7.2–13.5) mg/L) and Matsuda ISI (2.4 (1.7–3.7) vs. 4.2 (2.9–6.1), pall<0.01) than Nordic women. Even after adjusting for these differences, higher NT-proBNP levels remained associated with insulin sensitivity (22% higher NT-proBNP per SD Matsuda ISI, p = 0.015). Insulin sensitivity and adiponectin mediated 53% and 41% of the ethnic difference in NT-proBNP. Conclusions NT-proBNP levels are lower in South Asian than in Nordic women after GDM. Lower NT-proBNP levels correlate with impaired insulin sensitivity. Lower NT-proBNP levels in South Asian women could, therefore, be attributed to impaired insulin sensitivity rather than total body fat.

• Sletner, Line; Yajnik, Chittaranjan S.; Turowski, Gitta Erika; Michelsen, Trond Melbye; Sommer, Christine & Birkeland, Kåre Inge [Show all 8 contributors for this article] (2024). Placental weight, surface area, shape and thickness - Relations with maternal ethnicity and cardio-metabolic factors during pregnancy. Placenta. ISSN 0143-4004. 148, p. 69–76. doi: 10.1016/j.placenta.2024.02.002. Full text in Research Archive Show summary

  Introduction A better understanding of the determinants of placental growth is needed. Our primary aim was to explore associations between maternal ethnic origin and cardio-metabolic factors during pregnancy, and placental weight, surface area, shape and thickness. Methods A multi-ethnic population-based cohort study of 474 pregnant women examined at mean 15 and 28 weeks’ gestation. Placentas were inspected after birth by a placental pathologist. Outcome measures were trimmed placental weight and three uncorrelated placental components; surface area, shape (oval vs round) and thickness, created through a principal components analysis. Multivariate linear regression models were used to explore the associations with maternal factors. Results Compared with ethnic European women, mothers with South- and East Asian ethnicity had placentas with lower weight (−51 g (95% CI: 75, −27) and −55 g (−95, −14) respectively), primarily due to a smaller surface area. The association between South Asian ethnicity and placental surface area was still significant after adjusting for maternal characteristics and cardio-metabolic factors. Fat mass index in early pregnancy was associated with higher placental weight and thickness. Placental surface area was positively associated with mid-gestational increases in fat mass, fasting glucose and triglycerides and with the 2-h glucose value at the 28 week oral glucose tolerance test, and inversely with a mid-gestational increase in HDL-cholesterol. Discussion Mid-gestational changes in fat mass, glucose, triglycerides and cholesterol were associated with, but only partly explained ethnic differences in placental surface area, while maternal fat mass in early pregnancy was associated with placental thickness.

• Grannes, Helene; Ueland, Thor; Simeone, Paola; Liani, Rossella; Guagnano, Maria Teresa & Aukrust, Pål [Show all 14 contributors for this article] (2024). Liraglutide and not lifestyle intervention reduces soluble CD163 after comparable weight loss in obese participants with prediabetes or type 2 diabetes mellitus. Cardiovascular Diabetology. 23(1). doi: 10.1186/s12933-024-02237-8. Full text in Research Archive Show summary

  Background The GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus. Method Plasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase‐associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/ TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n=20) or liraglutide treatment (n=20), and in healthy subjects (n=13). Results At baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or liraglutide treatment, sCD163 decreased significantly in the liraglutide group vs. lifestyle (between-group difference p=0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inlfammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of liraglutide vs lifestyle group.

• Waage, Anne; Khan, Ammar; Labori, Knut Jørgen; Birkeland, Kåre Inge; Scholz, Hanne & Jenssen, Trond [Show all 9 contributors for this article] (2024). Implementation of a nationwide program for total pancreatectomy and islet autotransplantation in chronic pancreatitis: A Scandinavian single-center observational study. Scandinavian Journal of Surgery. ISSN 1457-4969. doi: 10.1177/14574969241298985. Full text in Research Archive
• Teigland, Tonje; Igland, Jannicke; Graue, Marit; Blytt, Kjersti Marie; Haltbakk, Johannes & Tell, Grethe S. [Show all 10 contributors for this article] (2024). Associations between diabetes and risk of short-term and long-term nursing home stays among older people receiving home care services: A nationwide registry study. BMC Geriatrics. 24(1). doi: 10.1186/s12877-024-05403-5. Full text in Research Archive Show summary

  Background Older people with diabetes who live at home and receive home care services (HCS) are vulnerable, which may result in a need for more care than the HCS can provide. In this study we aimed to explore associations between pharmacologically treated diabetes and the risk of short-term and long-term nursing home stays (NHS) among older people receiving HCS. Methods This nationwide registry study included older people ≥ 65 years receiving HCS, as registered in the Norwegian Information System for the Nursing and Care Sector (IPLOS) (2010–2014). Data from IPLOS were merged with data from the Norwegian Prescription Database and the Norwegian Patient Registry. Pharmacologically treated diabetes (hereafter referred to as diabetes) was defined based on prescriptions of glucose-lowering drugs (GLD) (≥ 1 prescription in the current or previous year). Persons not prescribed GLD were defined as not having diabetes. Based on Anatomical Therapeutic Chemical (ATC) codes we identified the following subgroups: persons without diabetes, persons using “non-insulin GLD only”, “insulin and non-insulin GLD” and “insulin only”. An NHS was defined as at least one stay during a given calendar year, where a short-term NHS is temporary, and a long-term NHS is permanent. Log-binomial regression was used to test for differences in NHS and results are reported as risk ratios (RR) with 95% CIs. Results Both insulin-treated subgroups had a higher risk of a short-term NHS (“insulin only” users RR 1.06 (CI 1.03–1.09) and “insulin and non-insulin GLD” users RR 1.04 (CI 1.02–1.06)) compared to those without diabetes. In general, persons with diabetes had a lower risk of a long-term NHS than those without diabetes (RR 0.92 (CI 0.89–0.94)). The subgroup using “insulin and non-insulin GLD” had the lowest risk of a long-term NHS (RR 0.86 (CI 0.81–0.91)). Conclusion Despite a lower risk of a long-term NHS among older people with diabetes, we found an increased risk of a short-term NHS among persons with insulin-treated diabetes who live at home and receive HCS. This calls for attention when planning health care, in order to provide coordinated and individualized care to prevent short-term NHS’s.

• Grannes, Helene; Sharma, Archana; Suntharalingam, Anita; Michelsen, Annika Elisabet; Aukrust, Pål & Ueland, Thor [Show all 10 contributors for this article] (2024). Plasma soluble TIM-3 is increased in normoglycemic South Asian women compared to Nordic women after gestational diabetes mellitus and associated with markers of metaflammation. Heliyon. 10(22). doi: 10.1016/j.heliyon.2024.e40339. Full text in Research Archive Show summary

  Background - Women with South Asian ethnicity have a higher risk of developing type 2 diabetes mellitus (T2DM) compared with white women of European descent, especially after gestational diabetes mellitus (GDM). Central obesity and adipose tissue dysfunction have been linked to their higher risk of T2DM, but the mechanisms are not known. We hypothesize that low-grade, persistent immune cell activation is involved in metabolic disturbances following GDM with different influence according to ethnicity.<p> <p>Methods - We measured plasma levels of T cell exhaustion marker soluble T cell immunoglobin mucin domain 3 (sTIM-3), sCD25, sCD27 and soluble lymphocyte activation gene (sLAG)-3 in 266 women of South Asian (n = 160) and white Nordic (n = 106) ethnic background with a history of GDM.<p> <p>Results - Baseline plasma concentration of sTIM-3 was higher in South Asian women compared to Nordic women (p < 0.001). This difference was driven by higher sTIM-3 in South Asian women with NGT, compared to their Nordic counterparts (p = 0.005) but there were no significant differences comparing Nordic and South Asian women with altered glucose tolerance (AGT). Soluble TIM-3 correlated positively with waist-height ratio (WHtR) and body mass index across all groups, but whereas sTIM-3 correlated moderately and consistently with markers of metaflammation in South Asians, this pattern was not found in Nordic women. Mediation analysis indicated that 15 % of the difference found in adipose insulin resistance between ethnicities could be mediated by sTIM-3, and that 33 % of the difference in sTIM-3 concentrations could be mediated by WHtR. Moreover, T cell markers sCD27 and sLAG3 were also increased in South Asian women compared with Nordic women, further supporting involvement of T cell activation in these women.<p> <p>Conclusion - We found increased levels of sTIM-3, as well as additional markers of T cell activation/exhaustion, in a population of normoglycemic South Asian women with previous gestational diabetes as compared to women of Nordic descent. The possible causal relationship between T cell activation and metabolic dysfunction in high-risk South Asian women is however still elusive and merits further investigation.

• Linares-Pineda, Teresa M.; Bargas, Nicolas Fragoso; Picón, María José; Molina-Vega, Maria; Jenum, Anne Karen & Sletner, Line [Show all 14 contributors for this article] (2024). DNA methylation risk score for type 2 diabetes is associated with gestational diabetes. Cardiovascular Diabetology. 23(1). doi: 10.1186/s12933-024-02151-z. Full text in Research Archive Show summary

  Background Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) share many pathophysiological factors including genetics, but whether epigenetic marks are shared is unknown. We aimed to test whether a DNA methylation risk score (MRS) for T2DM was associated with GDM across ancestry and GDM criteria. Methods In two independent pregnancy cohorts, EPIPREG (n = 480) and EPIDG (n = 32), DNA methylation in peripheral blood leukocytes was measured at a gestational age of 28 ± 2. We constructed an MRS in EPIPREG and EPIDG based on CpG hits from a published epigenome-wide association study (EWAS) of T2DM. Results With mixed models logistic regression of EPIPREG and EPIDG, MRS for T2DM was associated with GDM: odd ratio (OR)[95% CI]: 1.3 [1.1–1.8], P = 0.002 for the unadjusted model, and 1.4 [1.1–1.7], P = 0.00014 for a model adjusted by age, pre-pregnant BMI, family history of diabetes and smoking status. Also, we found 6 CpGs through a meta-analysis (cg14020176, cg22650271, cg14870271, cg27243685, cg06378491, cg25130381) associated with GDM, and some of their methylation quantitative loci (mQTLs) were related to T2DM and GDM. Conclusion For the first time, we show that DNA methylation marks for T2DM are also associated with GDM, suggesting shared epigenetic mechanisms between GDM and T2DM.

• Bjarkø, Vera Vik; Haug, Eirin Beate; Langhammer, Arnulf; Ruiz, Paz Lopez-Doriga; Carlsson, Sofia & Birkeland, Kåre Inge [Show all 10 contributors for this article] (2024). Clinical utility of novel diabetes subgroups in predicting vascular complications and mortality: up to 25 years of follow-up of the HUNT Study. BMJ Open Diabetes Research & Care. 12(6). doi: 10.1136/bmjdrc-2024-004493. Full text in Research Archive Show summary

  Introduction Cluster analysis has previously revealed five reproducible subgroups of diabetes, differing in risks of diabetic complications. We aimed to examine the clusters’ predictive ability for vascular complications as compared with established risk factors in a general adult diabetes population. Research design and methods Participants from the second (HUNT2, 1995–1997) and third (HUNT3, 2006–2008) surveys of the Norwegian population-based Trøndelag Health Study (HUNT Study) with adult-onset diabetes were included (n=1899). To identify diabetes subgroups, we used the same variables (age at diagnosis, body mass index, HbA1c, homeostasis model assessment estimates of beta cell function and insulin resistance, and glutamic acid decarboxylase antibodies) and the same data-driven clustering technique as in previous studies. We used Cox proportional hazards models to investigate associations between clusters and risks of vascular complications and mortality. We estimated the C-index and R2 to compare predictive abilities of the clusters to those of established risk factors as continuous variables. All models included adjustment for age, sex, diabetes duration and time of inclusion. Results We reproduced five subgroups with similar key characteristics as identified in previous studies. During median follow-up of 9–13 years (differing between outcomes), the clusters were associated with different risks of vascular complications and all-cause mortality. However, in prediction models, individual established risk factors were at least as good predictors as cluster assignment for all outcomes. For example, for retinopathy, the C-index for the model including clusters (0.65 (95% CI 0.63 to 0.68)) was similar to that of HbA1c (0.65 (95% CI 0.63 to 0.68)) or fasting C-peptide (0.66 (95% CI 0.63 to 0.68)) alone. For chronic kidney disease, the C-index for clusters (0.74 (95% CI 0.72 to 0.76)) was similar to that of triglyceride/high-density lipoprotein ratio (0.74 (95% CI 0.71 to 0.76)) or fasting C-peptide (0.74 (95% CI 0.72 to 0.76)), and baseline estimated glomerular filtration rate yielded a C-index of 0.76 (95% CI 0.74 to 0.78). Conclusions Cluster assignment did not provide better prediction of vascular complications or all-cause mortality compared with established risk factors.

• Kvist, Ahalya Anita Suntharalingam; Sharma, Archana; Sommer, Christine; Qvigstad, Elisabeth; Gulseth, Hanne Løvdal & Sollid, Stina Therese [Show all 12 contributors for this article] (2024). Adipose Tissue Insulin Resistance in South Asian and Nordic Women after Gestational Diabetes Mellitus. Metabolites. 14(5). doi: 10.3390/metabo14050288. Full text in Research Archive Show summary

  South Asians (SAs) have a higher risk of developing type 2 diabetes (T2D) than white Europeans, especially following gestational diabetes mellitus (GDM). Despite similar blood glucose levels post-GDM, SAs exhibit more insulin resistance (IR) than Nordics, though the underlying mechanisms are unclear. This study aimed to assess markers of adipose tissue (AT) IR and liver fat in SA and Nordic women post-GDM. A total of 179 SA and 108 Nordic women in Norway underwent oral glucose tolerance tests 1–3 years post-GDM. We measured metabolic markers and calculated the AT IR index and non-alcoholic fatty liver disease liver fat (NAFLD-LFS) scores. Results showed that normoglycaemic SAs had less non-esterified fatty acid (NEFA) suppression during the test, resembling prediabetes/T2D responses, and higher levels of plasma fetuin-A, CRP, and IL-6 but lower adiponectin, indicating AT inflammation. Furthermore, normoglycaemic SAs had higher NAFLD-LFS scores, lower insulin clearance, and higher peripheral insulin than Nordics, indicating increased AT IR, inflammation, and liver fat in SAs. Higher liver fat markers significantly contributed to the ethnic disparities in glucose metabolism, suggesting a key area for intervention to reduce T2D risk post-GDM in SAs.

• Jersin, Regine Åsen; Tallapragada, Divya Sri; Skartveit, Linn; Bjune, Mona Synnøve; Muniandy, Maheswary & Lee-Ødegård, Sindre [Show all 16 contributors for this article] (2023). Impaired Adipocyte SLC7A10 Promotes Lipid Storage in Association With Insulin Resistance and Altered BCAA Metabolism. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 108(9), p. 2217–2229. doi: 10.1210/clinem/dgad148. Full text in Research Archive Show summary

  Context The neutral amino acid transporter SLC7A10/ASC-1 is an adipocyte-expressed gene with reduced expression in insulin resistance and obesity. Inhibition of SLC7A10 in adipocytes was shown to increase lipid accumulation despite decreasing insulin-stimulated uptake of glucose, a key substrate for de novo lipogenesis. These data imply that alternative lipogenic substrates to glucose fuel continued lipid accumulation during insulin resistance in obesity. Objective We examined whether increased lipid accumulation during insulin resistance in adipocytes may involve alter flux of lipogenic amino acids dependent on SLC7A10 expression and activity, and whether this is reflected by extracellular and circulating concentrations of marker metabolites. Methods In adipocyte cultures with impaired SLC7A10, we performed RNA sequencing and relevant functional assays. By targeted metabolite analyses (GC-MS/MS), flux of all amino acids and selected metabolites were measured in human and mouse adipose cultures. Additionally, SLC7A10 mRNA levels in human subcutaneous adipose tissue (SAT) were correlated to candidate metabolites and adiposity phenotypes in 2 independent cohorts. Results SLC7A10 impairment altered expression of genes related to metabolic processes, including branched-chain amino acid (BCAA) catabolism, lipogenesis, and glyceroneogenesis. In 3T3-L1 adipocytes, SLC7A10 inhibition increased fatty acid uptake and cellular content of glycerol and cholesterol. SLC7A10 impairment in SAT cultures altered uptake of aspartate and glutamate, and increased net uptake of BCAAs, while increasing the net release of the valine catabolite 3- hydroxyisobutyrate (3-HIB). In human cohorts, SLC7A10 mRNA correlated inversely with total fat mass, circulating triacylglycerols, BCAAs, and 3-HIB. Conclusion Reduced SLC7A10 activity strongly affects flux of BCAAs in adipocytes, which may fuel continued lipogenesis during insulin resistance, and be reflected in increased circulating levels of the valine-derived catabolite 3-HIB.

• Fragoso-Bargas, Nicolas; Page, Christian Magnus; Joubert, Bonnie R.; London, Stephanie J.; Lee-Ødegård, Sindre & Opsahl, Julia Onsrud [Show all 13 contributors for this article] (2023). Epigenome-wide association study of serum folate in maternal peripheral blood leukocytes. Epigenomics. ISSN 1750-1911. 15(1), p. 39–52. doi: 10.2217/epi-2022-0427. Full text in Research Archive Show summary

  Aim: To perform an epigenome-wide association study (EWAS) of serum folate in maternal blood. Methods: Cross-ancestry (Europeans = 302, South Asians = 161) and ancestry-specific EWAS in the EPIPREG cohort were performed, followed by methyl quantitative trait loci analysis and association with cardiometabolic phenotypes. Replication was attempted using maternal folate intake and blood methylation data from the MoBa study and verified if the findings were significant in a previous EWAS of maternal serum folate in cord blood. Results & conclusion: cg19888088 (cross-ancestry) in EBF3, cg01952260 (Europeans) and cg07077240 (South Asians) in HERC3 were associated with serum folate. cg19888088 and cg01952260 were associated with diastolic blood pressure. cg07077240 was associated with variants in CASC15. The findings were not replicated and were not significant in cord blood.

• Graue, Marit; Igland, Jannicke; Haugstvedt, Anne; Hernar, Ingvild; Birkeland, Kåre Inge & Zoffmann, Vibeke [Show all 8 contributors for this article] (2023). Evaluation of an interprofessional follow-up intervention among people with type 2 diabetes in primary care—A randomized controlled trial with embedded qualitative interviews. PLOS ONE. 18(11). doi: 10.1371/journal.pone.0291255. Full text in Research Archive Show summary

  With an ageing population and improved treatments people live longer with their chronic diseases, and primary care clinics face more costly and difficult-to-treat multimorbid patients. To meet these challenges, current guidelines for the management of type 2 diabetes suggest that an interprofessional team should collaborate to enhance the delivery of worthwhile self-management support interventions. In this study, we aimed to evaluate the effects of an empowerment-based interprofessional follow-up intervention in people with type 2 diabetes in primary care on patient-reported outcomes, biomarkers and weight, and to explore the experiences of patients attending the intervention. We invited patients during regular visits to their general practitioners. The 12-month intervention included 1) empowerment-based counselling; 2) a standardized medical report. The control group received consultations with physicians only. The primary outcome was the Patient Activation Measure, a patient-reported measure assessing individual knowledge, skills, and confidence integral to managing one’s health and healthcare. After the trial we conducted qualitative interviews. We observed no difference in the primary outcome scores. On secondary outcomes we found a significant between-group intervention effect in favor of the intervention group, with mean differences in glycemic control after 12 months (B [95% CI] = -8.6 [-17.1, -0.1] mmol/l; p = 0.045), and significant within-group changes of weight (B [95% CI] = -1.8 kg [-3.3, -0.3]; p = 0.02) and waist circumference (B [95% CI] = -3.9 cm [-7.3, -0.6]; p = 0.02). The qualitative data showed that the intervention opened patients’ eyes for reflections and greater awareness, but they needed time to take on actions. The patients emphasized that the intervention gave rise to other insights and a greater understanding of their health challenges. We suggest testing the intervention among patients with larger disease burden and a more expressed motivation for change.

• Riise, Hilde Kristin Refvik; Graue, Marit; Igland, Jannicke; Birkeland, Kåre Inge & Kolltveit, Beate-Christin Hope (2023). Prevalence of increased risk of type 2 diabetes in general practice: a cross-sectional study in Norway. BMC Primary Care. 24(1). doi: 10.1186/s12875-023-02100-x. Full text in Research Archive Show summary

  Background Type 2 diabetes (T2D) is a global public health problem, but the onset can be delayed or prevented with adequate intervention in individuals with increased risk. Therefore, a major challenge in general practice is to identify individuals at risk of diabetes. However, limited knowledge is available about the prevalence of high diabetes risk individuals in a primary care population. In a cohort of consecutive patients in general practice we examined the prevalence of known diabetes and estimated risk of diabetes using The Finnish Diabetes Risk Score (FINDRISC) calculator, by sociodemographic and clinical characteristics. Methods This study was a cross-sectional study conducted in four general practices in Western and Eastern Norway. A total of 1682 individuals, 20–80 years of age, were assessed for eligibility from May to December 2019. We excluded patients who actively declined participation (n = 112), were lost because of various organization challenges (n = 103) and patients who did not fulfil the inclusions criteria (n = 63). Diabetes prevalence and prevalence of individuals at risk of T2D with 95% confidence intervals (CI) were estimated for the total sample, by age group and for men and women separately. We tested for differences between groups using t-test for continuous variables and chi-square test (Pearson Chi-Square) for categorical variables. Results Of 1404 individuals, 132 reported known diabetes, yielding a prevalence of 9.9% (95% CI 8.4–11.6). Among participants without a known diagnosis of diabetes, the following estimates of elevated risk assessment scores were found: FINDRISC score ≥ 11 32.8% (95% CI 30.3–35.4) and FINDRISC ≥ 15 10.0% (95% CI 8.6–11.9). Comparable results were found between the sexes. Conclusions Detection of unknown diabetes and individuals with increased risk, is of high public health relevance for early implementation of preventive measures aimed to reduce the risk of diabetes and its complications through lifestyle modification. A simple, non-expensive questionnaire, such as FINDRISC, may be valuable as an initial screening method in general practice to identify those in need for preventive measures.

• Moore, Timothy M.; Lee-Ødegård, Sindre; Olsen, Thomas; Morselli, Marco; Strumwasser, Alexander R. & Lin, Amanda J. [Show all 40 contributors for this article] (2023). Conserved multi-tissue transcriptomic adaptations to exercise training in humans and mice. Cell reports. 42(5). doi: 10.1016/j.celrep.2023.112499. Full text in Research Archive Show summary

  Physical activity is associated with beneficial adaptations in human and rodent metabolism. We studied over 50 complex traits before and after exercise intervention in middle-aged men and a panel of 100 diverse strains of female mice. Candidate gene analyses in three brain regions, muscle, liver, heart, and adipose tissue of mice indicate genetic drivers of clinically relevant traits, including volitional exercise volume, muscle metabolism, adiposity, and hepatic lipids. Although ∼33% of genes differentially expressed in skeletal muscle following the exercise intervention are similar in mice and humans independent of BMI, responsiveness of adipose tissue to exercise-stimulated weight loss appears controlled by species and underlying genotype. We leveraged genetic diversity to generate prediction models of metabolic trait responsiveness to volitional activity offering a framework for advancing personalized exercise prescription. The human and mouse data are publicly available via a user-friendly Web-based application to enhance data mining and hypothesis development.

• Teigland, Tonje; Igland, Jannicke; Tell, Grethe S.; Haltbakk, Johannes; Graue, Marit & Fismen, Anne-Siri [Show all 10 contributors for this article] (2022). The prevalence and incidence of pharmacologically treated diabetes among older people receiving home care services in Norway 2009–2014: a nationwide longitudinal study. BMC Endocrine Disorders. 22(1), p. 1–9. doi: 10.1186/s12902-022-01068-6. Full text in Research Archive Show summary

  Background A substantial proportion of older people who receive home care services (HCS) has diabetes and requires diabetes specific monitoring, treatment and self-care assistance. However, the prevalence and incidence rates of diabetes among older people in HCS are poorly described. The aim of the study is to estimate prevalence, incidence and time trends of pharmacologically treated diabetes among older people receiving HCS in Norway 2009–2014. Methods This nationwide observational cohort study is based on data from two population registries. The study population consisted of persons registered in the Norwegian Information System for the Nursing and Care Sector aged ≥ 65 years receiving HCS during at least one of the years 2009–2014. The Norwegian Prescription Database was utilized to identify participants’ prescriptions for glucose lowering drugs (GLD). The period prevalence was calculated each year as persons with one or more prescriptions of GLD in the current or previous year. Incident cases were defined as subjects receiving prescriptions of GLD for the first time in the given calendar year if there were no prescriptions of any GLD for that person during the previous two years. Results From 2009 to 2014, the number of older people receiving HCS increased from 112,487 to 125,593. The proportion of these who received GLD increased from 14.2% to 15.7% (p < 0.001) and was significantly higher among men than women. The annual incidence rate of diabetes among those receiving HCS showed a decreasing trend from 95.4 to 87.5 cases per 10,000 person-years from 2011 to 2014, but when stratifying on age group and gender, was significant only among the oldest women (age groups 85–89 years and 90 +). Conclusions The increasing prevalence of older people with diabetes who receive HCS highlights the importance of attention to treatment and care related to diabetes in the HCS.

• Bjarkø, Vera Vik; Haug, Eirin Beate; Sørgjerd, Elin Pettersen; Stene, Lars Christian Mørch; Ruiz, Paz Lopez-Doriga & Birkeland, Kåre Inge [Show all 11 contributors for this article] (2022). Undiagnosed diabetes: Prevalence and cardiovascular risk profile in a population-based study of 52,856 individuals. The HUNT Study, Norway. Diabetic Medicine. ISSN 0742-3071. 39(6). doi: 10.1111/dme.14829. Full text in Research Archive Show summary

  Aims We investigated the current extent of undiagnosed diabetes and prediabetes and their associated cardiovascular risk profile in a population-based study. Methods All residents aged ≥20 years in the Nord-Trøndelag region, Norway, were invited to the HUNT4 Survey in 2017–2019, and 54% attended. Diagnosed diabetes was self-reported, and in those reporting no diabetes HbA1c was used to classify undiagnosed diabetes (≥48 mmol/mol [6.5%]) and prediabetes (39–47 mmol/mol [5.7%–6.4%]). We estimated the age- and sex-standardized prevalence of these conditions and their age- and sex-adjusted associations with other cardiovascular risk factors. Results Among 52,856 participants, the prevalence of diabetes was 6.0% (95% CI 5.8, 6.2), of which 11.1% were previously undiagnosed (95% CI 10.1, 12.2). The prevalence of prediabetes was 6.4% (95% CI 6.2, 6.6). Among participants with undiagnosed diabetes, 58% had HbA1c of 48–53 mmol/mol (6.5%–7.0%), and only 14% (i.e., 0.1% of the total study population) had HbA1c >64 mmol/mol (8.0%). Compared with normoglycaemic participants, those with undiagnosed diabetes or prediabetes had higher body mass index, waist circumference, systolic blood pressure, triglycerides and C-reactive protein but lower low-density lipoprotein cholesterol (all p < 0.001). Participants with undiagnosed diabetes had less favourable values for every measured risk factor compared with those with diagnosed diabetes. Conclusions The low prevalence of undiagnosed diabetes suggests that the current case-finding-based diagnostic practice is well-functioning. Few participants with undiagnosed diabetes had very high HbA1c levels indicating severe hyperglycaemia. Nonetheless, participants with undiagnosed diabetes had a poorer cardiovascular risk profile compared with participants with known or no diabetes.

• Lee-Ødegård, Sindre; Olsen, Thomas; Norheim, Frode Amador; Drevon, Christian A & Birkeland, Kåre Inge (2022). Potential Mechanisms for How Long-Term Physical Activity May Reduce Insulin Resistance. Metabolites. 12(3)(208). doi: 10.3390/metabo12030208. Full text in Research Archive Show summary

  Insulin became available for the treatment of patients with diabetes 100 years ago, and soon thereafter it became evident that the biological response to its actions differed markedly between individuals. This prompted extensive research into insulin action and resistance (IR), resulting in the universally agreed fact that IR is a core finding in patients with type 2 diabetes mellitus (T2DM). T2DM is the most prevalent form of diabetes, reaching epidemic proportions worldwide. Physical activity (PA) has the potential of improving IR and is, therefore, a cornerstone in the prevention and treatment of T2DM. Whereas most research has focused on the acute effects of PA, less is known about the effects of long-term PA on IR. Here, we describe a model of potential mechanisms behind reduced IR after long-term PA to guide further mechanistic investigations and to tailor PA interventions in the therapy of T2DM. The development of such interventions requires knowledge of normal glucose metabolism, and we briefly summarize an integrated physiological perspective on IR. We then describe the effects of long-term PA on signaling molecules involved in cellular responses to insulin, tissue-specific functions, and whole-body IR.

• Sharma, Archana; Lee-Ødegård, Sindre; Qvigstad, Elisabeth; Sommer, Christine; Sattar, Naveed & Gill, Jason M.R. [Show all 10 contributors for this article] (2022). β-Cell Function, Hepatic Insulin Clearance, and Insulin Sensitivity in South Asian and Nordic Women After Gestational Diabetes Mellitus. Diabetes. ISSN 0012-1797. 71(12), p. 2530–2538. doi: 10.2337/db22-0622. Full text in Research Archive Show summary

  South Asian women have a higher risk of type 2 diabetes after gestational diabetes mellitus (GDM) than Nordic women; however, the mechanisms behind this difference remain unclear. We investigated insulin sensitivity, β-cell function, and hepatic insulin clearance in 179 South Asian and 108 Nordic women ∼17 months after GDM (mean age 35.3 years, BMI 29.1 kg/m2) by oral glucose tolerance test using deconvolution of C-peptide kinetics. Thirty-one percent of South Asian and 53% of Nordic participants were normoglycemic at the time of measurement. South Asian women had higher areas under the curve (AUCs) for glucose, prehepatic insulin, and peripheral insulin and lower insulin sensitivity, disposition index, and fasting hepatic insulin clearance than Nordic women. In the group with prediabetes or diabetes, South Asian women had similar AUCs for glucose and prehepatic insulin but a higher AUC for peripheral insulin, lower disposition index, and lower fasting hepatic insulin clearance than Nordic women. The waist-to-height ratio mediated ∼25–40% of the ethnic differences in insulin sensitivity in participants with normoglycemia. Overall, our novel data revealed that South Asian women with normoglycemia after GDM showed lower insulin secretion for a given insulin resistance and lower hepatic insulin clearance than Nordic women. South Asian women are at high risk of developing type 2 diabetes after GDM, and preventive efforts should be prioritized.

• Lee-Ødegård, Sindre; Ueland, Thor; Thorsby, Per Medbøe; Aukrust, Pål; Michelsen, Annika Elisabet & Halvorsen, Bente [Show all 8 contributors for this article] (2022). Fetuin-A mediates the difference in adipose tissue insulin resistance between young adult pakistani and norwegian patients with type 2 diabetes. BMC Endocrine Disorders. 22. doi: 10.1186/s12902-022-01127-y. Full text in Research Archive Show summary

  Background South-Asian immigrants to Western countries have a high prevalence of type 2 diabetes mellitus (T2DM) and increased adipose tissue insulin resistance (AT-IR), as compared to their Western counterparts. Fetuin-A is a hepatokine known to influence AT-IR. Aim Can plasma fetuin-A concentrations explain an ethnic difference in adipose tissue insulin resistance? Methods We performed a two-step euglycemic-hyperinsulinaemic clamp and measured plasma concentrations of fetuin-A and non-esterified fatty acids (NEFA), in 18 Pakistani and 21 Norwegians with T2DM (age 29–45y) in Norway. AT-IR was calculated as NEFA-suppression during the clamp. The adipokines/cytokines leptin, adiponectin, visfatin, PTX3, IL-1β, INF-γ, and IL-4 were measured in fasting plasma. Liver fat was estimated by CT-scans. Results Despite a lower BMI, Pakistani patients displayed higher AT-IR than Norwegians. NEFA-suppression during clamp was lower in Pakistani than Norwegians (mean=-20.6%, 95%CI=[-40.8, -0.01] and p = 0.046). Plasma fetuin-A concentration was higher in Pakistani than Norwegians (43.4 ng/mL[12.7,74.0], p = 0.007) and correlated negatively to %NEFA-suppression during clamp (rho=-0.39, p = 0.039). Plasma fetuin-A concentration explained 22% of the ethnic difference in NEFA-suppression during the clamp. Pakistani patients exhibited higher plasma leptin and lower PTX3 levels than Norwegian, and plasma visfatin correlated positively to plasma fetuin-A levels in the Pakistani patients. We observed no correlation between plasma fetuin-A and liver fat, but fetuin-A correlated negatively with plasma IL-1β, INF-γ, and IL-4 concentrations. Plasma IL-4 concentration was lower in Pakistani than in Norwegian patients. Conclusion Fetuin-A may contribute to explain the discrepancy in T2DM prevalence between Pakistani and Norwegians patients by influencing AT-IR.

• Rishaug, Tina; Henriksen, André; Aas, Anne-Marie; Hartvigsen, Gunnar; Birkeland, Kåre Inge & Årsand, Eirik (2022). Designing an e-Health Program for Lifestyle Changes in Diabetes Care A Qualitative Pre-Study in Norway. In Henriksen, André; Gabarron, Elia & Vimarlund, Vivian (Ed.), Proceedings of the 18th Scandinavian Conference on Health Informatics. Linköping Electronic Conference Proceedings. ISSN 9789179293444. doi: 10.3384/ecp187013. Full text in Research Archive Show summary

  Type 2 diabetes mellitus (T2D) and prediabetes prevalence rates are high. Consequences are serious, but current treatment is often not efficient for achieving remission. Remission may be achieved through lifestyle intervention. Frequent follow-up is necessary, and health care personnel (HCP) lack resources, time, and often adequate knowledge. Self-management of T2D can benefit from better use of Information and Communication Technologies (ICT), which may improve patient involvement and follow-up, and can provide new tools for lifestyle change. Virtual follow-up through ICT with HCP may reduce costs and reach more patients. An electronic health (e-health) program for T2D and prediabetes will be developed in collaboration with users, as part of a plan for a large randomized controlled trial (RCT).

• Sundström, Johan; Bodegard, Johan; Bollmann, Andreas; Vervloet, Marc G.; Mark, Patrick B. & Karasik, Avraham [Show all 14 contributors for this article] (2022). Prevalence, outcomes, and cost of chronic kidney disease in a contemporary population of 2·4 million patients from 11 countries: The CaReMe CKD study. The Lancet Regional Health - Europe. 20. doi: 10.1016/j.lanepe.2022.100438. Full text in Research Archive Show summary

  Background Digital healthcare systems data could provide insights into the global prevalence of chronic kidney disease (CKD). We designed the CaReMe CKD study to estimate the prevalence, key clinical adverse outcomes and costs of CKD across 11 countries. Methods Individual-level data of a cohort of 2·4 million contemporaneous CKD patients was obtained from digital healthcare systems in participating countries using a pre-specified common protocol; summarized using random effects meta-analysis. CKD and its stages were defined in accordance with current Kidney Disease: Improving Global Outcomes (KDIGO) criteria. CKD was defined by laboratory values or by a diagnosis code. Findings The pooled prevalence of possible CKD was 10·0% (95% confidence interval 8.5‒11.4; mean pooled age 75, 53% women, 38% diabetes, 60% using renin-angiotensin-aldosterone system inhibitors). Two out of three CKD patients identified by laboratory criteria did not have a corresponding CKD-specific diagnostic code. Among CKD patients identified by laboratory values, the majority (42%) were in KDIGO stage 3A; and this fraction was fairly consistent across countries. The share with CKD based on urine albumin-creatinine ratio (UACR) alone (KDIGO stages one and two) was 29%, with a substantial heterogeneity between countries. Adverse events were common; 6·5% were hospitalized for CKD or heart failure, and 6·2% died, annually. Costs for renal events and heart failure were consistently higher than costs for atherosclerotic events in CKD patients across all countries. Interpretation We estimate that CKD is present in one out of ten adults. These individuals experience significant adverse outcomes with associated costs. The prevalence of CKD is underestimated when using diagnostic codes alone. There is considerable public health potential in diagnosing CKD and providing treatments to those currently undiagnosed.

• Simeone, Paola; Tripaldi, Romina; Michelsen, Annika Elisabet; Ueland, Thor; Liani, Rossella & Ciotti, Sonia [Show all 14 contributors for this article] (2022). Effects of liraglutide vs. lifestyle changes on soluble suppression of tumorigenesis-2 (sST2) and galectin-3 in obese subjects with prediabetes or type 2 diabetes after comparable weight loss. Cardiovascular Diabetology. 21(1). doi: 10.1186/s12933-022-01469-w. Full text in Research Archive Show summary

  Background Soluble suppression of tumorigenesis-2 (sST2) and galectin (Gal)-3 are two biomarkers related to inflammation, metabolic disturbances and to myocardial fibrosis that characterize several cardiac pathological conditions. Increased circulating levels of these molecules have been associated with risk of cardiovascular death. Treatment with liraglutide, a glucagon-like peptide 1 analog, is associated with weight loss, improved glycemic control, and reduced cardiovascular risk. We wanted to assess (I) potential differences between subjects with prediabetes or type 2 diabetes mellitus (T2DM) and healthy controls in sST2 and Gal-3 circulating levels, and their relationship with glycemic control and markers of beta cell function and myocardial injury; (II) whether liraglutide treatment modulates these markers in subjects with prediabetes or early T2DM independently of weight loss; (III) whether baseline levels of any of these two molecules may predict the response to liraglutide treatment. Methods Forty metformin-treated obese subjects (BMI ≥ 30) with prediabetes [impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or both (n = 23)] or newly diagnosed T2DM (n = 17), were randomized to liraglutide or lifestyle counseling until achieving a comparable weight loss (7% of initial body weight). Thirteen subjects were enrolled as healthy controls for baseline sST2 and Gal-3 levels. Results Baseline sST2 levels were comparable between controls and obese patients (p = 0.79) whereas Gal-3 levels were significantly higher in patients as compared to controls (p < 0.001). Liraglutide treatment, but not weight loss achieved by lifestyle counseling, decreased plasma sST2 levels (− 9%, beta = − 14.9, standard deviation 6.9, p = 0.037) while Gal-3 levels did not change. A reduction in serum hs-Troponin I was observed after intervention, due to a 19% (p = 0.29) increase in the lifestyle arm, and a 25% decrease (p = 0.033) in the liraglutide arm (between-group difference p = 0.083). Lower baseline Gal-3 levels predicted a better improvement in beta cell function after liraglutide treatment. Conclusions Liraglutide-induced reduction in sST2 and possibly hs-TnI suggests that in obese patients with prediabetes or early T2DM this drug may have a positive effect on (cardiac) fibrosis, whereas plasma level of Gal-3 before liraglutide initiation may predict response to the drug in terms of beta cell function improvement. Trial registration Eudract: 2013-001356-36

• Pervjakova, Natalia; Moen, Gunn-Helen Øiseth; Borges, Maria-Carolina; Ferreira, Teresa; Cook, James P. & Allard, Catherine [Show all 73 contributors for this article] (2022). Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes. Human Molecular Genetics. ISSN 0964-6906. 31(19), p. 3377–3391. doi: 10.1093/hmg/ddac050. Full text in Research Archive Show summary

  Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10−8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10−54), TCF7L2 (P = 4.0 × 10−16), CDKAL1 (P = 1.6 × 10−14), CDKN2A-CDKN2B (P = 4.1 × 10−9) and HKDC1 (P = 2.9 × 10−8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

• Fragoso-Bargas, Nicolas; Elliott, Hannah R.; Lee-Ødegård, Sindre; Opsahl, Julia Onsrud; Sletner, Line & Jenum, Anne Karen [Show all 12 contributors for this article] (2022). Cross-Ancestry DNA Methylation Marks of Insulin Resistance in Pregnancy: An Integrative Epigenome-Wide Association Study. Diabetes. ISSN 0012-1797. 72(3), p. 415–426. doi: 10.2337/db22-0504. Full text in Research Archive
• Sharma, Archana; Nermoen, Ingrid; Qvigstad, Elisabeth; Tran, Anh Thi; Sommer, Christine & Sattar, Naveed [Show all 10 contributors for this article] (2022). High prevalence and significant ethnic differences in actionable HbA1C after gestational diabetes mellitus in women living in Norway. BMC Medicine. 20(1), p. 1–10. doi: 10.1186/s12916-022-02515-w. Full text in Research Archive Show summary

  Background The type 2 diabetes risk after gestational diabetes mellitus (GDM) is twice as high in South Asian compared to European women. Current guidelines differ regarding which test to use as a screening-tool post-GDM. We aimed to identify ethnic differences in the prevalence rates and early predictors for actionable HbA1c (defined as prediabetes and diabetes) short time after GDM. Methods This cross-sectional study, enrolling South Asian and Nordic women 1–3 years after a diagnosis of GDM, was undertaken at three hospitals in Norway. We performed a clinical and laboratory evaluation including an oral glucose tolerance test (OGTT). Medical records were used to retrieve data during pregnancy. Prediabetes was classified with HbA1c alone or combined with OGTT glucose measurements according to the WHO, WHO-IEC, and ADA criteria (fasting plasma glucose (FPG) 6.1–6.9 mmol/L, FPG 6.1–6.9 mmol/L and/or HbA1c 42-47 mmol/mol (6.0-6.4%), and FPG 5.6–6.9 mmol/L and/or HbA1c 39-47 mmol/mol (5.7-6.4%)). Ethnic differences in prevalence and predictors of glucose deterioration were assed by χ2 (Pearson) tests and logistic regression models. Results We included 163 South Asian and 108 Nordic women. Actionable HbA1c levels were highly prevalent and more so among South Asian than Nordic women (WHO-IEC-HbA1c: 25.8% vs. 6.5% (p ≤ 0.001), ADA-HbA1c: 58.3% vs. 22.2% (p ≤ 0.001)). Although adding OGTT-data gave higher combined prevalence rates of prediabetes and diabetes (WHO: 65.6% vs. 47.2% (p ≤ 0.05), WHO-IEC: 70.6% vs. 47.2% (p ≤ 0.001), ADA: 87.8% vs. 65.7% (p ≤ 0.001)), the excess risk in the South Asian women was best captured by the HbA1c. Important predictors for glucose deterioration after GDM were: South Asian ethnicity, GDM before the index pregnancy, use of glucose-lowering drugs in pregnancy, higher age, and higher in-pregnancy fasting glucose levels. Conclusions In women with GDM 1–3 year previously, we found high prevalence and significant ethnic differences in actionable ADA-HbA1c levels, with South Asian ethnicity, GDM before the index pregnancy, and the use of glucose-lowering drugs in pregnancy as the most important risk factors. This study reinforces the importance of annual screening—preferably with HbA1c measurements—to facilitate early intervention after GDM.

• Norhammar, Anna; Bodegard, Johan; Eriksson, Jan W.; Haller, Hermann; Linssen, Gerard C. M. & Banerjee, Amitava [Show all 17 contributors for this article] (2022). Cost of healthcare utilization associated with incident cardiovascular and renal disease in individuals with type 2 diabetes: A multinational, observational study across 12 countries. Diabetes, obesity and metabolism. ISSN 1462-8902. 24(7), p. 1277–1287. doi: 10.1111/dom.14698. Full text in Research Archive Show summary

  Aim To examine how the development of cardiovascular and renal disease (CVRD) translates to hospital healthcare costs in individuals with type 2 diabetes (T2D) initially free from CVRD. Methods Data were obtained from the digital healthcare systems of 12 nations using a prespecified protocol. A fixed country-specific index date of 1 January was chosen to secure sufficient cohort disease history and maximal follow-up, varying between each nation from 2006 to 2017. At index, all individuals were free from any diagnoses of CVRD (including heart failure [HF], chronic kidney disease [CKD], coronary ischaemic disease, stroke, myocardial infarction [MI], or peripheral artery disease [PAD]). Outcomes during follow-up were hospital visits for CKD, HF, MI, stroke, and PAD. Hospital healthcare costs obtained from six countries, representing 68% of the total study population, were cumulatively summarized for CVRD events occurring during follow-up. Results In total, 1.2 million CVRD-free individuals with T2D were identified and followed for 4.5 years (mean), that is, 4.9 million patient-years. The proportion of individuals indexed before 2010 was 18% (n = 207 137); 2010-2015, 31% (361 175); and after 2015, 52% (609 095). Overall, 184 420 (15.7%) developed CVRD, of which cardiorenal disease was most frequently the first disease to develop (59.7%), consisting of 23.0% HF and 36.7% CKD, and more common than stroke (16.9%), MI (13.7%), and PAD (9.7%). The total cumulative cost for CVRD was US$1 billion, of which 59.0% was attributed to cardiorenal disease, 3-, 5-, and 6-fold times greater than the costs for stroke, MI, and PAD, respectively. Conclusion Across all nations, HF or CKD was the most frequent CVRD manifestation to develop in a low-risk population with T2D, accounting for the highest proportion of hospital healthcare costs. These novel findings highlight the importance of cardiorenal awareness when planning healthcare.

• Sommer, Christine; Vangberg, Kjersti G; Moen, Gunn-Helen Øiseth; Evans, David M.; Lee-Ødegård, Sindre & Høgestøl, Ingvild Kristine [Show all 11 contributors for this article] (2022). Insulin and Body Mass Index Decrease Serum Soluble Leptin Receptor Levels in Humans. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 108(5), p. 1110–1119. doi: 10.1210/clinem/dgac699. Full text in Research Archive Show summary

  Context Serum soluble leptin receptor (sOb-R) may protect against future type 2 diabetes or serve as a marker for protective features, but how sOb-R is regulated is largely unknown. Objective This work aimed to test how serum sOb-R is influenced by glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity. Methods We performed an epidemiological triangulation combining cross-sectional, interventional, and Mendelian randomization study designs. In 5 independent clinical studies (n = 24-823), sOb-R was quantified in serum or plasma by commercial enzyme-linked immunosorbent assay kits using monoclonal antibodies. We performed mixed-model regression and 2-sample Mendelian randomization. Results In pooled, cross-sectional data, leveling by study, sOb-R was associated inversely with BMI (β [95% CI] −0.19 [−0.21 to −0.17]), body fat (−0.12 [−0.14 to −0.10), and fasting C-peptide (−2.04 [−2.46 to −1.62]). sOb-R decreased in response to acute hyperinsulinemia during euglycemic glucose clamp in 2 independent clinical studies (−0.5 [−0.7 to −0.4] and −0.5 [−0.6 to −0.3]), and immediately increased in response to intensive exercise (0.18 [0.04 to 0.31]) and food intake (0.20 [0.06 to 0.34]). In 2-sample Mendelian randomization, higher fasting insulin and higher BMI were causally linked to lower sOb-R levels (inverse variance weighted, −1.72 [−2.86 to −0.58], and −0.20 [−0.36 to −0.04], respectively). The relationship between hyperglycemia and sOb-R was inconsistent in cross-sectional studies and nonsignificant in intervention studies, and 2-sample Mendelian randomization suggested no causal effect of fasting glucose on sOb-R. Conclusion BMI and insulin both causally decreased serum sOb-R levels. Conversely, intensive exercise and food intake acutely increased sOb-R. Our results suggest that sOb-R is involved in short-term regulation of leptin signaling, either directly or indirectly, and that hyperinsulinemia may reduce leptin signaling.

• Waage, Christin; Mdala, Ibrahimu; Stigum, Hein; Jenum, Anne Karen; Birkeland, Kåre Inge & Shakeel, Nilam [Show all 9 contributors for this article] (2022). Lipid and lipoprotein concentrations during pregnancy and associations with ethnicity. BMC Pregnancy and Childbirth. 22(1). doi: 10.1186/s12884-022-04524-2. Full text in Research Archive Show summary

  Background To describe ethnic differences in concentrations of lipids and lipoproteins, and their changes, during pregnancy to postpartum. Methods This was a population-based cohort study conducted in primary antenatal care in Norway. The participants (n = 806) were healthy, pregnant women, 59% were ethnic minorities. Outcomes were triglycerides, total cholesterol, HDL- and LDL-cholesterol, analysed from fasting blood samples drawn at gestational age (weeks) 15, 28 and 14 weeks postpartum. We performed linear regression models and linear mixed models to explore the total effect of ethnicity on the outcomes, adjusting for gestational age /week postpartum, maternal age and education. The analyses are corrected for multiple testing using the Bonferroni correction. Results At gestational age 15, triglyceride concentrations were lower in women of African origin (1.03 mmol/mol (95% CI: 0.90, 1.16)) and higher in women of South Asian (primarily Pakistan and Sri Lanka) origin (1.42 mmol/mol (1.35, 1.49)) and East Asian (primarily Vietnam, Philippines and Thailand) origin (1.58 mmol/mol (1.43, 1.73)) compared with Western Europeans (1.26 mmol/mol (1.20, 1.32)). Women of Asian and African origin had a smaller increase in triglycerides, LDL- and total cholesterol from gestational age 15 to 28. At gestational age 28, LDL-cholesterol levels were lowest among East Asians (3.03 mmol/mol (2.72, 3.34)) compared with Western Europeans (3.62 mmol/mol (3.50, 3.74)). Triglycerides and HDL-cholesterol were lower postpartum than at gestational age 15 in all groups, but the concentration of LDL-cholesterol was higher, except in Africans. South and East Asian women had lower HDL-cholesterol and higher triglycerides postpartum, while African women had lower triglycerides than Western Europeans. Conclusion We found significant differences in the concentrations of lipids and lipoproteins and their changes during pregnancy and the early postpartum period related to ethnic origin.

• Kristófi, Robin; Bodegard, Johan; Norhammar, Anna; Thuresson, Marcus; Nathanson, David & Nyström, Thomas [Show all 8 contributors for this article] (2021). Cardiovascular and Renal Disease Burden in Type 1 Compared With Type 2 Diabetes: A Two-Country Nationwide Observational Study. Diabetes Care. ISSN 0149-5992. 44(5), p. 1211–1218. doi: 10.2337/dc20-2839. Full text in Research Archive Show summary

  OBJECTIVE Type 1 diabetes (T1D) and type 2 diabetes (T2D) increase risks of cardiovascular (CV) and renal disease (CVRD) compared with diabetes-free populations. Direct comparisons between T1D and T2D are scarce. We examined this by pooling full-population cohorts in Sweden and Norway. RESEARCH DESIGN AND METHODS A total of 59,331 patients with T1D and 484,241 patients with T2D, aged 18–84 years, were followed over a mean period of 2.6 years from 31 December 2013. Patients were identified in nationwide prescribed drug and hospital registries in Norway and Sweden. Prevalence and event rates of myocardial infarction (MI), heart failure (HF), stroke, chronic kidney disease (CKD), all-cause death, and CV death were assessed following age stratification in 5-year intervals. Cox regression analyses were used to estimate risk. RESULTS The prevalence of CV disease was similar in T1D and T2D across age strata, whereas CKD was more common in T1D. Age-adjusted event rates comparing T1D versus T2D showed that HF risk was increased between ages 65 and 79 years, MI between 55 and 79 years, and stroke between 40 and 54 years (1.3–1.4-fold, 1.3–1.8-fold, and 1.4–1.7-fold, respectively). CKD risk was 1.4–3.0-fold higher in T1D at all ages. The all-cause death risk was 1.2–1.5-fold higher in T1D at age >50 years, with a similar trend for CV death. CONCLUSIONS Adult patients with T1D compared with those with T2D had an overall greater risk of cardiorenal disease (HF and CKD) across ages, MI and all-cause death at middle-older ages, and stroke at younger ages. The total age-adjusted CVRD burden and risks were greater among patients with T1D compared with those with T2D, highlighting their need for improved prevention strategies.

• Bleskestad, Kristiane Birkeland; Nordheim, Espen; Lindahl, Jørn Petter Hanto; Midtvedt, Karsten; Pihlstrøm, Hege K. & Horneland, Rune [Show all 10 contributors for this article] (2021). Insulin secretion and action after pancreas transplantation. A retrospective single-center study. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 81(5), p. 365–370. doi: 10.1080/00365513.2021.1926535. Full text in Research Archive Show summary

  We explored glucometabolic and renal function after engraftment in all 159 consecutive patients with type 1 diabetes who received pancreas transplantation alone (PTA, n = 80) or simultaneous pancreas and kidney transplantation (SPK, n = 79) in Norway from 2012 until 2017. We report fasting levels of plasma glucose (FPG), C-peptide, eGFR and the homeostasis model assessment of insulin sensitivity (HOMA2(%S)) and beta-cell function (HOMA2(%B)) measured one to three times weekly during the first 8 and at 52 weeks after transplantation. One year after engraftment, in the PTA and SPK groups 52 and 64 were normoglycaemic without exogenous insulin, and two and zero patients were dead. Data at the 52-week visit were missing for 5 and 6 patients in the respective groups. During the first 8 weeks, FPG was lower, C-peptide and HOMA2(%S) were higher and eGFR was lower in the SPK group as compared with the PTA group (all p < .05). 30 out of 157 living patients needed insulin treatment 52 weeks after transplantation, 9/79 in the SPK group and 21/78 in the PTA group (p = .02). In conclusion, patients who underwent SPK showed lower insulin sensitivity, but higher insulin secretory capacity and lower mean blood glucose levels the first 8 weeks after transplantation. Also, a higher proportion of patients in the SPK group were insulin-free after 1 year, compared with the PTA group.

• Birkeland, Eline; Gharagozlian, Sedegheh; Gulseth, Hanne L.; Birkeland, Kåre I.; Hartmann, Bolette & Holst, Jens J. [Show all 8 contributors for this article] (2021). Effects of prebiotics on postprandial GLP-1, GLP-2 and glucose regulation in patients with type 2 diabetes: A randomised, double-blind, placebo-controlled crossover trial. Diabetic Medicine. ISSN 0742-3071. 38(10), p. 1–10. doi: 10.1111/dme.14657. Full text in Research Archive Show summary

  Aims We aimed to investigate the effect of prebiotic inulin-type fructans (ITF) versus a control supplement on postprandial levels of glucagon-like peptide-1 and -2 (GLP-1 and -2), glucose and insulin in people with type 2 diabetes. Methods Adult men and women with type 2 diabetes were randomised in a double-blind, placebo-controlled crossover study. The study participants received 16 g/d ITF and 16 g/d control supplement (maltodextrin) for 6 weeks each in two phases separated by a 4-week washout. A standardised mixed-meal test was performed before and after each intake period. The primary end point was changes in the GLP-1 response, and secondary end points were GLP-2, glucose and insulin responses. Data were analysed using mixed-model analysis. Results A total of 29 participants were included in the study. Differences between and within the two treatments in estimated area under the curves were not significant. Yet, the predicted means for meal-induced GLP-1 response in plasma showed a 4.8% decline after the prebiotic treatment and an 8.6% increase after the control treatment (difference in changes between the treatments, p < 0.001). Fasting or postprandial glucose, insulin or GLP-2 levels were not changed. Conclusions Our findings do not support that ITF improve incretin responses or glucose regulations in this population. Clinicaltrials.gov (NCT02569684).

• Sharma, Archana; Birkeland, Kåre I.; Nermoen, Ingrid; Qvigstad, Elisabeth; Tran, Anh T. & Gulseth, Hanne L. [Show all 9 contributors for this article] (2021). Understanding mechanisms behind unwanted health behaviours in Nordic and South Asian women and how they affect their gestational diabetes follow-ups: A qualitative study. Diabetic Medicine. ISSN 0742-3071. 38(10), p. 1–12. doi: 10.1111/dme.14651. Full text in Research Archive Show summary

  Aims: The type 2 diabetes risk following gestational diabetes mellitus (GDM) is high, particularly among South Asian women in Western countries. Our study aimed to advance the knowledge regarding the mechanisms behind suboptimal follow-up in the Nordic and South Asian women with previous GDM by comparing (1) their experiences, (2) health and disease perceptions and (3) barriers to and facilitators of health-promoting behaviours. Methods: This qualitative study was conducted in three hospital outpatient clinics in Norway, comprising six focus group interviews with 28 women 1–3 years after a pregnancy with GDM. The participants were purposively sampled and grouped according to their ethnicity. The data were analysed using thematic analysis, and a theoretical approach was applied to support the analysis and discuss the study's findings. Results: Five main themes were identified: lack of resilience, emotional distress, ‘caught between a rock and a hard place’, postpartum abandonment and insufficient guidance. The key determinants of the maintenance of unwanted health behaviours after GDM were consistent across the ethnic groups. Although the importance of a culturally sensitive approach was emphasised, it appeared secondary to the need for a more organised public healthcare during and after GDM. Conclusions: Women's real-life constraints, combined with the inadequate healthcare-service implementation, could explain the non-adherence to the lifestyle-changes guidelines essential for preventing diabetes post-GDM. We suggest promoting specific coping strategies and changing the healthcare service approach rather than relying on women's capacity to initiate the necessary changes.

• Fatima, Farhat; Hjelmesæth, Jøran Sture; Birkeland, Kåre Inge; Gulseth, Hanne Løvdal; Hertel, Jens Kristoffer & Svanevik, Marius [Show all 11 contributors for this article] (2021). Gastrointestinal hormones and β-cell function after gastric bypass and sleeve gastrectomy: a randomized controlled trial (Oseberg). Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 107(2), p. e756–e766. doi: 10.1210/clinem/dgab643. Full text in Research Archive Show summary

  Context Whether Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) differentially affect postprandial gastrointestinal hormones and β-cell function in type 2 diabetes remains unclear. Objective To compare gastrointestinal hormones and β-cell function assessed by an oral glucose tolerance test (OGTT) 5 weeks and 1 year after surgery hypothesizing higher GLP-1 levels and greater β-cell response to glucose after RYGB than after SG. Design, Setting, Patients, and Interventions Randomized, triple blind, single-center trial at a tertiary care center in Norway. Primary outcomes; diabetes remission and IVGTT derived β-cell function. Participants with obesity and type 2 diabetes allocated (1:1) to RYGB or SG. Main outcome measures Gastrointestinal hormone profiles and insulin secretion [β-cell glucose sensitivity (β-GS)] derived from 180 minutes OGTTs. Results 106 patients (67% women), mean (SD) age 48 (10) years. Diabetes remission rates at 1-year were higher after RYGB than after SG, 77% versus 48%, p = 0.002. Incremental area under the curve (iAUC0-180) glucagon-like peptide-1 (GLP-1) and β-GS increased more after RYGB than after SG, 1-year between-group difference 1173 pmol/l*min (95% CI 569 to 1776), p = 0.0010, and 0.45 pmol/kg/min/mmol (95% CI 0.15 to 0.75), p = 0.0032, respectively. Post-surgery, fasting and postprandial ghrelin levels were higher and decremental AUC0-180 ghrelin, iAUC0-180 glucose-dependent insulinotropic polypeptide, and iAUC0-60 glucagon were greater after RYGB than after SG. Diabetes remission at 1 year was associated with higher β-GS and higher GLP-1 secretion. Conclusions RYGB was associated with greater improvement in β-cell function and higher postprandial GLP-1 levels than SG.

• Øyen, Jannike; Brantsæter, Anne Lise; Nøstbakken, Ole Jakob; Birkeland, Kåre Inge; Haugen, Margaretha & Madsen, Lise [Show all 7 contributors for this article] (2021). Intakes of Fish and Long-chain n-3 Polyunsaturated Fatty Acid Supplements During Pregnancy and Subsequent Risk of Type 2 Diabetes in a Large Prospective Cohort Study of Norwegian Women. Diabetes Care. ISSN 0149-5992. 44(10), p. 2337–2345. doi: 10.2337/dc21-0447. Full text in Research Archive
• Fismen, Anne-Siri; Igland, Jannicke; Teigland, Tonje; Tell, Grethe S.; Østbye, Truls & Haltbakk, Johannes [Show all 10 contributors for this article] (2021). Pharmacologically treated diabetes and hospitalization among older Norwegians receiving homecare services from 2009 to 2014: A nationwide register study. BMJ Open Diabetes Research & Care. 9(1). doi: 10.1136/bmjdrc-2020-002000. Full text in Research Archive Show summary

  Introduction The aim was to assess whether annual hospitalization (admissions, length of stay and total days hospitalized) among persons >65 years receiving home care services in Norway were higher for persons with diabetes than those without diabetes. Given the growing prevalence of diabetes, this issue has great importance for policy makers who must plan for meeting these needs. Research design and methods Data were obtained from national Norwegian registries, and the study population varied from 112 487 to 125 593 per calendar year during 2009–2014. Diabetes was defined as having been registered with at least one prescription for blood glucose lowering medication. Overall and cause-specific hospitalization were compared, as well as temporal trends in hospitalization. Hospitalization outcomes for persons with and without diabetes were compared using log-binomial regression or quantile regression, adjusting for age and gender. Results are reported as incidence rate ratios (IRRs). Results Higher total hospitalization rates (IRR 1.17; 95% CI 1.12 to 1.22) were found among persons with, versus without, diabetes, and this difference remained stable throughout the study period. Similar reductions over time in hospital length of stay were observed among persons with and without diabetes, but total annual days hospitalized decreased significantly (p=0.001) more among those with diabetes than among those without diabetes. Conclusions Among older recipients of home care services in Norway, diabetes was associated with a higher overall risk of hospitalization and increased days in the hospital. Given the growing prevalence of diabetes, it is important for policy makers to plan for meeting these needs.

• Sletner, Line; Moen, Aina Elisabeth Fossum; Yajnik, Chittaranjan S; Kiryushchenko, Nadezhda; Sommer, Christine & Birkeland, Kåre Inge [Show all 8 contributors for this article] (2021). Maternal Glucose and LDL-Cholesterol Levels Are Related to Placental Leptin Gene Methylation, and, Together With Nutritional Factors, Largely Explain a Higher Methylation Level Among Ethnic South Asians. Frontiers in Endocrinology. 12. doi: 10.3389/fendo.2021.809916. Full text in Research Archive Show summary

  Background Leptin, mainly secreted by fat cells, plays a core role in the regulation of appetite and body weight, and has been proposed as a mediator of metabolic programming. During pregnancy leptin is also secreted by the placenta, as well as being a key regulatory cytokine for the development, homeostatic regulation and nutrient transport within the placenta. South Asians have a high burden of type 2 diabetes, partly attributed to a “thin-fat-phenotype”. Objective Our aim was to investigate how maternal ethnicity, adiposity and glucose- and lipid/cholesterol levels in pregnancy are related to placental leptin gene ( LEP ) DNA methylation. Methods We performed DNA methylation analyses of 13 placental LEP CpG sites in 40 ethnic Europeans and 40 ethnic South Asians participating in the STORK-Groruddalen cohort. Results South Asian ethnicity and gestational diabetes (GDM) were associated with higher placental LEP methylation. The largest ethnic difference was found for CpG11 [5.8% (95% CI: 2.4, 9.2), p&amp;lt;0.001], and the strongest associations with GDM was seen for CpG5 [5.2% (1.4, 9.0), p=0.008]. Higher maternal LDL-cholesterol was associated with lower placental LEP methylation, in particular for CpG11 [-3.6% (-5.5, -1.4) per one mmol/L increase in LDL, p&amp;lt;0.001]. After adjustments, including for nutritional factors involved in the one-carbon-metabolism cycle (vitamin D, B12 and folate levels), ethnic differences in placental LEP methylation were strongly attenuated, while associations with glucose and LDL-cholesterol persisted. Conclusions Maternal glucose and lipid metabolism is related to placental LEP methylation, whilst metabolic and nutritional factors largely explain a higher methylation level among ethnic South Asians.

• Haugen, Anders Johan Smedman; Hallan, Stein; Langberg, Nina Elisabeth Borthen; Dahle, Dag Olav; Pihlstrøm, Hege K. & Birkeland, Kåre Inge [Show all 11 contributors for this article] (2021). Increased risk of ischaemic heart disease after kidney donation. Nephrology, Dialysis and Transplantation. ISSN 0931-0509. doi: 10.1093/ndt/gfab054. Full text in Research Archive Show summary

  Background Previous reports suggest increased risk of hypertension and cardiovascular mortality after kidney donation. In this study we investigate the occurrence of ischaemic heart disease and cerebrovascular disease, diabetes and cancer in live kidney donors compared with healthy controls eligible for donation. Methods Different diagnoses were assessed in 1029 kidney donors and 16 084 controls. The diagnoses at follow-up were self-reported for the controls and registered by a physician for the donors. Stratified logistic regression was used to estimate associations with various disease outcomes, adjusted for gender, age at follow-up, smoking at baseline, body mass index at baseline, systolic blood pressure at baseline and time since the donation. Results The mean observation time was 11.3 years [standard deviation (SD) 8.1] for donors versus 16.4 years (SD 5.7) for controls. The age at follow-up was 56.1 years (SD 12.4) in donors versus 53.5 years (SD 11.1) in controls and 44% of donors were males versus 39.3% in the controls. At follow-up, 35 (3.5%) of the donors had been diagnosed with ischaemic heart disease versus 267 (1.7%) of the controls. The adjusted odds ratio for ischaemic heart disease was 1.64 (confidence interval 1.10–2.43; P = 0.01) in donors compared with controls. There were no significant differences for the risks of cerebrovascular disease, diabetes or cancer. Conclusions During long-term follow-up of kidney donors, we found an increased risk of ischaemic heart disease compared with healthy controls. This information may be important in the follow-up and selection process of living kidney donors.

• Langberg, Nina Elisabeth Borthen; Jenssen, Trond Geir; Haugen, Anders; Mjøen, Geir; Birkeland, Kåre Inge & Åsberg, Anders [Show all 8 contributors for this article] (2021). Endothelial Dysfunction and 6-Year Risk of Mortality in Kidney Transplant Recipients. Transplantation direct. 8(1), p. 1–6. doi: 10.1097/TXD.0000000000001262. Full text in Research Archive Show summary

  Background. Endothelial dysfunction is an early and potentially reversible stage in the atherosclerotic process. We assessed endothelial dysfunction noninvasively in kidney transplant recipients (KTRs) and evaluated the association with mortality and graft outcomes. Methods. Flow-mediated dilation (FMD) was measured in arteria brachialis by ultrasound, with baseline diameters obtained at rest and maximal diameters obtained during reactive hyperemia occurring after 5 min of forearm occlusion. FMD% is the percentage difference of flow-mediated dilation relative to baseline. Endpoints on mortality and graft outcomes were collected from The Norwegian Renal Registry. The distribution of risk according to FMD levels was assessed in Cox regression using a restricted cubic spline function. FMD was dichotomized using receiver operating characteristic analysis to identify optimal cut points at maximal sensitivity and specificity. Results. From a total of 269 KTRs in 2012, 152 (56.5%) were eligible and examined 10 wk after transplantation, and 145 had successful FMD measurements. During a mean follow-up of 6.5 y, 26 patients died, 11 lost their graft, and 34 experienced either graft loss or death. Mortality increased with lower FMD levels until about 5% dilation and did not change with further reduction in FMD% (P for nonlinearity <0.01). An optimal cut point of FMD ≤5.36% defined impaired endothelial function and FMD% below this level, was associated with fatal outcome, hazard ratio (HR), 9.80 (1.29–74.62), P = 0.03, uncensored graft loss, HR, 7.80 (1.83–33.30), P = 0.01, but an association with death-censored graft loss was lost after adjusting for pulse pressure, HR, 4.58 (0.55–37.92), P = 0.16. Conclusions. We found that impaired FMD is strongly associated with mortality in KTRs.

• Nordheim, Espen; Lindahl, Jørn Petter Hanto; Carlsen, Rasmus Kirkeskov; Åsberg, Anders; Birkeland, Kåre I. & Horneland, Rune [Show all 9 contributors for this article] (2021). Patient selection for islet or solid organ pancreas transplantation: experiences from a multidisciplinary outpatient-clinic approach. Endocrine Connections. 10(2), p. 230–239. doi: 10.1530/EC-20-0519. Full text in Research Archive Show summary

  Objective - β-cell replacement therapy (βCRT), including pancreas transplantation alone (PTA) and islet transplantation (ITX), is a treatment option for selected type 1 diabetes patients. All potential candidates for βCRT in Norway are referred to one national transplant centre for evaluation before any pre-transplant workup is started. This evaluation was performed by a transplant nephrologist alone prior to 2015 and by a multidisciplinary team (MDT) from 2015. We have reviewed the allocation of patients to treatment modality and the 1-year clinical outcome for the patients after transplantation.<p> <p>Research design and methods - Medical charts of all patients evaluated for βCRT between 2010 and 2020 in Norway were retrospectively analysed and the outcome of patients receiving βCRT were studied.<p> <p>Results - One hundred and forty-four patients were assessed for βCRT eligibility between 2010 and 2020. After MDT evaluation was introduced for βCRT eligibility in 2015, the percentage of referred patients accepted for the transplant waiting list fell from 84% to 40% (P < 0.005). One year after transplantation, 73% of the PTA and none of the ITX patients were independent of exogenous insulin, 8% of the PTA and 90% of the ITX patients had partial graft function while 19% of the PTA and 10% of the ITX patients suffered from graft loss.<p> <p>Conclusion - The acceptance rate for βCRT was significantly reduced during a 10-year observation period and 81% of the PTA and 90% of the ITX patients had partial or normal graft function 1 year post-transplant.

• Fragoso-Bargas, Nicolas; Opsahl, Julia Onsrud; Kiryushchenko, Nadezhda; Böttcher, Yvonne; Lee-Ødegård, Sindre & Qvigstad, Elisabeth [Show all 15 contributors for this article] (2021). Cohort profile: Epigenetics in Pregnancy (EPIPREG) – Population-based sample of European and South Asian pregnant women with epigenome-wide DNA methylation (850k) in peripheral blood leukocytes. PLOS ONE. 16(8), p. 1–15. doi: 10.1371/journal.pone.0256158. Full text in Research Archive Show summary

  Pregnancy is a valuable model to study the association between DNA methylation and several cardiometabolic traits, due to its direct potential to influence mother’s and child’s health. Epigenetics in Pregnancy (EPIPREG) is a population-based sample with the aim to study associations between DNA-methylation in pregnancy and cardiometabolic traits in South Asian and European pregnant women and their offspring. This cohort profile paper aims to present our sample with genetic and epigenetic data and invite researchers with similar cohorts to collaborative projects, such as replication of ours or their results and meta-analysis. In EPIPREG we have quantified epigenome-wide DNA methylation in maternal peripheral blood leukocytes in gestational week 28±1 in Europeans (n = 312) and South Asians (n = 168) that participated in the population-based cohort STORK Groruddalen, in Norway. DNA methylation was measured with Infinium MethylationEPIC BeadChip (850k sites), with technical validation of four CpG sites using bisulphite pyrosequencing in a subset (n = 30). The sample is well characterized with few missing data on e.g. genotype, universal screening for gestational diabetes, objectively measured physical activity, bioelectrical impedance, anthropometrics, biochemical measurements, and a biobank with maternal serum and plasma, urine, placenta tissue. In the offspring, we have repeated ultrasounds during pregnancy, cord blood, and anthropometrics up to 4 years of age. We have quantified DNA methylation in peripheral blood leukocytes in nearly all eligible women from the STORK Groruddalen study, to minimize the risk of selection bias. Genetic principal components distinctly separated Europeans and South Asian women, which fully corresponded with the self-reported ethnicity. Technical validation of 4 CpG sites from the methylation bead chip showed good agreement with bisulfite pyrosequencing. We plan to study associations between DNA methylation and cardiometabolic traits and outcomes.

• Birkeland, Eline; Gharagozlian, Sedegheh; Birkeland, Kåre I.; Holm, Oda Kristine S.; Thorsby, Per Medbøe & Aas, Anne-Marie (2021). Effect of inulin-type fructans on appetite in patients with type 2 diabetes: A randomised controlled crossover trial. Journal of Nutritional Science (JNS). 10, p. 1–11. doi: 10.1017/jns.2021.70. Full text in Research Archive Show summary

  Abstract The aim of the study was to investigate the effect of prebiotic fibres on appetite-regulating hormones, subjective feeling of appetite and energy intake in subjects with type 2 diabetes. Data presented are secondary outcomes of a study investigating the effect of prebiotics on glucagon-like peptide-1 and glycaemic regulation. We conducted a randomised and placebo-controlled crossover trial to evaluate the effects of 16 g/d of inulin-type fructans or a control supplement (maltodextrin) for 6 weeks in randomised order, with a 4-week washout period in-between, on appetite in thirty-five men and women with type 2 diabetes. Data were collected at visits before and after each treatment: plasma concentration of the satiety-related peptides ghrelin and peptide YY (PYY) were assessed during a standardised mixed meal. The subjective sensation of appetite was evaluated in response to an ad libitum lunch by rating the visual analogue scale. Twenty-nine individuals (twelve women) were included in the analyses. Compared to control treatment, the prebiotics did not affect ghrelin ( P =0⋅71) or the ratings of hunger ( P = 0⋅62), satiety ( P = 0⋅56), fullness ( P = 0⋅73) or prospective food consumption ( P = 0⋅98). Energy intake also did not differ between the treatments. However, the response of PYY increased significantly after the control treatment with mean ( sem ) 11⋅1 (4⋅3) pg/ml when compared to the prebiotics −0⋅3 (4⋅3) pg/ml ( P = 0⋅013). We observed no effect of inulin-type fructans on appetite hormones, subjective feeling of appetite or energy intake in patients with type 2 diabetes.

• Haugen, Anders Johan Smedman; Hallan, Stein; Langberg, Nina Elisabeth Borthen; Dahle, Dag Olav; Pihlstrøm, Hege & Birkeland, Kåre I. [Show all 11 contributors for this article] (2020). Increased long-term risk for hypertension in kidney donors – a retrospective cohort study. Transplant International. ISSN 0934-0874. 33(5), p. 536–543. doi: 10.1111/tri.13576. Full text in Research Archive Show summary

  Kidney donors may be at increased risk of end-stage renal disease and premature mortality. Elevated blood pressure after donation may contribute to the increased risks. In this cohort study, we have assessed long-term risk for the development of hypertension in kidney donors compared to a control group potentially eligible as donors. Follow-up data were obtained from previous living kidney donors. A healthy control group with baseline assessment from similar time periods as the donor nephrectomies was selected. Hypertension was defined as blood pressure >140/90, use of blood pressure medication, or established diagnosis of hypertension. Stratified logistic regression was used to estimate risk of hypertension at follow-up, adjusted for systolic blood pressure at baseline, age at follow-up, time since donation/baseline, gender, smoking at baseline, and BMI at baseline. A total of 368 donors (36%) had hypertension at follow-up, and 241 of these (23%) were using blood pressure medication. In adjusted stratified logistic regression analyses, odds ratio for hypertension was significantly increased (1.25, 95% confidence interval 1.12–1.39, P < 0.001) in donors compared with controls. Kidney donors appear to be at increased long-term risk for hypertension compared with healthy controls. This finding supports regular follow-up of blood pressure in kidney donors.

• Opsahl, Julia; Moen, Gunn-Helen Øiseth; Qvigstad, Elisabeth; Böttcher, Yvonne; Birkeland, Kåre Inge & Sommer, Christine (2020). Epigenetic signatures associated with maternal body mass index or gestational weight gain: a systematic review. Journal of Developmental Origins of Health and Disease. ISSN 2040-1744. doi: 10.1017/S2040174420000811. Full text in Research Archive
• Hansen, Anne-Marte; Wium, Cecilie; Lee-Ødegård, Sindre; Tierney, Audrey C.; McCarthy, Danielle & Roche, Helen M. [Show all 9 contributors for this article] (2020). Substantial inter-individual variations in insulin secretion and sensitivity across the glucometabolic spectrum. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 80(4), p. 282–290. doi: 10.1080/00365513.2020.1730433. Full text in Research Archive Show summary

  Impaired insulin secretion and action are important for development of type 2 diabetes (T2D) and metabolic syndrome (MetS). Despite recognized heterogeneity of these glucometabolic disorders, few data are available of biological variation in insulin secretion and action among individuals with T2D and MetS. The aim of this study was to explore the inter-individual variations using gold standard methods in a cross-sectional study of two independent cohorts of phenotypically well-characterized subjects. Cohort I included 486 subjects with MetS, and cohort II 62 subjects with established T2D. First phase insulin secretion was defined as the incremental area under the curve 0–8 min (iAUC0–8 min) during an intravenous glucose tolerance test (IVGTT). Insulin sensitivity was measured as the insulin sensitivity index (SI) modelled from IVGTT in cohort I, and in II as total glucose disposal (TGD) estimated from a euglycaemic-hyperinsulinaemic clamp. Variation is given as total range and, fold-variation between 5%- and 95%-percentile. The iAUC0–8 min ranged from −60 to 3397 mUL−1min−1 among subjects with MetS and from −263 to 1194 mUL−1min−1 in subjects with T2D, representing a more than 10-fold variation. Insulin sensitivity ranged from SI 0.19 to 15.29 (mU/L)−1min−1 among subjects with MetS and TGD 12.9–101.6 μmolkgFFM−1min−1 in subjects with T2D, representing a 6.8 and 5.5-fold variation, respectively. The other components of MetS; BMI, waist-hip ratio, HDL-cholesterol, triglycerides and blood pressure (BP), showed a 1.4–4.7-fold variation. In conclusion, our data demonstrated extensive inter-individual variations in insulin secretion and sensitivity. These variations may be essential to take into account when planning clinical research and treatment in subjects with T2D and MetS.

• Birkeland, Kåre I. (2020). Some Lessons Learned About Diabetes and COVID-19 During the Early Stage of the Epidemic in Norway. Journal of Diabetes Science and Technology. 14(4), p. 718–719. doi: 10.1177/1932296820929371. Full text in Research Archive
• Birkeland, Eline; Gharagozlian, Sedegheh; Birkeland, Kåre I.; Valeur, Jørgen; Måge, Ingrid & Rud, Ida [Show all 7 contributors for this article] (2020). Prebiotic effect of inulin-type fructans on faecal microbiota and short-chain fatty acids in type 2 diabetes: a randomised controlled trial. European Journal of Nutrition. ISSN 1436-6207. 59, p. 3325–3338. doi: 10.1007/s00394-020-02282-5. Full text in Research Archive Show summary

  Purpose Compared to a healthy population, the gut microbiota in type 2 diabetes presents with several unfavourable features that may impair glucose regulation. The aim of this study was to evaluate the prebiotic efect of inulin-type fructans on the faecal microbiota and short-chain fatty acids (SCFA) in patients with type 2 diabetes. Methods The study was a placebo controlled crossover study, where 25 patients (15 men) aged 41–71 years consumed 16 g of inulin-type fructans (a mixture of oligofructose and inulin) and 16-g placebo (maltodextrin) for 6 weeks in randomised order. A 4-week washout separated the 6 weeks treatments. The faecal microbiota was analysed by high-throughput 16S rRNA amplicon sequencing and SCFA in faeces were analysed using vacuum distillation followed by gas chromatography. Results Treatment with inulin-type fructans induced moderate changes in the faecal microbiota composition (1.5%, p=0.045). A bifdogenic efect was most prominent, with highest positive efect on operational taxonomic units (OTUs) of Bifdobacterium adolescentis, followed by OTUs of Bacteroides. Signifcantly higher faecal concentrations of total SCFA, acetic acid and propionic acid were detected after prebiotic consumption compared to placebo. The prebiotic fbre had no efects on the concentration of butyric acid or on the overall microbial diversity. Conclusion Six weeks supplementation with inulin-type fructans had a signifcant bifdogenic efect and induced increased concentrations of faecal SCFA, without changing faecal microbial diversity. Our fndings suggest a moderate potential of inulin-type fructans to improve gut microbiota composition and to increase microbial fermentation in type 2 diabetes. Trial registration The trial is registered at clinicaltrials.gov (NCT02569684).

• Nordheim, Espen; Dahle, Dag Olav; Halden, Thea Anine Strøm; Birkeland, Kåre I.; Åsberg, Anders & Hartmann, Anders [Show all 8 contributors for this article] (2020). Endothelial function after pancreas transplantation - A single-center observational study. Clinical Transplantation. ISSN 0902-0063. 34:e13815(3), p. 1–7. doi: 10.1111/ctr.13815. Full text in Research Archive Show summary

  <i>Background</i> - Patients with diabetes mellitus treated with successful pancreas transplantation (PTX) normalize hyperglycemia, but are exposed to immunosuppressive drugs that may impair endothelial function. This study aimed to evaluate endothelial function in single PTX recipients.<p><p> <i>Methods</i> - Flow‐mediated dilatation (FMD) in the brachial artery was measured by ultrasound 8 weeks after transplantation in single PTX (n = 27) and compared with healthy controls (n = 58), simultaneous pancreas and kidney recipients (n = 9), and kidney transplant recipients with (n = 41) and without (n = 95) diabetes mellitus. Adjustments for age, gender, blood pressure, and body mass index were included in a linear regression model. Changes in FMD from before to 1 year after transplantation were assessed in a subgroup of PTX recipients (n = 9).<p><p> <i>Results</i> - Flow‐mediated dilatation% in PTX recipients was not inferior to healthy controls (8.7 ± 3.6 vs 7.7 ± 3.3, <i>P</i> = .06) and simultaneous pancreas and kidney recipients (6.7 ± 4.5, <i>P</i> = .24) in an adjusted model, and superior to kidney recipients with and without diabetes (3.0 ± 3.0 and 4.8 ± 3.3, respectively, both <i>P</i> < .005). FMD% improved significantly from eight weeks to one year after PTX, mean 7.9 ± 4.2% vs 11.8 ± 4.8% (N = 9; <i>P</i> = .03).<p><p> <i>Conclusion</i> - Flow‐mediated dilatation is well preserved in patients undergoing pancreas transplantation and is not impaired when immunosuppressive drugs are introduced.

• Moen, Gunn-Helen; Brumpton, Ben Michael; Willer, Cristen J.; Åsvold, Bjørn Olav; Birkeland, Kåre I. & Wang, Geng [Show all 13 contributors for this article] (2020). Mendelian randomization study of maternal influences on birthweight and future cardiometabolic risk in the HUNT cohort. Nature Communications. 11:5404, p. 1–12. doi: 10.1038/s41467-020-19257-z. Full text in Research Archive Show summary

  There is a robust observational relationship between lower birthweight and higher risk of cardiometabolic disease in later life. The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that adverse environmental factors in utero increase future risk of cardiometabolic disease. Here, we explore if a genetic risk score (GRS) of maternal SNPs associated with offspring birthweight is also associated with offspring cardiometabolic risk factors, after controlling for offspring GRS, in up to 26,057 mother–offspring pairs (and 19,792 father–offspring pairs) from the Nord-Trøndelag Health (HUNT) Study. We find little evidence for a maternal (or paternal) genetic effect of birthweight associated variants on offspring cardiometabolic risk factors after adjusting for offspring GRS. In contrast, offspring GRS is strongly related to many cardiometabolic risk factors, even after conditioning on maternal GRS. Our results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes in population based samples of individuals.

• Knudsen, Søren Tang; Bodegard, Johan; Birkeland, Kåre I.; Furuseth, Kristian; Thuresson, Marcus & Lindh, Anders [Show all 11 contributors for this article] (2020). Risk factor management of type 2 diabetic patients in primary care in the Scandinavian countries between 2003 and 2015. Primary Care Diabetes. ISSN 1751-9918. 15(2), p. 262–268. doi: 10.1016/j.pcd.2020.09.006. Full text in Research Archive Show summary

  Aims To observe and report population demography, comorbidities, risk factor levels and risk factor treatment in a sample of individuals treated for type 2 diabetes in primary care in Norway, Sweden and Denmark. Methods Retrospective observational cohort using extraction of data from electronic medical records linked with national health care registries. Results Sixty primary care clinics participated with annual cross-sectional data (2003 to 2015). In 2015 the sample consisted of 31,632 individuals. Mean age (64.5–66.8 years) and proportion of women (43–45%) were similar. The prevalence of cardiovascular disease in 2015 was 40.7%, 41.6% and 38.0% for Norway, Sweden and Denmark, respectively and 84% to 89% of patients were receiving a pharmacological anti-diabetic treatment. More Danish patients reached targets for HbA1c and LDL cholesterol, while more patients in Sweden and Denmark met the blood pressure target of <130/80 mmHg as compared to Norway. Conclusions In three comparable public primary health care systems we found a high prevalence of cardiovascular disease and differences in risk factor treatment and attainment of risk factor goals. With recent guideline changes there is potential for further prevention of diabetes complications in primary care in the future.

• Birkeland, Kåre I.; Bodegard, Johan; Eriksson, Jan W.; Norhammar, Anna; Haller, Hermann & Linssen, Gerard C.M. [Show all 16 contributors for this article] (2020). Heart failure and chronic kidney disease manifestation and mortality risk associations in type 2 diabetes: A large multinational cohort study. Diabetes, obesity and metabolism. ISSN 1462-8902. 22(9), p. 1607–1618. doi: 10.1111/dom.14074. Full text in Research Archive Show summary

  Aims To examine the manifestation of cardiovascular or renal disease (CVRD) in patients with type 2 diabetes (T2D) initially free from CVRD as well as the mortality risks associated with these diseases. Methods Patients free from CVRD were identified from healthcare records in England, Germany, Japan, the Netherlands, Norway and Sweden at a fixed date. CVRD manifestation was defined by first diagnosis of cardiorenal disease, or a stroke, myocardial infarction (MI) or peripheral artery disease (PAD) event. The mortality risk associated with single CVRD history of heart failure (HF), chronic kidney disease (CKD), MI, stroke or PAD was compared with that associated with CVRD‐free status. Results Of 1 177 896 patients with T2D, 772 336 (66%) were CVRD‐free and followed for a mean of 4.5 years. A total of 137 081 patients (18%) developed a first CVRD manifestation, represented by CKD (36%), HF (24%), stroke (16%), MI (14%) and PAD (10%). HF or CKD was associated with increased cardiovascular and all‐cause mortality risk: hazard ratio (HR) 2.02 (95% confidence interval [CI] 1.75–2.33) and HR 2.05 (95% CI 1.82–2.32), respectively. HF and CKD were separately associated with significantly increased mortality risks, and the combination was associated with the highest cardiovascular and all‐cause mortality risk: HRs 3.91 (95% CI 3.02–5.07) and 3.14 (95% CI 2.90–3.40), respectively. Conclusion In a large multinational study of >750 000 CVRD‐free patients with T2D, HF and CKD were consistently the most frequent first cardiovascular disease manifestations and were also associated with increased mortality risks. These novel findings show these cardiorenal diseases to be important and serious complications requiring improved preventive strategies.

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• Birkeland, Kåre Inge; Gullestad, Lars & Aabakken, Lars (2022). Indremedisin I. Fagbokforlaget. ISBN 9788245043365. 479 p. Full text in Research Archive
• Birkeland, Kåre Inge; Gullestad, Lars & Aabakken, Lars (2022). Indremedisin I & II, 2. utgave. Fagbokforlaget. ISBN 9788245040968. 1024 p. Full text in Research Archive

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• Kongerud, Ingrid Charlotte; Midtvedt, Karsten; Solbu, Marit Dahl; Øvrehus, Marius Altern; Eikrem, Øystein Solberg & Eide, Ivar Anders [Show all 10 contributors for this article] (2026). Can sodium-glucose cotransporter 2 (SGLT2) inhibition preserve renal structure and function in de novo kidney transplant recipients? Protocol for a randomised, double-blind, placebo-controlled trial assessing the efficacy of dapagliflozin on kidney structure, function and safety in kidney transplant recipients in Norway—the DEAK study. doi: 10.1136/bmjopen-2026-117263. Full text in Research Archive Show summary

  Introduction Recent studies have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease in people at high cardiovascular risk, with or without type 2 diabetes. To date, all published studies have excluded kidney transplant recipients (KTRs). The Dapagliflozin Early After Kidney Transplantation (DEAK) study aims to prospectively evaluate the effects of the SGLT2 inhibitor dapagliflozin on kidney function, histopathology and metabolic outcomes among de novo KTRs. Methods and analyses This nationwide, investigator-initiated, single-transplant-centre, randomised, placebo-controlled, prospective clinical trial with two parallel groups aims to enrol 330 de novo adult KTRs (aged 18–75 years) with an estimated glomerular filtration rate (eGFR) of at least 25 mL/min/1.73 m². Participants are enrolled 6–8 weeks after transplantation and randomised 1:1 to receive dapagliflozin 10 mg/day or placebo for 3 years. Recipients with conditions that may intermittently affect kidney function, such as recent acute rejection or ongoing infection, are ineligible for inclusion. The primary endpoint of the study is the difference in the chronic eGFR slope between treatment groups over 3 years, estimated using the European Kidney Function Consortium equation. Secondary and safety endpoints include changes in measured GFR (iohexol clearance), urinary albumin/creatinine ratio, blood pressure, infections and safety clinical chemistry. Exploratory endpoints evaluated after 1.5 years include changes in body composition and glucose tolerance; between-group differences in urinary metabolomics; transplant kidney biopsy inflammation and fibrosis scores (n=140) and kidney biopsy messenger RNA and protein expression (n=50). The protocol also includes a 10-year poststudy registry follow-up of eGFR slope, cardiovascular events and graft and patient survival. Ethics and dissemination The study protocol (EudraCT number: 2022-002428-10) has been approved by the Norwegian Medical Products Agency, the Regional Committee for Medical Research Ethics in Southeast Norway (REK Southeast number 426076) and by the data protection offices at the participating hospitals. The main results will be published in international, peer-reviewed scientific journals. Trial registration number NCT05788276.

• Bargas, Nicolas Fragoso; Mcbride, Nancy S.; Lee-Ødegård, Sindre; Lawlor, Deborah A.; Yousefi, Paul D. & Moen, Gunn-Helen [Show all 14 contributors for this article] (2025). Correction to: Epigenome-wide association study of objectively measured physical activity in peripheral blood leukocytes (BMC Genomics, (2025), 26, 1, (62), 10.1186/s12864-025-11262-0). BMC Genomics. 26(1). doi: 10.1186/s12864-025-11311-8. Full text in Research Archive
• Rishaug, Tina; Aas, Anne-Marie; Henriksen, André; Hartvigsen, Gunnar; Birkeland, Kåre Inge & Årsand, Eirik (2024). What are end-users' needs and preferences for a comprehensive e-health program for type 2 diabetes? - A qualitative user preference study. Full text in Research Archive
• Rishaug, Tina; Aas, Anne-Marie; Henriksen, André; Hartvigsen, Gunnar; Birkeland, Kåre Inge & Årsand, Eirik (2024). What are end-users’ needs and preferences for a comprehensive e-health program for type 2 diabetes? – A qualitative user preference study. Full text in Research Archive
• Teigland, Tonje; Igland, Jannicke; Blytt, Kjersti Marie; Haltbakk, Johannes; Graue, Marit & Birkeland, Kåre Inge [Show all 9 contributors for this article] (2024). Differences in causes of death and mortality risk among older people with and without diabetes in Norwegian home care services. A nationwide registry study. Full text in Research Archive
• Rishaug, Tina; Henriksen, André; Aas, Anne-Marie; Hartvigsen, Gunnar; Birkeland, Kåre Inge & Årsand, Eirik (2024). DiAchieve: Preliminary Results from a Study on End-Users' Preferences for a Novel E-Health Program for Type 2 Diabetes. Full text in Research Archive
• Rishaug, Tina; Henriksen, André; Aas, Anne-Marie; Hartvigsen, Gunnar; Birkeland, Kåre Inge & Årsand, Eirik (2024). DiAchieve: Preliminary Results from a Study on End-Users' Preferences for a Novel E-Health Program for Type 2 Diabetes. Diabetes Technology & Therapeutics. ISSN 1520-9156. 26(S2), p. A-345–A-345. Full text in Research Archive
• Waage, Christin; Toftemo, Ingun; Brænd, Anja Maria; Sletner, Line; Sommer, Christine & Birkeland, Kåre Inge [Show all 10 contributors for this article] (2023). Cohort profile update: the Norwegian STORK Groruddalen (STORK G) pregnancy and birth cohort—the role of ethnicity and causal pathways for obesity, type 2 diabetes, cardiovascular disease and other health issues. BMJ Open. 13(10), p. 1–11. doi: 10.1136/bmjopen-2023-076251. Full text in Research Archive Show summary

  Purpose The STORK Groruddalen cohort was set up in 2008 to explore ethnic differences in: (1) maternal health, primarily gestational diabetes (GDM) and related health issues during pregnancy and post partum, and effects of exposures on risk for type 2 diabetes, cardiovascular disease and other health issues, and (2) offspring’s growth and body composition, overweight/obesity and effects of early life exposures. Participants 823 women (74% of invited) were followed from gestational week (GW) 15. Data were collected from 618 fathers. In total, 59% of women and 53% of fathers had origin from non-Western countries. Maternal mean age was 29.9 years (SD 4.9), and body mass index (BMI) 25.3 kg/m 2 (4.9). Data were obtained from 772 women (94%) at GW 28, and 662 women (80%) 14 weeks post partum. Eleven years post partum, 385 women (53% of eligible/47% of original cohort) attended, age was 42.0 years (4.8) and BMI 27.1 kg/m 2 (5.1). We have data for 783 children at birth, and for 586 at last time point, mean age 8.6 (0.5) years, weight 30.7 (6.8) kg and length 133.9 (6.3) cm. Findings to date We collected questionnaire data from parents, clinical measurements and blood samples from mothers, and data on children’s growth (mid-pregnancy to 8 years). Our biobank includes maternal blood and urine samples, biopsy material from placentas and umbilical venous cord blood. We found several clinically important differences in maternal health, with higher risk in ethnic minority groups for GDM, insulin resistance, vitamin D and iron deficiency, depressive symptoms and physical inactivity. Contrasting patterns of fetal growth and risk of overweight/thinness at preschool age were observed across ethnic groups. Maternal GDM, obesity and high gestational weight gain were associated with children’s BMI trajectories. Future plans We will examine the impact of maternal and fetal health and development during pregnancy on long- term outcomes for mothers and offspring.

• Rishaug, Tina; Henriksen, André; Aas, Anne-Marie; Hartvigsen, Gunnar; Birkeland, Kåre Inge & Årsand, Eirik (2023). Involving end users in the design and development of an e-health program for lifestyle changes in type 2 diabetes. Full text in Research Archive
• Teigland, Tonje; Igland, Jannicke; Tell, Grethe S.; Graue, Marit; Blytt, Kjersti Marie & Haltbakk, Johannes [Show all 10 contributors for this article] (2023). Differences in short-term nursing home admissions among older people with and without diabetes receiving home care services in Norway. A nationwide registry study. Full text in Research Archive
• Rishaug, Tina; Henriksen, André; Aas, Anne-Marie; Hartvigsen, Gunnar; Birkeland, Kåre Inge & Årsand, Eirik (2023). DiAchieve - A New e-Health Lifestyle Program for Improved Self-Management and Remission of Type 2 Diabetes. Full text in Research Archive
• Teigland, Tonje; Igland, Jannicke; Tell, Grethe S.; Graue, Marit; Blytt, Kjersti & Haltbakk, Johannes [Show all 10 contributors for this article] (2023). Risk of nursing home admission among persons with diabetes receiving home care services in Norway. A nationwide study. Full text in Research Archive
• Rishaug, Tina; Henriksen, André; Aas, Anne-Marie; Hartvigsen, Gunnar; Birkeland, Kåre Inge & Årsand, Eirik (2023). DiAchieve - A Qualitative Pre-Study. Full text in Research Archive
• Goh, Su-Yen; Kosiborod, Mikhail N.; Lam, Carolyn S. P.; Cavender, Matthew A.; Kohsaka, Shun & Norhammar, Anna [Show all 14 contributors for this article] (2023). Lower risk of cardiovascular events and death associated with initiation of sodium-glucose cotransporter-2 inhibitors versus sulphonylureas: Analysis from the CVD-REAL 2 study. Diabetes, obesity and metabolism. ISSN 1462-8902. doi: 10.1111/dom.15092. Full text in Research Archive
• Waage, Christin; Mdala, Ibrahimu; Brænd, Anja Maria; Jenum, Anne Karen & Birkeland, Kåre Inge (2023). Prediabetes and diabetes 11 years after pregnancy in ethnic minority groups with and without gestational diabetes. Full text in Research Archive
• Bargas, Nicolas Fragoso; Linares-Pineda, Teresa; Molina-Vega, María; Picón, María José; Jenum, Anne Karen & Sletner, Line [Show all 14 contributors for this article] (2023). Methylation risk score for gestational diabetes on DNA methylation patterns associated with type 2 diabetes. Full text in Research Archive
• Birkeland, Kåre Inge; Meling, Sondre V.; Alsnes, Ingvild Vatten; Svensson, Emelie; Gullestad, Lars & Jenssen, Trond (2023). Nye internasjonale anbefalingerfor type 2-diabetes – hva gjør vi i Norge? 143(3), p. 1–6. doi: 10.4045/tidsskr.22.0672. Full text in Research Archive
• Rishaug, Tina; Henriksen, André; Aas, Anne-Marie; Hartvigsen, Gunnar; Birkeland, Kåre Inge & Årsand, Eirik (2023). Involving end users in the design and development of an e-health program for lifestyle changes in type 2 diabetes. Diabetes Technology & Therapeutics. ISSN 1520-9156. doi: 10.1089/dia.2023.2525.abstracts. Full text in Research Archive
• Rishaug, Tina; Henriksen, André; Aas, Anne-Marie; Hartvigsen, Gunnar; Birkeland, Kåre Inge & Årsand, Eirik (2022). Designing an e-Health Program for Lifestyle Changes in Diabetes Care: A Qualitative Pre-Study in Norway. Full text in Research Archive
• Teigland, Tonje; Igland, Jannicke; Tell, Grethe S.; Haltbakk, Johannes; Graue, Marit & Fismen, Anne-Siri [Show all 10 contributors for this article] (2022). Correction: The prevalence and incidence of pharmacologically treated diabetes among older people receiving home care services in Norway 2009–2014: a nationwide longitudinal study (BMC Endocrine Disorders, (2022), 22, 1, (159), 10.1186/s12902-022-01068-6). BMC Endocrine Disorders. 22(1). doi: 10.1186/s12902-022-01091-7. Full text in Research Archive
• Lee-Ødegård, Sindre; Norheim, Frode Amador; Langleite, Torgrim Mikal; Gulseth, Hanne Løvdal; Birkeland, Kåre Inge & Drevon, Christian A (2022). Correction to: Effects of long-term exercise on plasma adipokine levels and inflammation-related gene expression in subcutaneous adipose tissue in sedentary dysglycaemic, overweight men and sedentary normoglycaemic men of healthy weight (Diabetologia, (2019), 62, 6, (1048-1064), 10.1007/s00125-019-4866-5). Diabetologia. ISSN 0012-186X. doi: 10.1007/s00125-022-05841-z. Full text in Research Archive
• Teigland, Tonje; Igland, Jannicke; Tell, Grethe S.; Graue, Marit; Haltbakk, Johannes & Birkeland, Kåre Inge [Show all 10 contributors for this article] (2022). Comorbidity among older people with pharmacologically treated diabetes receiving home care services in Norway. Full text in Research Archive
• Teigland, Tonje; Igland, Jannicke; Tell, Grethe S.; Haltbakk, Johannes; Fismen, Anne-Siri & Birkeland, Kåre Inge [Show all 10 contributors for this article] (2022). INCREASING PREVALENCE OF PHARMACOLOGICALLY TREATED DIABETES AMONG PERSONS RECEIVING HOME CARE SERVICES IN NORWAY (2009-2014). A NATIONWIDE STUDY. Full text in Research Archive
• Fragoso-Bargas, Nicolas; Lee-Ødegård, Sindre; Moen, Gunn-Helen Øiseth; oppsahl, JO; Sletner, Line & Jenum, Anne Karen [Show all 13 contributors for this article] (2022). Epigenome-Wide Association Study of objectively measured moderate physical activity in pregnan. Full text in Research Archive Show summary

  Epigenome-Wide Association Study of objectively measured moderate physical activity in pregnancy Nicolas Fragoso-Bargas1,2, Sindre Lee-Ødegård2, Gunn-Helen Moen2,3,4,5, Julia O. Opsahl2, Line Sletner2,6, Anne Karen Jenum2, Paul Franks7, Rashmi B. Prasad8, Leif C. Groop8, Elisabeth Qvigstad1,2, Kåre I. Birkeland2, Kåre R. Richardsen9, Christine Sommer1 1Oslo University Hospital, Oslo, Norway, 2University of Oslo, Oslo, Norway, 3The University of Queensland Diamantina Institute, Brisbane, Australia, 4Norwegian University of Science and Technology, Trondheim, Norway, 5University of Bristol, UK, 6Akershus University Hospital, Oslo, Norway, 7Lund University Genetic and Molecular Epidemiology, Malmö, Sweden, 8Lund University Diabetes Centre, Malmö, Sweden,9Oslo Metropolitan University, Oslo, Norway. Physical activity (PA) is recommended during pregnancy to reduce the risk of excessive weight gain and gestational diabetes mellitus, and to improve general health. DNA methylation (DNAm) has been proposed as a potential molecular mechanism through which physical activity (PA) mediates the effects on the transcriptome. Here we performed an epigenome-wide association study (EWAS) of objectively measured moderate physical activity in pregnancy, which has not been performed previously. In EPIPREG (a sub-sample of the population-based STORK Groruddalen study) we quantified DNAm at gestational week 28 (±2 SD) with Illumina’s Infinium Methylation EPIC BeadChip. With SenseWear™ Pro3 Armband, we measured hours per day of moderate PA (3.0 to 6.0 metabolic equivalent for task (MET)) and steps/day. DNAm outliers that were 4 times the interquartile range below or above the 25TH and 75TH percentiles respectively were removed, before the beta values were transformed to M-values. Of the 472 that passed the EWAS quality control, 239 European (EUR) and 109 South Asian women (SA) had two valid days of recorded PA (19.2h per day), and were non-outliers (±4 SD) in their respective ethnic group. We used two approaches to test the association between M-values and moderate PA (hours/day): 1) A trans-ethnic approach using mixed linear models adjusted for blood cell proportions, age, smoking, number of steps, number of valid days (between 2 to 8), and ethnicity as a random intercept, and 2) through separate analyses in EUR and SA using linear modelling adjusted with the before mentioned covariates. We accepted a false discovery rate of 10%. In the trans-ethnic analysis, only cg08148261 located in the promoter area of LDHB was significantly associated with moderate PA. In Europeans, eight sites were significant: cg19031974 (BSN-AS2), cg19053287 (MCF2L) cg14930390 (MUTED), cg18517050 (CIAPIN1) and cg26191378 (TMUB1), located near promoter areas, cg27160968 (ESRRA) and cg15879426 (c17orf101) located in exon boundaries, and cg10421808 which is unannotated. In South Asians, only cg05999993 in the promoter area of AOAH was associated with moderate PA. Most of the sites showed decreased DNAm at increased moderate PA (hours/day), while in cg10421808, cg14930390 and cg15879426 the opposite was observed. In conclusion, we found several significant associations between DNAm and moderate PA. Several CpGs were located near gene promoter areas, which could imply altered transcription of the respective genes. These findings suggest that PA may exert changes in DNAm with important transcriptional implications during pregnancy.

• Fragoso-Bargas, Nicolas; Lee-Ødegård, Sindre; Moen, Gunn-Helen Øiseth; Oppsahl, JO; Sletner, Line & Jenum, Anne Karen [Show all 12 contributors for this article] (2022). Epigenome-Wide Association Study of objectively measured physical activity in pregnancy. Full text in Research Archive
• Birkeland, Eline; Gharagozlian, Sedegheh; Birkeland, Kåre I.; Valeur, Jørgen; Måge, Ingrid & Rud, Ida [Show all 7 contributors for this article] (2020). Correction to: Prebiotic effect of inulin‑type fructans on faecal microbiota and short‑chain fatty acids in type 2 diabetes: a randomised controlled trial. European Journal of Nutrition. ISSN 1436-6207. doi: 10.1007/s00394-020-02314-0. Full text in Research Archive
• Hjelmesæth, Jøran; Fatima, Farhat; Birkeland, Kåre I.; Svanevik, Marius & Hofsø, Dag (2020). Metabolic surgery: one size fits all? - Authors' reply. The Lancet Diabetes and Endocrinology. ISSN 2213-8587. 8, p. 273–273. doi: 10.1016/S2213-8587(20)30027-9. Full text in Research Archive
• Stene, Lars Christian Mørch; Ruiz, Paz Lopez-Doriga; Åsvold, Bjørn Olav; Bjarkø, Vera Vik; Sørgjerd, Elin Pettersen & Njølstad, Inger [Show all 9 contributors for this article] (2020). Hvor mange har diabetes i Norge i 2020? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(17). doi: 10.4045/tidsskr.20.0849. Full text in Research Archive
• Teigland, Tonje; Igland, Jannicke; Tell, Grethe S.; Haltbakk, Johannes; Fismen, Anne-Siri & Birkeland, Kåre Inge [Show all 10 contributors for this article] (2020). Trends in prevalence and incidence of pharmacologically treated diabetes among elderly receiving home care services in Norway (2009-2014): A nationvide study. Full text in Research Archive
• Birkeland, Kåre I.; Bodegard, Johan; Banerjee, Amitava; Kim, Dae Jung; Norhammar, Anna & Eriksson, Jan W. [Show all 15 contributors for this article] (2020). Lower cardiorenal risk with sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes without cardiovascular and renal diseases: A large multinational observational study. Diabetes, obesity and metabolism. ISSN 1462-8902. 23(1), p. 75–85. doi: 10.1111/dom.14189. Full text in Research Archive
• Bergum, Hilde Marie; Klemsdal, Tor Ole; Grimsmo, Jostein & Birkeland, Kåre Inge (2025). Long Term Effects of Multiple Lifestyle Intervention in subjects with elevated Cardiovascular Risk. Universitetet i Oslo. ISSN 9788234806469. Full text in Research Archive Show summary

  Cardiovascular diseases remain a leading cause of premature morbidity and mortality. Despite strong evidence relating modifiable risk factors to cardiovascular disease, and preventive guidelines emphasizing lifestyle intervention, risk factor control remains suboptimal and long-term effects are insufficiently documented. The meta-analysis included as the first paper in this thesis concluded that lifestyle interventions have limited impact on major cardiovascular risk factors after 24 months, though a modest reduction in systolic blood pressure may be clinically relevant. The main aim of the thesis was to evaluate the efficacy of a newly developed multifactorial lifestyle intervention in individuals at elevated risk. The programme was based on existing structures in Norwegian health care, combining a hospital course with follow-up through primary care and local resources. Efficacy was assessed in a randomized controlled trial with 601 participants completing 36 months follow-up, using four global risk scores (NORRISK, Framingham, PROCAM, NORRISK 2) and selected risk factors. All four scores improved significantly in the intervention group, corresponding to ~20% relative risk reduction. Smoking and metabolic syndrome prevalence declined significantly more in the intervention group vs controls. No significant differences were found for blood pressure or lipids, though LDL and triglyceride changes were borderline significant. Physical activity increased significantly more in the intervention group. Psychological well-being improved in both groups, with a greater increase in the intervention group. Medication use was high, but participation reduced the need for new prescriptions. No effects were observed on markers of inflammation or glucose metabolism. These results are promising for addressing the need for effective preventive interventions, which aligns with a key health policy objective in Norway, and should encourage further efforts to improve preventive programs.

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