Publications by authors named "Allan Vaag"

267 Publications

Differential DNA Methylation and Expression of MicroRNAs in Adipose Tissue from Twin Pairs Discordant for Type 2 Diabetes.

Diabetes 2021 Jul 27. Epub 2021 Jul 27.

Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden.

The prevalence of type 2 diabetes (T2D) is increasing worldwide but current treatments have limitations. MicroRNAs (miRNAs) may play a key role in the development of T2D and can be targets for novel therapies. Here, we examined whether T2D is associated with altered expression and DNA methylation of miRNAs using adipose tissue from 14 monozygotic twin pairs discordant for T2D. Four members each of the miR-30 and let-7-families were downregulated in adipose tissue from subjects with T2D versus controls, which was confirmed in an independent T2D case-control cohort. Further, DNA methylation of five CpG sites annotated to gene promoters of differentially expressed miRNAs, including miR-30a and let-7a-3, was increased in T2D versus control subjects. Luciferase experiments showed that increased DNA methylation of the promoter reduced its transcription Silencing of miR-30 in adipocytes resulted in reduced glucose uptake and TBC1D4 phosphorylation; downregulation of genes involved in demethylation and carbohydrate/lipid/amino acid metabolism; and upregulation of immune system genes. In conclusion, T2D is associated with differential DNA methylation and expression of miRNAs in adipose tissue. Downregulation of the miR-30 family may lead to reduced glucose uptake and altered expression of key genes associated with T2D.
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http://dx.doi.org/10.2337/db20-0324DOI Listing
July 2021

Perinatal famine is associated with excess risk of proliferative retinopathy in patients with type 2 diabetes.

Acta Ophthalmol 2021 Jun 24. Epub 2021 Jun 24.

Department of Clinical Science, Center for Diabetes Research, University of Bergen, Bergen, Norway.

Purpose: Intrauterine undernutrition is associated with increased risk of type 2 diabetes. Children born premature or small for gestational age were reported to have abnormal retinal vascularization. However, whether intrauterine famine act as a trigger for diabetes complications, including retinopathy, is unknown. The aim of the current study was to evaluate long-term effects of perinatal famine on the risk of proliferative diabetic retinopathy (PDR).

Methods: We studied the risk for PDR among type 2 diabetes patients exposed to perinatal famine in two independent cohorts: the Ukrainian National Diabetes Registry (UNDR) and the Hong Kong Diabetes Registry (HKDR). We analysed individuals born during the Great Famine (the Holodomor, 1932-1933) and the WWII (1941-1945) famine in 101 095 (3601 had PDR) UNDR participants. Among 3021 (251 had PDR) HKDR participants, we studied type 2 diabetes patients exposed to perinatal famine during the WWII Japanese invasion in 1942-1945.

Results: During the Holodomor and WWII, perinatal famine was associated with a 1.76-fold (p = 0.019) and 3.02-fold (p = 0.001) increased risk of severe PDR in the UNDR. The risk for PDR was 1.66-fold elevated among individuals born in 1942 in the HKDR (p < 0.05). The associations between perinatal famine and PDR remained statistically significant after corrections for HbA1c in available 18 507 UNDR (p  < 0.001) and in 3021 HKDR type 2 diabetes patients (p < 0.05).

Conclusion: In conclusion, type 2 diabetes patients, exposed to perinatal famine, have increased risk of PDR compared to those without perinatal famine exposure. Further studies are needed to understand the underlying mechanisms and to extend this finding to other diabetes complications.
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http://dx.doi.org/10.1111/aos.14948DOI Listing
June 2021

Vitamin D concentrations from neonatal dried blood spots and the risk of early-onset type 2 diabetes in the Danish D-tect case-cohort study.

Diabetologia 2021 Jul 24;64(7):1572-1582. Epub 2021 May 24.

Research Unit for Dietary Studies, The Parker Institute, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark.

Aims/hypothesis: The aim of this study was to examine the influence of neonatal vitamin D concentration on the development of early-onset type 2 diabetes in a large population sample.

Methods: We conducted a case-cohort study utilising data from the Danish biobank and registers. Neonatal vitamin D was assessed measuring 25-hydroxyvitamin D [25(OH)D] concentrations on the dried blood spot samples from the Biological Specimen Bank for Neonatal Screening. Cases of type 2 diabetes (n = 731) were retrieved from the Danish National Patient Register for all individuals born in Denmark between 1 May 1981 and 31 December 1992. The sub-cohort (n = 1765) was randomly selected from all children born in the same period. We used a weighted Cox proportional hazard model assessing the hazard of first type 2 diabetes diagnoses by quintiles of 25(OH)D and restricted cubic spline.

Results: The median 25(OH)D concentration (IQR) among cases was 21.3 nmol/l (13.3-34.1) and 23.9 nmol/l (13.7-35.7) in the sub-cohort. There was no indication of a potential lower risk of early-onset type 2 diabetes among individuals in the higher quintile of vitamin D concentration compared with the lowest (HR 0.97 [95% CI 0.71, 1.33] p = 0.85; HR 1.29 [95% CI 0.92, 1.83] p = 0.14).

Conclusions/interpretation: The results of this study do not support the hypothesis that higher neonatal vitamin D concentrations are associated with a lower risk of early-onset type 2 diabetes in adulthood.
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http://dx.doi.org/10.1007/s00125-021-05450-2DOI Listing
July 2021

VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics.

Nat Commun 2021 04 23;12(1):2431. Epub 2021 Apr 23.

Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden.

Insulin resistance and lower muscle quality (strength divided by mass) are hallmarks of type 2 diabetes (T2D). Here, we explore whether alterations in muscle stem cells (myoblasts) from individuals with T2D contribute to these phenotypes. We identify VPS39 as an important regulator of myoblast differentiation and muscle glucose uptake, and VPS39 is downregulated in myoblasts and myotubes from individuals with T2D. We discover a pathway connecting VPS39-deficiency in human myoblasts to impaired autophagy, abnormal epigenetic reprogramming, dysregulation of myogenic regulators, and perturbed differentiation. VPS39 knockdown in human myoblasts has profound effects on autophagic flux, insulin signaling, epigenetic enzymes, DNA methylation and expression of myogenic regulators, and gene sets related to the cell cycle, muscle structure and apoptosis. These data mimic what is observed in myoblasts from individuals with T2D. Furthermore, the muscle of Vps39 mice display reduced glucose uptake and altered expression of genes regulating autophagy, epigenetic programming, and myogenesis. Overall, VPS39-deficiency contributes to impaired muscle differentiation and reduced glucose uptake. VPS39 thereby offers a therapeutic target for T2D.
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http://dx.doi.org/10.1038/s41467-021-22068-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065135PMC
April 2021

Replication of DNA Methylation Variation Reported in Cord Blood Samples From GDM-Affected Pregnancies in Preadolescent and Adolescent Offspring of Women With GDM.

Diabetes Care 2021 05 8;44(5):e87-e88. Epub 2021 Mar 8.

Translational Type 2 Diabetes Research, Steno Diabetes Center Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.2337/dc21-0248DOI Listing
May 2021

Relationship between insulin sensitivity and gene expression in human skeletal muscle.

BMC Endocr Disord 2021 Feb 27;21(1):32. Epub 2021 Feb 27.

Department of Clinical Sciences, Diabetes & Endocrinology, Lund University, University Hospital Malmö, SE-20502, Malmö, Sweden.

Background: Insulin resistance (IR) in skeletal muscle is a key feature of the pre-diabetic state, hypertension, dyslipidemia, cardiovascular diseases and also predicts type 2 diabetes. However, the underlying molecular mechanisms are still poorly understood.

Methods: To explore these mechanisms, we related global skeletal muscle gene expression profiling of 38 non-diabetic men to a surrogate measure of insulin sensitivity, i.e. homeostatic model assessment of insulin resistance (HOMA-IR).

Results: We identified 70 genes positively and 110 genes inversely correlated with insulin sensitivity in human skeletal muscle, identifying autophagy-related genes as positively correlated with insulin sensitivity. Replication in an independent study of 9 non-diabetic men resulted in 10 overlapping genes that strongly correlated with insulin sensitivity, including SIRT2, involved in lipid metabolism, and FBXW5 that regulates mammalian target-of-rapamycin (mTOR) and autophagy. The expressions of SIRT2 and FBXW5 were also positively correlated with the expression of key genes promoting the phenotype of an insulin sensitive myocyte e.g. PPARGC1A.

Conclusions: The muscle expression of 180 genes were correlated with insulin sensitivity. These data suggest that activation of genes involved in lipid metabolism, e.g. SIRT2, and genes regulating autophagy and mTOR signaling, e.g. FBXW5, are associated with increased insulin sensitivity in human skeletal muscle, reflecting a highly flexible nutrient sensing.
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http://dx.doi.org/10.1186/s12902-021-00687-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912896PMC
February 2021

One-year intensive lifestyle intervention and improvements in health-related quality of life and mental health in persons with type 2 diabetes: a secondary analysis of the U-TURN randomized controlled trial.

BMJ Open Diabetes Res Care 2021 01;9(1)

Department of Public Health, University of Copenhagen, Copenhagen, Denmark.

Introduction: The effects of lifestyle interventions in persons with type 2 diabetes (T2D) on health-related quality of life (HRQoL) and subjective well-being are ambiguous, and no studies have explored the effect of exercise interventions that meet or exceed current recommended exercise levels. We investigated whether a 1-year intensive lifestyle intervention is superior in improving HRQoL compared with standard care in T2D persons.

Research Design And Methods: We performed secondary analyses of a previously conducted randomized controlled trial (April 2015 to August 2016). Persons with non-insulin-dependent T2D (duration ≤10 years) were randomized to 1-year supervised exercise and individualized dietary counseling (ie, 'U-TURN'), or standard care. The primary HRQoL outcome was change in the 36-item Short Form Health Survey (SF-36) physical component score (PCS) from baseline to 12 months of follow-up, and a key secondary outcome was changes in the SF-36 mental component score (MCS).

Results: We included 98 participants (U-TURN group=64, standard care group=34) with a mean age of 54.6 years (SD 8.9). Between-group analyses at 12-month follow-up showed SF-36 PCS change of 0.8 (95% CI -0.7 to 2.3) in the U-TURN group and deterioration of 2.4 (95% CI -4.6 to -0.1) in the standard care group (difference of 3.2, 95% CI 0.5 to 5.9, p=0.02) while no changes were detected in SF-36 MCS. At 12 months, 19 participants (30%) in the U-TURN group and 6 participants (18%) in the standard care group achieved clinically significant improvement in SF-36 PCS score (adjusted risk ratio 2.6, 95% CI 1.0 to 4.5 corresponding to number needed to treat of 4, 95% CI 1.6 to infinite).

Conclusion: In persons with T2D diagnosed for less than 10 years, intensive lifestyle intervention improved the physical component of HRQoL, but not the mental component of HRQoL after 1 year, compared with standard care.

Trial Registration Number: NCT02417012.
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http://dx.doi.org/10.1136/bmjdrc-2020-001840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812095PMC
January 2021

Lifestyle Intervention in Pregnant Women With Obesity Impacts Cord Blood DNA Methylation, Which Associates With Body Composition in the Offspring.

Diabetes 2021 04 11;70(4):854-866. Epub 2021 Jan 11.

Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden

Maternal obesity may lead to epigenetic alterations in the offspring and might thereby contribute to disease later in life. We investigated whether a lifestyle intervention in pregnant women with obesity is associated with epigenetic variation in cord blood and body composition in the offspring. Genome-wide DNA methylation was analyzed in cord blood from 208 offspring from the Treatment of Obese Pregnant women (TOP)-study, which includes pregnant women with obesity randomized to lifestyle interventions comprised of physical activity with or without dietary advice versus control subjects (standard of care). DNA methylation was altered at 379 sites, annotated to 370 genes, in cord blood from offspring of mothers following a lifestyle intervention versus control subjects (false discovery rate [FDR] <5%) when using the Houseman reference-free method to correct for cell composition, and three of these sites were significant based on Bonferroni correction. These 370 genes are overrepresented in gene ontology terms, including response to fatty acids and adipose tissue development. Offspring of mothers included in a lifestyle intervention were born with more lean mass compared with control subjects. Methylation at 17 sites, annotated to, for example, , , , and , partially mediates the effect of the lifestyle intervention on lean mass in the offspring (FDR <5%). Moreover, 22 methylation sites were associated with offspring BMI scores during the first 3 years of life ( < 0.05). Overall, lifestyle interventions in pregnant women with obesity are associated with epigenetic changes in offspring, potentially influencing the offspring's lean mass and early growth.
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http://dx.doi.org/10.2337/db20-0487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980200PMC
April 2021

Impact of prolonged fasting on insulin secretion, insulin action, and hepatic versus whole body insulin secretion disposition indices in healthy young males.

Am J Physiol Endocrinol Metab 2021 02 7;320(2):E281-E290. Epub 2020 Dec 7.

Steno Diabetes Center Copenhagen, Gentofte, Denmark.

The extent to which reduced insulin secretion during prolonged fasting reflects failure to compensate for whole body insulin resistance or a normal adjustment to potentially increased hepatic insulin action is unknown. We examined the effects of 36- versus 12-h fasting on insulin secretion and whole body versus hepatic insulin action in 13 healthy young males. Hepatic glucose production and insulin action were studied using stable isotopes, whereas whole body insulin action and insulin secretion were studied using an intravenous glucose tolerance test (IVGTT) and minimal modeling. Insulin, glucose, and lipid profiles were subsequently measured during a refeeding meal test. Prolonged fasting caused a minor reduction of first-phase insulin secretion in a context of improved hepatic insulin action, contrasting an increase in whole body insulin resistance. Accordingly, prolonged fasting was associated with opposite-directed effects on hepatic versus whole body insulin secretion disposition indices. Thirty-six-hour fasting compared with 12-h fasting was associated with increased serum insulin levels during the refeeding meal test. In conclusion, reduced insulin secretion during prolonged fasting may represent a healthy response to improved hepatic insulin action. Use of insulin secretion disposition indices without taking organ-specific insulin action into account may lead to erroneous conclusions. Thirty-six-hour prolonged, compared with 12-h overnight fasting, is associated with slightly reduced first-phase insulin secretion in the face of opposite-directed changes in hepatic versus whole body insulin action in healthy young males. The paradoxical finding of increased hepatic versus decreased whole body insulin secretion disposition indices during prolonged fasting challenges the physiological understanding and validity of insulin secretion disposition indices not taking organ-specific insulin action into account.
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http://dx.doi.org/10.1152/ajpendo.00433.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260368PMC
February 2021

Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes.

Sci Transl Med 2020 09;12(561)

Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University Hospital, 214 28 Malmö, Sweden.

Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin. We explored whether blood-based epigenetic markers could discriminate metformin response and tolerance by analyzing genome-wide DNA methylation in drug-naïve patients with T2D at the time of their diagnosis. DNA methylation of 11 and 4 sites differed between glycemic responders/nonresponders and metformin-tolerant/intolerant patients, respectively, in discovery and replication cohorts. Greater methylation at these sites associated with a higher risk of not responding to or not tolerating metformin with odds ratios between 1.43 and 3.09 per 1-SD methylation increase. Methylation risk scores (MRSs) of the 11 identified sites differed between glycemic responders and nonresponders with areas under the curve (AUCs) of 0.80 to 0.98. MRSs of the 4 sites associated with future metformin intolerance generated AUCs of 0.85 to 0.93. Some of these blood-based methylation markers mirrored the epigenetic pattern in adipose tissue, a key tissue in diabetes pathogenesis, and genes to which these markers were annotated to had biological functions in hepatocytes that altered metformin-related phenotypes. Overall, we could discriminate between glycemic responders/nonresponders and participants tolerant/intolerant to metformin at diagnosis by measuring blood-based epigenetic markers in drug-naïve patients with T2D. This epigenetics-based tool may be further developed to help patients with T2D receive optimal therapy.
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http://dx.doi.org/10.1126/scitranslmed.aaz1803DOI Listing
September 2020

Effects of an intensive lifestyle intervention on the underlying mechanisms of improved glycaemic control in individuals with type 2 diabetes: a secondary analysis of a randomised clinical trial.

Diabetologia 2020 11 20;63(11):2410-2422. Epub 2020 Aug 20.

The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.

Aims/hypothesis: The aim was to investigate whether an intensive lifestyle intervention, with high volumes of exercise, improves beta cell function and to explore the role of low-grade inflammation and body weight.

Methods: This was a randomised, assessor-blinded, controlled trial. Ninety-eight individuals with type 2 diabetes (duration <10 years), BMI of 25-40 kg/m, no use of insulin and taking fewer than three glucose-lowering medications were randomised (2:1) to either the standard care plus intensive lifestyle group or the standard care alone group. Standard care consisted of individual guidance on disease management, lifestyle advice and blinded regulation of medication following a pre-specified algorithm. The intensive lifestyle intervention consisted of aerobic exercise sessions that took place 5-6 times per week, combined with resistance exercise sessions 2-3 times per week, with a concomitant dietary intervention aiming for a BMI of 25 kg/m. In this secondary analysis beta cell function was assessed from the 2 h OGTT-derived disposition index, which is defined as the product of the Matsuda and the insulinogenic indices.

Results: At baseline, individuals were 54.8 years (SD 8.9), 47% women, type 2 diabetes duration 5 years (IQR 3-8) and HbA was 49.3 mmol/mol (SD 9.2); 6.7% (SD 0.8). The intensive lifestyle group showed 40% greater improvement in the disposition index compared with the standard care group (ratio of geometric mean change [RGM] 1.40 [95% CI 1.01, 1.94]) from baseline to 12 months' follow-up. Plasma concentration of IL-1 receptor antagonist (IL-1ra) decreased 30% more in the intensive lifestyle group compared with the standard care group (RGM 0.70 [95% CI 0.58, 0.85]). Statistical single mediation analysis estimated that the intervention effect on the change in IL-1ra and the change in body weight explained to a similar extent (59%) the variance in the intervention effect on the disposition index.

Conclusions/interpretation: Our findings show that incorporating an intensive lifestyle intervention, with high volumes of exercise, in individuals with type 2 diabetes has the potential to improve beta cell function, associated with a decrease in low-grade inflammation and/or body weight.

Trial Registration: ClinicalTrials.gov NCT02417012 Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05249-7DOI Listing
November 2020

Prediction of carotid intima-media thickness and its relation to cardiovascular events in persons with type 2 diabetes.

J Diabetes Complications 2020 10 18;34(10):107681. Epub 2020 Jul 18.

Department of Research, Nordsjaellands Hospital, Hilleroed, Denmark; Steno Diabetes Center Sjaelland, Holbaek, Denmark. Electronic address:

Aims: To investigate measures of carotid intima-media thickness (IMT) and conventional cardiovascular (CV) risk factors as predictors of future carotid IMT, and the prediction of CV events during follow-up based on measures of carotid IMT.

Methods: Observational longitudinal study including 230 persons with type 2 diabetes (T2D).

Results: Mean age at follow-up was 66.7 (SD 8.5) years, 30.5% were women and mean body mass index (BMI) was 31.8 (4.4) kg/m. Carotid IMT was measured at baseline, after 18 months of intervention in the Copenhagen Insulin and Metformin Therapy (CIMT) trial and after a mean follow-up of 6.4 (1.0) years. Baseline carotid IMT, carotid IMT after 18 months' intervention, and CV risk factors (age, sex and baseline systolic blood pressure) gave the best prediction of carotid IMT (root mean-squared error of prediction of 0.106 and 95% prediction error probability interval of -0.160, 0.204).

Conclusions: Measures of carotid IMT combined with CV risk factors at baseline predicts attained carotid IMT better than measures of carotid IMT or CV risk factors alone. Carotid IMT did not predict CV events, and the present results do not support the use of carotid IMT as a predictor of CV events in persons with T2D.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107681DOI Listing
October 2020

Early glycemic changes after initiation of oral anti-diabetic medication and risk of major adverse cardiovascular events: results from a large primary care population of patients with type 2 diabetes.

Eur Heart J Cardiovasc Pharmacother 2020 Jul 2. Epub 2020 Jul 2.

Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Aims: To determine the risk of major cardiovascular events (MACE) and death, associated with an early large and rapid decline in HbA1C following first time initiation of an oral antidiabetic drug (OAD).

Methods And Results: We included 10,518 primary care patients with T2D, who initiated an OAD for the first time. For each individual, we measured a decline in HbA1C, as the difference between the pre-treatment HbA1C (within 3 months before OAD initiation) and the post-treatment HbA1C (within 1.5-4.5 months after OAD initiation), divided by the time between the two measurements. The decline was reported in mmol/mol change per 3 months in HbA1C and categorized by the median decline into levels of steep (≥ 9 mmol/mol [≥ 0.8%]) and flat decline (< 9 mmol/mol per 3 mo. [< 0.8%]). Pre-treatment HbA1C was categorized by the median, into levels of low (48-62 mmol/mol) and high (> 62 mmol/mol). Multiple Cox regression was used to study the effect of decline (steep vs. flat) on the outcome hazard rates separately for patients with low and high pre-treatment HbA1C. Analyses were adjusted for age, sex, traditional cardiovascular risk factors, severe comorbidities, and concomitant medication treatment. During a median follow-up time of 7.7 years, 1,625 developed MACE and 2,323 died. We found that a steep decline vs. a flat decline was significantly associated with a decreased hazard for MACE, both in individuals with high (HR 0.81; 95% CI 0.69-0.94; P = 0.005) and low pre-treatment HbA1C (HR 0.79; 95% CI 0.66-0.96; P = 0.015). The hazard of MACE was more pronounced on the short-term vs. long-term in individuals with high pre-treatment HbA1C. We found no significant association between combinations of pre-treatment HbA1C and decline categories and hazard of all-cause mortality. However, a combination of a low pre-treatment HbA1C and steep decline was associated with increased 1-year mortality (HR 1.52; 95% CI 1.00-2.29; P = 0.048) and hypoglycemia (HR 1.82; 95% CI 1.11-2.98; P = 0.017).

Conclusion: A combination of a high pre-treatment HbA1C and a steep decline in HbA1C was associated with a decreased short-term risk of MACE. A low pre-treatment HbA1C and a steep decline was associated with a long-term reduced risk of MACE, but a short-term increased risk of death and hypoglycaemia.
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http://dx.doi.org/10.1093/ehjcvp/pvaa072DOI Listing
July 2020

Dyslipidemia at diagnosis of childhood acute lymphoblastic leukemia.

PLoS One 2020 6;15(4):e0231209. Epub 2020 Apr 6.

Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.

As survival of acute lymphoblastic leukemia (ALL) exceeds 90%, limiting therapy-related toxicity has become a key challenge. Cardio-metabolic dysfunction is a challenge during and after childhood ALL therapy. In a single center study, we measured triglycerides (TG), total cholesterol (TC), high (HDL) and low density lipoproteins (LDL) levels at diagnosis and assessed the association with BMI, early therapy response, on-therapy hyperlipidemia and the toxicities; thromboembolism, osteonecrosis and pancreatitis. We included 127 children (1.0-17.9 years) all treated according to the NOPHO ALL2008 protocol. Dyslipidemia was identified at ALL-diagnosis in 99% of the patients, dominated by reduced HDL levels (98%) and mild hypertriglyceridemia (61%). Hypertriglyceridemia was not associated with body mass index (P = 0.71). Five percent of patients had mild hypercholesterolemia, 14% had mild hypocholesterolemia, 13% had decreased and 1% elevated LDL-levels. Increased TG and TC levels at ALL-diagnosis were not associated with any on-therapy lipid levels. Lipid levels and BMI were not associated to MRD after induction therapy; However, BMI and hypercholesterolemia were associated with worse risk group stratification (P<0.045 for all). The cumulative incidence of thromboembolism was increased both for patients with hypo- (20.0%) and hypercholesterolemia (16.7%) compared to patients with normal TC levels (2.2%) at diagnosis (P = 0.0074). In conclusion, dyslipidemic changes were present prior to ALL-therapy in children with ALL but did not seem to affect dysmetabolic traits during therapy and were not predictive of on-therapy toxicities apart from an association between dyscholesterolemia at time of ALL-diagnosis and risk of thromboembolism. However, the latter should be interpreted with caution due to low number in the groups.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231209PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135240PMC
July 2020

Lactation Duration and Long-term Risk for Incident Type 2 Diabetes in Women With a History of Gestational Diabetes Mellitus.

Diabetes Care 2020 04 10;43(4):793-798. Epub 2020 Feb 10.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD

Objective: We examined the association of lactation duration with incident type 2 diabetes among women with a history of gestational diabetes mellitus (GDM).

Research Design And Methods: We monitored 4,372 women with a history of GDM participating in the Nurses' Health Study II for incident type 2 diabetes over 25 years up to 2017. Lactation history was obtained through follow-up questionnaires to calculate lactation duration. Follow-up blood samples were collected from a subset of these women at median age of 58 years through the Diabetes & Women's Health Study.

Results: We documented 873 incident cases of type 2 diabetes during 87,411 person-years of follow-up. Longer duration of lactation was associated with lower risk of type 2 diabetes for both total lactation (hazard ratio 1.05 [95% CI 0.83-1.34] for up to 6 months, 0.91 [0.72-1.16] for 6-12 months, 0.85 [0.67-1.06] for 12-24 months, and 0.73 [0.57-0.93] for >24 months, compared with 0 months; -trend = 0.003) and exclusive breastfeeding (-trend = 0.002) after adjustment for age, ethnicity, family history of diabetes, parity, age at first birth, smoking, diet quality, physical activity, and prepregnancy BMI. Longer duration of lactation was also associated with lower HbA, fasting plasma insulin, and C-peptide concentrations among women without type 2 diabetes at follow-up (all adjusted -trend ≤0.04).

Conclusions: Longer duration of lactation is associated with a lower risk of type 2 diabetes and a favorable glucose metabolic biomarker profile among women with a history of GDM. The underlying mechanisms and impact on diabetes complications, morbidity, and mortality remain to be determined.
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http://dx.doi.org/10.2337/dc19-2237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085808PMC
April 2020

Dose-Response Effects of Exercise on Glucose-Lowering Medications for Type 2 Diabetes: A Secondary Analysis of a Randomized Clinical Trial.

Mayo Clin Proc 2020 03 30;95(3):488-503. Epub 2020 Jan 30.

Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Objective: To investigate whether a dose-response relationship exists between volume of exercise and discontinuation of glucose-lowering medication treatment in patients with type 2 diabetes.

Patients And Methods: Secondary analyses of a randomized controlled exercise-based lifestyle intervention trial (April 29, 2015 to August 17, 2016). Patients with non-insulin-dependent type 2 diabetes were randomly assigned to an intensive lifestyle intervention (U-TURN) or standard-care group. Both groups received lifestyle advice and objective target-driven medical regulation. Additionally, the U-TURN group received supervised exercise and individualized dietary counseling. Of the 98 randomly assigned participants, 92 were included in the analysis (U-TURN, n=61, standard care, n=31). Participants in the U-TURN group were stratified into tertiles based on accumulated volumes of exercise completed during the 1-year intervention.

Results: Median exercise levels of 178 (interquartile range [IQR], 121-213; lower tertile), 296 (IQR, 261-310; intermediate tertile), and 380 minutes per week (IQR, 355-446; upper tertile) were associated with higher odds of discontinuing treatment with glucose-lowering medication, with corresponding odds ratios of 12.1 (95% CI, 1.2-119; number needed to treat: 4), 30.2 (95% CI, 2.9-318.5; 3), and 34.4 (95% CI, 4.1-290.1; 2), respectively, when comparing with standard care. Cardiovascular risk factors such as glycated hemoglobin A levels, fitness, 2-hour glucose levels, and triglyceride levels were improved significantly in the intermediate and upper tertiles, but not the lower tertile, compared with the standard-care group.

Conclusion: Exercise volume is associated with discontinuation of glucose-lowering medication treatment in a dose-dependent manner, as are important cardiovascular risk factors in well-treated participants with type 2 diabetes and disease duration less than 10 years. Further studies are needed to support these findings.

Study Registration: ClinicalTrials.gov registration (NCT02417012).
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http://dx.doi.org/10.1016/j.mayocp.2019.09.005DOI Listing
March 2020

Nut Consumption and Renal Function Among Women With a History of Gestational Diabetes.

J Ren Nutr 2020 09 17;30(5):415-422. Epub 2020 Jan 17.

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. Electronic address:

Objective: Nut intake has been associated with reduced cardiometabolic risk, but few studies have examined its association with renal function. We examined associations between nut intake and renal function among women with previous gestational diabetes mellitus (GDM), a population with an increased risk for renal dysfunction.

Design And Methods: This study included 607 women with a history of GDM who participated in the Diabetes & Women's Health Study (2012-2014) follow-up clinical examination in Denmark. At the clinic, biospecimens were collected, and habitual intake of nuts (9 types) in the past year was assessed using a food frequency questionnaire. A total of 330 women free of major chronic diseases were included in the analysis. Total nut intake was classified as none (≤1 serving/month), monthly (2-3 servings/month), weekly (1-6 servings/week), and daily (≥1 serving/day). One serving was defined as 28 g. Renal function markers included estimated glomerular rate (eGFR) and urinary albumin-to-creatinine ratio (UACR), calculated based on plasma creatinine (mg/dL), and urinary albumin (mg/L), and creatinine (mg/dL) measurements, respectively. We estimated percent differences with 95% confidence intervals for each outcome by nut intake, adjusted for current body mass index, age, physical activity, energy intake, alcohol consumption, and vegetables intake.

Results: We observed a nonlinear association between total nut intake and UACR with lowest UACR values among women with weekly intake. Compared to women with weekly intake (n = 222), the adjusted UACR values were higher by 86% [95% confidence interval: 15%, 202%], 24% [-1%, 54%], and 117% [22%, 288%] among women with no (n = 13), monthly (n = 86), and daily (n = 9) intake, respectively. Compared to weekly consumers, daily nut consumers also had 9% [0%, 19%] significantly higher eGFR values, but eGFR values were similar among women with no and monthly intake.

Conclusion: Moderate nut consumption may be beneficial to kidney health among women with prior GDM.
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http://dx.doi.org/10.1053/j.jrn.2019.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365752PMC
September 2020

Genetic factors and risk of type 2 diabetes among women with a history of gestational diabetes: findings from two independent populations.

BMJ Open Diabetes Res Care 2020 01;8(1)

Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA

Objective: Women with a history of gestational diabetes mellitus (GDM) have an exceptionally high risk for type 2 diabetes (T2D). Yet, little is known about genetic determinants for T2D in this population. We examined the association of a genetic risk score (GRS) with risk of T2D in two independent populations of women with a history of GDM and how this association might be modified by non-genetic determinants for T2D.

Research Design And Methods: This cohort study included 2434 white women with a history of GDM from the Nurses' Health Study II (NHSII, n=1884) and the Danish National Birth Cohort (DNBC, n=550). A GRS for T2D was calculated using 59 candidate single nucleotide polymorphisms for T2D identified from genome-wide association studies in European populations. An alternate healthy eating index (AHEI) score was derived to reflect dietary quality after the pregnancy affected by GDM.

Results: Women on average were followed for 21 years in NHSII and 13 years in DNBC, during which 446 (23.7%) and 155 (28.2%) developed T2D, respectively. The GRS was generally positively associated with T2D risk in both cohorts. In the pooled analysis, the relative risks (RRs) for increasing quartiles of GRS were 1.00, 0.97, 1.25 and 1.19 (p trend=0.02). In both cohorts, the association appeared to be stronger among women with poorer (AHEI
Conclusions: Among white women with a history of GDM, higher GRS for T2D was associated with an increased risk of T2D.
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http://dx.doi.org/10.1136/bmjdrc-2019-000850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039588PMC
January 2020

Abdominal fat distribution measured by ultrasound and aerobic fitness in young Danish men born with low and normal birth weight.

Obes Res Clin Pract 2019 Nov - Dec;13(6):529-532. Epub 2019 Nov 19.

Steno Diabetes Center, Gentofte, Denmark; Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark. Electronic address:

Abdominal subcutaneous and visceral adipose tissue thickness was examined by ultrasound in 17 men with low birth weight (LBW) and 26 with normal BW control individuals to determine if abdominal obesity in LBW individuals is due to increased visceral or subcutaneous fat mass/thickness, or both. Men born with LBW had an increased waist-to-hip ratio (P = 0.04), greater abdominal fat thickness (P = 0.05) and increased visceral (VAT) and subcutaneous adipose tissue (SAT) thickness compared with controls, however the latter not statistically significant (P = 0.08, P = 0.10). A significant difference between birth weight groups in both SAT (P = 0.04) and VAT (P = 0.03) was found after adjustment for weight, whereas no significant difference in either SAT (P = 0.93) or VAT (P = 0.30) was found after adjustment for BMI. Increased waist-to-hip ratio in LBW individuals is due to increased total abdominal fat including both subcutaneous and visceral fat.
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http://dx.doi.org/10.1016/j.orcp.2019.10.008DOI Listing
July 2020

Increased leptin, decreased adiponectin and FGF21 concentrations in adolescent offspring of women with gestational diabetes.

Eur J Endocrinol 2019 Dec;181(6):691-700

Department of Endocrinology, Diabetes and Bone-metabolic Research Unit, Rigshospitalet, Copenhagen, Denmark.

Objective: Fetal exposure to gestational diabetes mellitus (GDM) increases the risk of metabolic diseases in the offspring. Leptin, adiponectin, and fibroblast growth factor 21 (FGF21) may play potential roles in the underlying disease mechanisms. We investigated the impact of fetal exposure to GDM on leptin, adiponectin, and FGF21 concentrations and their associations with measures of adiposity and metabolic traits during childhood/adolescence.

Design And Methods: The follow-up study included 504 GDM and 540 control offspring aged 9-16 from the Danish National Birth Cohort. Anthropometric measurements, fasting blood samples, puberty status and fat percentages by dual-energy X-ray absorptiometry were examined. Serum concentrations of leptin, adiponectin, and FGF21 were measured by validated immune assays.

Results: GDM offspring had 38% (95% CI: 22-55%) higher leptin, 0.6 mg/L (95% CI: -1.2, -0.04 mg/L) lower adiponectin, and 32% (95% CI: -47%, -12%) lower FGF21 concentrations than control offspring (P < 0.05). After adjustment for confounders including maternal pre-pregnancy BMI, GDM offspring had borderline higher leptin (P = 0.06) and significantly lower FGF21 concentrations (P = 0.006). When accounting for offspring BMI z-score, GDM exposure had no significant independent effect on leptin or adiponectin concentrations, whereas FGF21 was still significant. In univariate analyses, leptin and adiponectin were associated with fasting insulin, HOMA-IR, and adiposity, and FGF21 with total fat percentage.

Conclusions: GDM offspring had higher leptin, lower adiponectin and FGF21 concentrations than control offspring. Elevated leptin and decreased adiponectin concentrations associated with adverse metabolic traits and were most likely driven by higher obesity prevalence among GDM offspring. The functional implications of decreased FGF21 concentrations among GDM offspring need to be further explored.
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http://dx.doi.org/10.1530/EJE-19-0658DOI Listing
December 2019

Epigenome- and Transcriptome-wide Changes in Muscle Stem Cells from Low Birth Weight Men.

Endocr Res 2020 Feb 30;45(1):58-71. Epub 2019 Sep 30.

Department of Endocrinology, Diabetes and Bone-metabolic Research Unit, Copenhagen, Denmark.

: Being born with low birth weight (LBW) is a risk factor for muscle insulin resistance and type 2 diabetes (T2D), which may be mediated by epigenetic mechanisms programmed by the intrauterine environment. Epigenetic mechanisms exert their prime effects in developing cells. We hypothesized that muscle insulin resistance in LBW subjects may be due to early differential epigenomic and transcriptomic alterations in their immature muscle progenitor cells.: Muscle progenitor cells were obtained from 23 healthy young adult men born at term with LBW, and 15 BMI-matched normal birth weight (NBW) controls. The cells were subsequently cultured and differentiated into myotubes. DNA and RNA were harvested before and after differentiation for genome-wide DNA methylation and RNA expression measurements.After correcting for multiple comparisons (q ≤ 0.05), 56 CpG sites were found to be significantly, differentially methylated in myoblasts from LBW compared with NBW men, of which the top five gene-annotated CpG sites () previously have been associated to regulation of cholesterol, fatty acid and glucose metabolism and muscle development or hypertrophy. LBW men displayed markedly decreased myotube gene expression levels of the AMPK-repressing tyrosine kinase gene and the histone deacetylase gene . Silencing of and was associated with impaired myotube formation, which for reduced muscle glucose uptake.: The data provides evidence of impaired muscle development predisposing LBW individuals to T2D is linked to and potentially caused by distinct DNA methylation and transcriptional changes including down regulation of and in their immature myoblast stem cells.
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http://dx.doi.org/10.1080/07435800.2019.1669160DOI Listing
February 2020

Associations between ambient air pollution and noise from road traffic with blood pressure and insulin resistance in children from Denmark.

Environ Epidemiol 2019 Oct 30;3(5):e069. Epub 2019 Sep 30.

Department of Epidemiology Research, Centre for Fetal Programming, Statens Serum Institute, Copenhagen, Denmark.

Background: Road traffic is a major source of air pollution and noise. Both exposures may contribute to increased blood pressure and metabolic disease; however, few studies have examined these relationships in children.

Objectives: We aimed to investigate whether long-term exposures to air pollution and noise from road traffic were associated with increased blood pressure and insulin resistance in children.

Methods: Cardiometabolic outcomes were derived from a follow-up examination of 629 children (10-15 years old) enrolled in the Danish National Birth Cohort. We evaluated associations with prenatal and postnatal residential exposure to nitrogen dioxide (NO) and noise from road traffic (L) using historical addresses and linear regression models.

Results: A 10-unit increase in postnatal exposure to NO and L was associated with a 0.31 (-0.87, 1.48) and 0.18 (-0.61, 0.96) mmHg changes in diastolic blood pressure, respectively. In contrast, both exposures were associated with decreased systolic blood pressure. After adjustment and mutual adjustment for NO, exposure to L was associated with a statistical significant decrease in systolic blood pressure both during prenatal and postnatal life, but the majority of the associations evaluated did not reach statistical significance. Inverse associations were observed for plasma fasting glucose, insulin, and HOMA of insulin resistance for both exposures, exposure windows, before and after adjustment.

Conclusions: The findings do not support evidence of associations between long-term exposures to air pollution and road traffic noise, increased blood pressure, and a metabolic profile characteristic of increased risk for glucose intolerance or type 2 diabetes later in life.
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http://dx.doi.org/10.1097/EE9.0000000000000069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939405PMC
October 2019

Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study.

Diabetes 2019 12 10;68(12):2315-2326. Epub 2019 Sep 10.

MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical Medicine, University of Cambridge, Cambridge, U.K.

Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to , , and ). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs and found one MVP, cg00574958 at , with a possible direct causal role in T2DM. None of the implicated genes were previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.
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http://dx.doi.org/10.2337/db18-0290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868468PMC
December 2019

Fasting unmasks differential fat and muscle transcriptional regulation of metabolic gene sets in low versus normal birth weight men.

EBioMedicine 2019 Sep 19;47:341-351. Epub 2019 Aug 19.

Department of Clinical Sciences, Epigenetics and Diabetes Unit, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden. Electronic address:

Background: Individuals born with low birth weight (LBW) have an increased risk of metabolic diseases when exposed to diets rich in calories and fat but may respond to fasting in a metabolically preferential manner. We hypothesized that impaired foetal growth is associated with differential regulation of gene expression and epigenetics in metabolic tissues in response to fasting in young adulthood.

Methods: Genome-wide expression and DNA methylation were analysed in subcutaneous adipose tissue (SAT) and skeletal muscle from LBW and normal birth weight (NBW) men after 36 h fasting and after an isocaloric control study using microarrays.

Findings: Transcriptome analyses revealed that expression of genes involved in oxidative phosphorylation (OXPHOS) and other key metabolic pathways were lower in SAT from LBW vs NBW men after the control study, but paradoxically higher in LBW vs NBW men after 36 h fasting. Thus, fasting was associated with downregulated OXPHOS and metabolic gene sets in NBW men only. Likewise, in skeletal muscle only NBW men downregulated OXPHOS genes with fasting. Few epigenetic changes were observed in SAT and muscle between the groups.

Interpretation: Our results provide insights into the molecular mechanisms in muscle and adipose tissue governing a differential metabolic response in subjects with impaired foetal growth when exposed to fasting in adulthood. The results support the concept of developmental programming of metabolic diseases including type 2 diabetes. FUND: The Swedish Research Council, the Danish Council for Strategic Research, the Novo Nordisk foundation, the Swedish Foundation for Strategic Research, The European Foundation for the Study of Diabetes, The EU 6th Framework EXGENESIS grant and Rigshospitalet.
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http://dx.doi.org/10.1016/j.ebiom.2019.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796584PMC
September 2019

Type 2 diabetes remission 1 year after an intensive lifestyle intervention: A secondary analysis of a randomized clinical trial.

Diabetes Obes Metab 2019 10 30;21(10):2257-2266. Epub 2019 Jun 30.

Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Aim: To investigate whether an intensive lifestyle intervention induces partial or complete type 2 diabetes (T2D) remission.

Materials And Methods: In a secondary analysis of a randomized, assessor-blinded, single-centre trial, people with non-insulin-dependent T2D (duration <10 years), were randomly assigned (2:1, stratified by sex, from April 2015 to August 2016) to a lifestyle intervention group (n = 64) or a standard care group (n = 34). The primary outcome was partial or complete T2D remission, defined as non-diabetic glycaemia with no glucose-lowering medication at the outcome assessments at both 12 and 24 months from baseline. All participants received standard care, with standardized, blinded, target-driven medical therapy during the initial 12 months. The lifestyle intervention included 5- to 6-weekly aerobic and combined aerobic and strength training sessions (30-60 minutes) and individual dietary plans aiming for body mass index ≤25 kg/m . No intervention was provided during the 12-month follow-up period.

Results: Of the 98 randomized participants, 93 completed follow-up (mean [SD] age 54.6 [8.9] years; 46 women [43%], mean [SD] baseline glycated haemoglobin 49.3 [9.3] mmol/mol). At follow-up, 23% of participants (n = 14) in the intervention and 7% (n = 2) in the standard care group met the criteria for any T2D remission (odds ratio [OR] 4.4, 95% confidence interval [CI] 0.8-21.4]; P = 0.08). Assuming participants lost to follow-up (n = 5) had relapsed, the OR for T2D remission was 4.4 (95% CI 1.0-19.8; P = 0.048).

Conclusions: The statistically nonsignificant threefold increased remission rate of T2D in the lifestyle intervention group calls for further large-scale studies to understand how to implement sustainable lifestyle interventions among people with T2D.
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http://dx.doi.org/10.1111/dom.13802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6772176PMC
October 2019

Diabetes & Women's Health (DWH) Study: an observational study of long-term health consequences of gestational diabetes, their determinants and underlying mechanisms in the USA and Denmark.

BMJ Open 2019 05 1;9(4):e025517. Epub 2019 May 1.

Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.

Purpose: Women who experience gestational diabetes mellitus (GDM) are at exceptionally high-risk of developing type 2 diabetes (T2DM) later in life. However, limited information is available about genetic and environmental factors that are implicated in the progression from GDM to T2DM.

Participants: The Diabetes & Women's Health (DWH) Study applied a hybrid design, which combined new prospective data collection with existing data in two prospective cohorts, the Danish National Birth Cohort (DNBC) and the Nurses' Health Study II (NHS II). In total, the DWH Study identified 7759 women with a GDM diagnosis from both cohorts; 4457 women participated in the DWH Study data collection, which included two cycles of follow-up from 2012 to 2014 and 2014 to 2016.

Findings To Date: Progression from GDM to T2DM was high. In the NHS II group, by 2013, 23.1% (n=846/3667) developed T2DM. In the DNBC group, at cycle 1 (2012-2014), the progression rate was even higher: 27.2% (n=215/790) had developed T2DM. Furthermore, we have shown that women who had GDM experienced a significantly greater risk of hypertension and cardiovascular diseases, as well as early stages of glomerular hyperfiltration and renal damage. Moreover, the DWH Study findings have shown that healthful diet and lifestyle factors and weight control were related to a lower risk of T2DM, hypertension and cardiovascular diseases.

Future Plans: Primary data collection for the DWH Study is complete and investigators are currently investigating interactions of the abovementioned modifiable factors with T2DM genetic susceptibility in determining the risk of progression from GDM to T2DM. Findings from ongoing work will provide further insights for identifying more precise prevention strategies for T2DM and comorbidities in this high-risk population. Future work will examine novel biomarkers of health and disease in this cohort.
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http://dx.doi.org/10.1136/bmjopen-2018-025517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502016PMC
May 2019

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Nat Genet 2019 05 1;51(5):804-814. Epub 2019 May 1.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
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http://dx.doi.org/10.1038/s41588-019-0403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522365PMC
May 2019

Prospective study of gestational diabetes and fatty liver scores 9 to 16 years after pregnancy.

J Diabetes 2019 Nov 12;11(11):895-905. Epub 2019 Jun 12.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Background: Women with gestational diabetes mellitus (GDM) may be at an increased risk of liver complications because chronic hyperglycemia is a risk factor for liver fat accumulation and potential liver dysfunction. Large prospective studies examining liver fat accumulation following a GDM pregnancy are lacking.

Methods: The Diabetes & Women's Health Study (2012-2014) examined the association between GDM and subsequent fatty liver scores among 607 women with and 619 women without GDM in the Danish National Birth Cohort. Nine to 16 years postpartum, a clinical examination was performed, with measurement of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase, from which fatty liver scoring indices were calculated to assess liver fat score, fatty liver index, hepatic steatosis index, and liver fat percentage. Relative risks (RR) with 95% confidence intervals (CI) for elevated liver scoring indices by GDM status were assessed adjusting for major risk factors, including prepregnancy body mass index.

Results: Women with prior GDM had higher adjusted ALT and AST levels than women without GDM (by 6.7% [95% CI 1.7-12.0] and 4.8% [95% CI 0.6-9.1], respectively). Women with GDM also had adjusted increased risks for elevated liver fat score (RR 2.34; 95% CI 1.68-3.27), fatty liver index (RR 1.59; 95% CI 1.27-1.99), and hepatic steatosis index (RR 1.44; 95% CI 1.21-1.71).

Conclusions: Women with GDM during pregnancy were at an increased risk for fatty liver 9 to 16 years postpartum. Gestational diabetes mellitus may serve as another risk indicator for the early identification and prevention of liver fat accumulation.
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http://dx.doi.org/10.1111/1753-0407.12934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791726PMC
November 2019

ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations.

Diabetes 2019 03 9;68(3):502-514. Epub 2019 Jan 9.

Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

The rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacking selectively in skeletal muscle have improved insulin sensitivity. The molecular link between ADAMTS9 and insulin signaling was characterized further in a model where ADAMTS9 was overexpressed in skeletal muscle. This selective overexpression resulted in decreased insulin signaling presumably mediated through alterations of the integrin β1 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondrial function in mouse muscle-an observation found to be of translational character because humans carrying the risk allele have decreased expression of mitochondrial markers. Finally, we found that the link between ADAMTS9 overexpression and impaired insulin signaling could be due to accumulation of harmful lipid intermediates. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS9 as a potential novel mode of treating insulin resistance.
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http://dx.doi.org/10.2337/db18-0418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385758PMC
March 2019

In utero exposure to extra vitamin D from food fortification and the risk of subsequent development of gestational diabetes: the D-tect study.

Nutr J 2018 11 2;17(1):100. Epub 2018 Nov 2.

Research Unit for Dietary Studies at The Parker Institute Bispebjerg and Frederiksberg Hospital, part of the Copenhagen University Hospital - The capital Region, Nordre Fasanvej 57, vej 8, entrance 11, 2000, Frederiksberg, Denmark.

Background: The primary aim of this study was to assess whether exposure during fetal life to extra vitamin D from food fortification was associated with a reduction in the risk of subsequently developing gestational diabetes mellitus (GDM). Furthermore, we examined whether the effect of the vitamin D from fortification differed by women's season of birth.

Methods: This semi-ecological study is based on the cancellation in 1985 of the mandatory policy to fortify margarine with vitamin D in Denmark, with inclusion of entire national adjacent birth cohorts either exposed or unexposed to extra vitamin D in utero. The identification of GDM cases later in life among both exposure groups was based on the Danish national health registers. Logistic regression analyses generating odds ratios (ORs) and 95% confidence intervals (95% CIs) were performed.

Results: Women who were prenatally exposed to the extra vitamin D from fortification tended to have a lower risk of subsequently developing GDM than unexposed women (OR 0.87, 95%CI 0.74,1.02, P = 0.08). When analyses were stratified by women's season of birth, exposed women born in spring had a lower risk of developing GDM compared to unexposed subjects (OR 0.68, 95%CI 0.50,0.94, p = 0.02).

Conclusion: This study suggests that prenatal exposure to extra vitamin D from mandatory fortification may lower the risk of developing gestational diabetes among spring-born women.

Trial Registration: This study is part of the D-tect project, which is registered on clinicaltrials.gov: NCT03330301 .
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http://dx.doi.org/10.1186/s12937-018-0403-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215342PMC
November 2018
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