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Dysregulation of circulating lipids is a central element for the metabolic syndrome. However, it is not well established whether human subcutaneous adipose tissue is affected by or affect circulating lipids through epigenetic mechanisms. Hence, our aim was to investigate the association between circulating lipids and DNA methylation levels in human adipose tissue. DNA methylation and gene expression were analysed genome-wide in subcutaneous adipose tissue from two different cohorts, including 85 men and 93 women, respectively. Associations between DNA methylation and circulating levels of triglycerides, low-density lipoprotein, high-density lipoprotein and total cholesterol were analysed. Causal mediation analyses tested if adipose tissue DNA methylation mediates the effects of triglycerides on gene expression or insulin resistance. We found 115 novel associations between triglycerides and adipose tissue DNA methylation, e.g. in the promoter of RFS1, ARID2 and HOXA5 in the male cohort (P ≤ 1.1 × 10−7), and 63 associations, e.g. within the gene body of PTPRN2 and COL6A3 in the female cohort. We further connected these findings to altered mRNA expression levels in adipose tissue (e.g. HOXA5, IL11 and FAM45B). Interestingly, there was no overlap between methylation sites associated with triglycerides in men and the sites found in women, which points towards sex-specific effects of triglycerides on the epigenome. Finally, a causal mediation analysis provided support for adipose tissue DNA methylation as a partial mediating factor between circulating triglycerides and insulin resistance. This study identified novel epigenetic alterations in adipose tissue associated with circulating lipids. Identified epigenetic changes seem to mediate effects of triglycerides on insulin resistance.

The extent to which increased liver fat content influences differences in circulating metabolites and/or lipids between low-birth-weight (LBW) individuals, at increased risk of type 2 diabetes (T2D), and normal-birth-weight (NBW) controls is unknown. The objective of the study was to perform untargeted serum metabolomics and lipidomics analyses in 26 healthy, non-obese early-middle-aged LBW men, including five men with screen-detected and previously unrecognized non-alcoholic fatty liver disease (NAFLD), compared with 22 age- and BMI-matched NBW men (controls). While four metabolites (out of 65) and fifteen lipids (out of 279) differentiated the 26 LBW men from the 22 NBW controls (p ≤ 0.05), subgroup analyses of the LBW men with and without NAFLD revealed more pronounced differences, with 11 metabolites and 56 lipids differentiating (p ≤ 0.05) the groups. The differences in the LBW men with NAFLD included increased levels of ornithine and tyrosine (PFDR ≤ 0.1), as well as of triglycerides and phosphatidylcholines with shorter carbon-chain lengths and fewer double bonds. Pathway and network analyses demonstrated downregulation of transfer RNA (tRNA) charging, altered urea cycling, insulin resistance, and an increased risk of T2D in the LBW men with NAFLD. Our findings highlight the importance of increased liver fat in the pathogenesis of T2D in LBW individuals. The extent to which increased liver fat content influences differences in circulating metabolites and/or lipids between low-birth-weight (LBW) individuals, at increased risk of type 2 diabetes (T2D), and normal-birth-weight (NBW) controls is unknown. The objective of the study was to perform untargeted serum metabolomics and lipidomics analyses in 26 healthy, non-obese early-middle-aged LBW men, including five men with screen-detected and previously unrecognized non-alcoholic fatty liver disease (NAFLD), compared with 22 age- and BMI-matched NBW men (controls). While four metabolites (out of 65) and fifteen lipids (out of 279) differentiated the 26 LBW men from the 22 NBW controls (p ≤ 0.05), subgroup analyses of the LBW men with and without NAFLD revealed more pronounced differences, with 11 metabolites and 56 lipids differentiating (p ≤ 0.05) the groups. The differences in the LBW men with NAFLD included increased levels of ornithine and tyrosine (PFDR ≤ 0.1), as well as of triglycerides and phosphatidylcholines with shorter carbon-chain lengths and fewer double bonds. Pathway and network analyses demonstrated downregulation of transfer RNA (tRNA) charging, altered urea cycling, insulin resistance, and an increased risk of T2D in the LBW men with NAFLD. Our findings highlight the importance of increased liver fat in the pathogenesis of T2D in LBW individuals.

Background Effective and sustainable implementation of physical activity (PA) in type 2 diabetes (T2D) health care has in general not been successful. Efficacious and contemporary approaches to support PA adherence and adoption are required. Objective The primary objective of this study was to investigate the effectiveness of including an app-based (InterWalk) approach in municipality-based rehabilitation to increase moderate-and-vigorous PA (MVPA) across 52 weeks compared with standard care among individuals with T2D. Methods The study was designed as a parallel-group, randomized trial with 52 weeks’ intervention and subsequent follow-up for effectiveness (52 weeks from baseline). Participants were recruited between January 2015 and December 2016 and randomly allocated (2:1) into 12 weeks of (1) standard care + InterWalk app–based interval walking training (IWT; IWT group; n=140), or (2) standard care + the standard exercise program (StC group; n=74). Following 12 weeks, the IWT group was encouraged to maintain InterWalk app–based IWT (3 times per week for 30-60 minutes) and the StC group was encouraged to maintain exercise without structured support. Moreover, half of the IWT group (IWTsupport group, n=54) received additional motivational support following the 12-week program until 52-week follow-up. The primary outcome was change in objectively measured MVPA time (minutes/day) from baseline to 52-week follow-up. Key secondary outcomes included changes in self-rated physical and mental health–related quality of life (HRQoL), physical fitness, weight, and waist circumference. Results Participants had a mean age of 59.6 (SD 10.6) years and 128/214 (59.8%) were men. No changes in MVPA time were observed from baseline to 52-week follow-up in the StC and IWT groups (least squares means [95% CI] 0.6 [–4.6 to 5.8] and –0.2 [–3.8 to 3.3], respectively) and no differences were observed between the groups (mean difference [95% CI] –0.8 [–8.1 to 6.4] minutes/day; P=.82). Physical HRQoL increased by a mean of 4.3 (95% CI 1.8 to 6.9) 12-item Short-Form Health Survey (SF-12) points more in the IWT group compared with the StC group (Benjamini-Hochberg adjusted P=.007) and waist circumference apparently decreased a mean of –2.3 (95% CI –4.1 to –0.4) cm more in the IWT group compared with the StC group but with a Benjamini-Hochberg adjusted P=.06. No between-group differences were observed among the remaining key secondary outcomes. Conclusions Among individuals with T2D referred to municipality-based lifestyle programs, randomization to InterWalk app–based IWT did not increase objectively measured MVPA time over 52 weeks compared with standard health care, although apparent benefits were observed for physical HRQoL. Trial Registration ClinicalTrials.gov NCT02341690; https://clinicaltrials.gov/ct2/show/NCT02341690

Background: Ectopic fat deposition resulting from impaired subcutaneous adipose tissue expandability may take center stage in the pathophysiological events linking low birth weight (LBW) with increased risk of developing Type 2 diabetes (T2D) . However, the extent to which adult LBW subjects exhibit increased hepatic fat accumulation is controversial. Methods and Results: Using 1H MR spectroscopy, we found a significantly increased hepatic fat content (P=0.014) in 26 early middle-aged and non-obese LBW males compared with 21 BMI- and age-matched normal birth weight (NBW) controls. Interestingly, 5 LBW (20%) versus no NBW subjects, had previously unrecognized overt nonalcoholic fatty liver disease (NAFLD) with a median hepatic fat content of 9.45%. The LBW w/NAFLD displayed widespread metabolic changes compared with both NBW and LBW w/o NAFLD subjects including hepatic insulin resistance (P=0.02) , increased fasting plasma triglycerides (TGs) (P=0.03) , cholesterol (P=0.05) , leptin, C-peptide and GLP-1 levels, as well as decreased adiponectin levels (P-range: 0.02-0.007) . Among 65 distinct metabolites and 279 lipids identified by untargeted serum metabolomic and lipidomic analyses, the levels of 7 metabolites including ornithine and citrulline, were different (P Conclusion: The data support a role for ectopic fat deposition in the pathophysiological events and trajectories linking LBW with increased risk of developing T2D and associated cardiometabolic traits including dyslipidemia. Disclosure L.Elingaard-larsen: None. T.Hansen: None. C.Brøns: Stock/Shareholder; Novo Nordisk. A.A.Vaag: Stock/Shareholder; AstraZeneca. L.Justesen: None. S.O.Villumsen: None. A.B.Thuesen: None. J.Størling: None. L.M.Sparks: None. M.Kim: None. C.Legido-quigley: None. E.R.Danielsen: None. Funding Novo Nordisk Foundation (NNF15OC0016692) , Aase and Ejnar Danielsens Fond, Augustinus Foundation, Simon Spies Fonden, TrygFonden.

Background: We hypothesized that low birth weight (LBW) subjects with a known increased risk of type 2 diabetes exhibit increased sensitivity towards the deleterious metabolic effects of 4-weeks high carbohydrate overfeeding (HCOF) compared with normal birth weight (NBW) controls. Methods: Untargeted serum metabolomics and lipidomics were measured before and after 4-weeks HCOF (+25% energy) in 26 non-obese men with LBW (2789±174 g) and 21 normal birth weight (NBW) men/controls (3804±172 g) matched for BMI and age. Data were analyzed using a combination of advanced statistical and bioinformatical tools. Results: Among 65 identified metabolites, 8 metabolites were affected differentially by HCOF between the two groups (p Conclusion: The results document severe differential perturbations of lipid metabolism in LBW men exposed to HCOF. Public health initiatives promoting low carbohydrate diets in LBW subjects are warranted. Disclosure S.O.Villumsen: None. A.A.Vaag: Stock/Shareholder; AstraZeneca. L.Justesen: None. L.Elingaard-larsen: None. A.B.Thuesen: None. M.Kim: None. C.Legido-quigley: None. E.R.Danielsen: None. T.Hansen: None. C.Brøns: Stock/Shareholder; Novo Nordisk.

Background: Low birth weight (LBW) individuals are at increased risk of developing Type 2 diabetes (T2D) , especially when exposed to an affluent dietary pattern. Impaired subcutaneous adipose tissue expandability and ectopic fat storage may represent key features explaining the link between LBW and risk of T2D. We hypothesized that a 4-week simple carbohydrate overfeeding challenge (+25% energy) (COF) would adversely influence dysmetabolic traits including hepatic fat content in LBW compared to normal birth weight (NBW) men. Methods: Twenty-two non-obese LBW and 21 age- and BMI-matched NBW men with a mean age of 37.6 years were included. Body composition, hepatic fat (MR spectroscopy) , glucose and insulin metabolism, hepatic glucose production (HGP; deuterium glucose) , energy metabolism (indirect calorimetry) and selected plasma biomarkers (multiplex ELISA) were measured before and after 4 weeks COF. Results: Fasting plasma glucose and C-peptide levels, as well as energy expenditure (EE) and fat oxidation (FOX) rates increased significantly more in response to COF among the LBW compared to NBW subjects (all P Conclusion: LBW compared to NBW subjects respond to COF with differential increments in plasma glucose, C-peptide, leptin and FGF21 levels, as well as increased EE and FOX rates. The results underscore the importance of LBW individuals avoiding simple carbohydrate overfeeding. Further studies are needed to understand the role of increased hepatic fat and insulin resistance as key mechanisms linking LBW with increased risk of T2D. Disclosure C.Brøns: Stock/Shareholder; Novo Nordisk. A.B.Thuesen: None. L.Justesen: None. L.Elingaard-larsen: None. J.Størling: None. E.R.Danielsen: None. T.Hansen: None. A.A.Vaag: Stock/Shareholder; AstraZeneca. Funding Novo Nordisk Foundation (NNF15OC0016692) , Aase and Ejnar Danielsens Fond, Augustinus Foundation, Simon Spies Fonden, TrygFonden.

Background: Low birth weight, indictive of a poor fetal environment, is a risk factor for type 2 diabetes (T2D) . Most previous studies were based on cross sectional prevalence data and not designed to study the timing of onset of T2D in relation to birth weight (BW) . Furthermore, earlier studies have not adjusted for common genetic variation influencing BW. We aimed to examine associations of BW with age-specific incidence of T2D using BW polygenetic risk scores (BWPRS) to adjust for genetic confounding. Methods: Adults (30-60 years) enrolled in the Inter99 cohort from 1999-20with information on BW from original birth records, and without diabetes at baseline were eligible. Birth records were linked with individual-level data on T2D incidence from the Danish Diabetes Register and key covariates from the Inter99 study. Incidence rates of T2D as a function of age, sex and BW were modelled using Poisson regression and adjusted for adult BMI, socioeconomic status, maternal history of diabetes and BWPRS. Results: Among 4584 participants there were 438 incident cases of T2D during a mean follow-up of 18 years. BW was inversely associated with T2D with a higher incidence in men. T2D incidence increased with age and the rate of increase was higher in persons with lower BW compared with higher BW in a dose-response manner. Conclusion: A lower birth weight is associated with a greater increase in incidence rate of T2D in a non-genetic manner. Disclosure R.Wibaek: Stock/Shareholder; Novo Nordisk A/S. G.S.Andersen: Stock/Shareholder; Novo Nordisk A/S. A.Linneberg: None. N.Grarup: None. T.Hansen: None. C.Brøns: Stock/Shareholder; Novo Nordisk. D.Vistisen: Research Support; Bayer AG, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi, Stock/Shareholder; Novo Nordisk A/S. A.A.Vaag: Stock/Shareholder; AstraZeneca. Funding Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation (NNF17SA0031406)

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. NEW & NOTEWORTHY 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.

Objective Ectopic liver fat deposition, resulting from impaired subcutaneous adipose tissue expandability, may represent an age-dependent key feature linking low birth weight (LBW) with increased risk of type 2 diabetes (T2D). We examined whether presumably healthy early middle-aged, non-obese LBW subjects exhibit increased liver fat content, whether increased liver fat in LBW is associated with the severity of dysmetabolic traits and finally whether such associations may be confounded by genetic factors. Methods Using 1H magnetic resonance spectroscopy, we measured hepatic fat content in 26 early middle-aged, non-obese LBW and 22 BMI-matched normal birth weight (NBW) males. Endogenous glucose production was measured by stable isotopes, and a range of plasma adipokine and gut hormone analytes were measured by multiplex ELISA. Genetic risk scores were calculated from genome-wide association study (GWAS) data for birth weight, height, T2D, plasma cholesterol and risk genotypes for non-alcoholic fatty liver disease (NAFLD). Results The LBW subjects had significantly increased hepatic fat content compared with NBW controls (P= 0.014), and 20% of LBW vs no controls had overt NAFLD. LBW subjects with NAFLD displayed widespread metabolic changes compared with NBW and LBW individuals without NAFLD, including hepatic insulin resistance, plasma adipokine and gut hormone perturbations as well as dyslipidemia. As an exception, plasma adiponectin levels were lower in LBW subjects both with and without NAFLD as compared to NBW controls. Genetic risk for selected differential traits did not differ between groups. Conclusion Increased liver fat content including overt NAFLD may be on the critical path linking LBW with increased risk of developing T2D in a non-genetic manner.

Aim: The TCF7L2 gene variant rs7903146 has the largest effect on type 2 diabetes risk reported in genome-wide association studies, however its role in adipose tissue development and function is unk...

Introduction: Breast cancer (BC) is the most common cancer among women worldwide. With increasing survival rates, focus has expanded to long-term adverse effects of adjuvant chemotherapy and/or aromatase inhibitors. Weight gain during chemotherapy has been well documented, but the underlying mechanisms remain unclear. A change in glucose and insulin metabolism is a possible consequence. Methods: We searched PubMed on the 4th of May 2018, and found eight articles that compared measurements of glucose and insulin before and after chemotherapy and/or aromatase inhibitors in woman with BC. Results: A general trend of increased glucose and insulin is seen and likely to be caused by weight gain and/or changes in body composition as a consequence of adjuvant treatment of BC. Discussion: Due to methodological limitations including short follow-up times and small sample sizes, further studies are required to better describe metabolic consequences of adjuvant chemotherapy and/or aromatase inhibitors. Future studies could help identify patients in high-risk of developing cardiometabolic disease after BC treatment.

BACKGROUND Effective and sustainable implementation of physical activity (PA) in type 2 diabetes (T2D) health care has in general not been successful. Efficacious and contemporary approaches to support PA adherence and adoption are required. OBJECTIVE The primary objective of this study was to investigate the effectiveness of including an app-based (InterWalk) approach into municipality-based rehabilitation to increase moderate-and-vigorous PA (MVPA) across 52 weeks compared with standard care among individuals with T2D. METHODS The study was designed as a parallel-group, randomized trial with 52 weeks intervention and subsequent follow-up for effectiveness (52 weeks from baseline). Participants were recruited between January 2015 and December 2016 and randomly allocated (2:1) into 12 weeks of (1) standard care + InterWalk app-based interval walking training (IWT) (IWT group; n=140), or (2) standard care + the standard exercise program (StC group, n=74). Following 12 weeks, the IWT group was encouraged to maintain InterWalk app-based IWT (3 times per week for 30-60 minutes) and the StC group was encouraged to maintain exercise without structured support. Moreover, half of the IWT group (IWTsupport group, n=54) received additional motivational support following the 12-week program until 52-week follow-up. The primary outcome was change in objectively measured MVPA time (min/day) from baseline to 52-week follow-up. Key secondary outcomes included changes in self-rated physical and mental health-related quality of life (HRQoL), physical fitness, weight and waist circumference. RESULTS Participants had a mean (SD) age of 59.6 (10.6) years of which 128 (59.8%) were men. No changes in MVPA time were observed from baseline to the 52-week follow-up in the StC and IWT groups (least squares means [95% CI]: 0.6 [-4.6 to 5.8] and -0.2 [-3.8 to 3.3], respectively) and no differences were observed between the groups (mean difference [95% CI]: -0.8 [-8.1 to 6.4] min/day, P=.82). Physical HRQoL increased by 4.3 (1.8 to 6.9) SF-12 points more in the IWT group compared with the StC group (Benjamini-Hochberg adjusted P=.007) and waist circumference apparently decreased 2.3 [-4.1 to -0.4] cm more in the IWT group compared with the StC group but weith a Benjamini-Hochberg adjusted P=.06. No between-group differences were observed among the remaining key secondary outcomes. CONCLUSIONS Among individuals with T2D referred to municipality-based lifestyle programs, randomization to InterWalk app-based IWT did not increase objectively measured MVPA time over 52 weeks compared with standard health care, although apparent benefits were observed for physical HRQoL. CLINICALTRIAL www.clinicaltrials.gov (NCT02341690)

Aim The relative roles(s) of impaired insulin secretion vs. insulin resistance in the development of gestational diabetes mellitus depend upon multiple risk factors and diagnostic criteria. Here, we explored their relative contribution to gestational diabetes as defined by the WHO 1999 (GDM1999) and adapted WHO 2013 (GDM2013) criteria, excluding the 1-h glucose value, in a high-risk Indian population from Punjab. Methods Insulin secretion (HOMA2-B) and insulin action (HOMA2-IR) were assessed in 4665 Indian women with or without gestational diabetes defined by the GDM1999 or adapted GDM2013 criteria. Results Gestational diabetes defined using both criteria was associated with decreased insulin secretion compared with pregnant women with normal glucose tolerance. Women with gestational diabetes defined by the adapted GDM2013, but not GDM1999 criteria, were more insulin resistant than pregnant women with normal glucose tolerance, and furthermore displayed lower insulin secretion than GDM1999 women. Urban habitat, illiteracy, high age and low BMI were independently associated with reduced insulin secretion, whereas Sikh religion, increasing age and BMI, as well as a family history of diabetes were independently associated with increased insulin resistance. Conclusions Gestational diabetes risk factors influence insulin secretion and action in North Indian women in a differential manner. Gestational diabetes classified using the adapted GDM2013 compared with GDM1999 criteria is associated with more severe impairments of insulin secretion and action. This article is protected by copyright. All rights reserved.

Background Subjects born with low birth weight (LBW) display a more energy-conserving response to fasting compared with normal birth weight (NBW) subjects. However, the molecular mechanisms explaining these metabolic differences remain unknown. Environmental influences may dynamically affect epigenetic marks, also in postnatal life. Here, we aimed to study the effects of short-term fasting on leptin (LEP) and adiponectin (ADIPOQ) DNA methylation and gene expression in subcutaneous adipose tissue (SAT) from subjects with LBW and NBW. Methods Twenty-one young LBW men and 18 matched NBW controls were studied during 36 h fasting. Eight subjects from each group completed a control study (overnight fast). We analyzed SAT LEP and ADIPOQ methylation (Epityper MassARRAY), gene expression (q-PCR), and adipokine plasma levels. Results After overnight fast (control study), LEP and ADIPOQ DNA methylation levels were higher in LBW compared to those in NBW subjects (p ≤ 0.03) and increased with 36 h fasting in NBW subjects only (p ≤ 0.06). Both LEP and ADIPOQ methylation levels were positively associated with total body fat percentage (p ≤ 0.05). Plasma leptin levels were higher in LBW versus NBW subjects after overnight fasting (p = 0.04) and decreased more than threefold in both groups after 36 h fasting (p ≤ 0.0001). Conclusions This is the first study to demonstrate that fasting induces changes in DNA methylation. This was shown in LEP and ADIPOQ promoters in SAT among NBW but not LBW subjects. The altered epigenetic flexibility in LBW subjects might contribute to their differential response to fasting, adipokine levels, and increased risk of metabolic disease. Electronic supplementary material The online version of this article (doi:10.1186/s13148-017-0340-8) contains supplementary material, which is available to authorized users.

Dysfunctional adipose tissue is associated with an increased risk of developing type 2 diabetes (T2D). One characteristic of a dysfunctional adipose tissue is the reduced expandability of the subcutaneous adipose tissue leading to ectopic storage of fat in organs and/or tissues involved in the pathogenesis of T2D that can cause lipotoxicity. Accumulation of lipids in the skeletal muscle is associated with insulin resistance, but the majority of previous studies do not prove any causality. Most studies agree that it is not the intramuscular lipids per se that causes insulin resistance, but rather lipid intermediates such as diacylglycerols, fatty acyl-CoAs and ceramides and that it is the localization, composition and turnover of these intermediates that play an important role in the development of insulin resistance and T2D. Adipose tissue is a more active tissue than previously thought, and future research should thus aim at examining the exact role of lipid composition, cellular localization and the dynamics of lipid turnover on the development of insulin resistance. In addition, ectopic storage of fat has differential impact on various organs in different phenotypes at risk of developing T2D; thus, understanding how adipogenesis is regulated, the interference with metabolic outcomes and what determines the capacity of adipose tissue expandability in distinct population groups is necessary. This study is a review of the current literature on the adipose tissue expandability hypothesis and how the following ectopic lipid accumulation as a consequence of a limited adipose tissue expandability may be associated with insulin resistance in muscle and liver.

Background: 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.Results: 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 (SKI, ARMCX3, NR5A2, NEUROG, ESRRG) 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 FYN and the histone deacetylase gene HDAC7. Silencing of FYN and HDAC7 was associated with impaired myotube formation, which for HDAC7 reduced muscle glucose uptake.Conclusions: 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 HDAC7 and FYN in their immature myoblast stem cells.

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.

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., Insulin resistance and lower muscle strength in relation to mass are hallmarks of type 2 diabetes. Here, the authors report alterations in muscle stem cells from individuals with type 2 diabetes that may contribute to these phenotypes through VPS39 mediated effects on autophagy and epigenetics.

Telomeres are protein-bound regions of repetitive nucleotide sequences (TTAGGG) at the end of human chromosomes, and their length is a marker of cellular aging. Intrauterine growth restriction is associated with shorter blood cell telomeres at birth and individuals with type 2 diabetes have shorter telomeres. Individuals with a low birth weight (LBW) have an increased risk of metabolic disease and type 2 diabetes. Therefore, we aimed to investigate the relationship between birth weight and telomere length and the association between birth weight, telomere length and cardiometabolic phenotype in adulthood. Young, healthy men with LBW (n = 55) and normal birth weight (NBW) (n = 65) were examined including blood pressure, blood samples and body composition. Leukocyte telomere length was determined using a high-throughput qPCR method. The LBW men were more insulin resistant as determined by the HOMA-IR index. There was no difference in telomere length between LBW and NBW subjects. When adjusting for birth weight and cohort effect, significant negative associations between telomere length and fasting glucose (P = 0.003) and HbA1c (P = 0.0008) were found. In conclusion, no significant difference in telomere length was found between LBW and NBW men. The telomere length was negatively associated with glucose concentrations and HbA1c levels within the normal non-diabetic range independent of birth weight.

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.

Objective Gestational diabetes mellitus (GDM) is a transient form of diabetes characterized by impaired insulin secretion and action during pregnancy. Population-based differences in prevalence exist which could be explained by phenotypic and genetic differences. The aim of this study was to examine these differences in pregnant women from Punjab, India and Scandinavia. Methods Eighty-five GDM/T2D loci in European and/or Indian populations from previous studies were assessed for association with GDM based on Swedish GDM criteria in 4018 Punjabi Indian and 507 Swedish pregnant women. Selected loci were replicated in Scandinavian cohorts, Radiel (N = 398, Finnish) and STORK/STORK-G (N = 780, Norwegian). Results Punjabi Indian women had higher GDM prevalence, lower insulin secretion and better insulin sensitivity than Swedish women. There were significant frequency differences of GDM/T2D risk alleles between both populations. rs7178572 at HMG20A, previously associated with GDM in South Indian and European women, was replicated in North Indian women. The T2D risk SNP rs11605924 in the CRY2 gene was associated with increased GDM risk in Scandinavian but decreased GDM risk in Punjabi Indian women. No other overlap was seen between GDM loci in both populations. Conclusions Gestational diabetes mellitus is more common in Indian than Swedish women, which partially can be attributed to differences in insulin secretion and action. There was marked heterogeneity in the GDM phenotypes between the populations which could only partially be explained by genetic differences.

Accumulation of fat in the hepatocytes also called non-alcoholic fatty liver disease (NAFLD) refers to a spectrum of liver disease ranging from simple fatty liver (steatosis), to nonalcoholic steatohepatitis (NASH) to liver cirrhosis. NAFLD is the most common liver disease in the world and the prevalence of NAFLD usually parallel that of obesity. NAFLD is caused by interactions between many environmental and genetic factors, and is associated with metabolic dysfunction including insulin resistance and dyslipidemia and is thus increasing the risk of type 2 diabetes (T2D).

Low birth weight (LBW) individuals have an increased risk of developing insulin resistance and type 2 diabetes compared with normal birth weight (NBW) individuals. We hypothesised that LBW individuals exhibit an increased fatty acid flux into lipogenesis in non-adipose tissue with a resulting accumulation of lipotoxic lipids, including ceramides, in the blood. Therefore, we measured fasting plasma levels of 27 ceramides in 18 young, healthy, LBW men and 25 NBW controls after an isocaloric control diet and a 5-day high-fat, high-calorie diet by HPLC-HRMS. LBW men did not show elevated plasma ceramide levels after the control or high-fat, high-calorie diet. An increased fatty acid oxidation rate in these individuals during both diets may limit ceramide synthesis and thereby compensate for a likely increased fatty acid load to non-adipose tissue. Interestingly, LBW and NBW men decreased d18:0–18:1/d18:1–18:0 and d18:1–24:2/d18:2–24:1 levels and increased the d18:0–24:1a level in response to overfeeding. Plasma d18:0–24:1a and total ceramide levels were positively associated with the fasting blood glucose level and endogenous glucose production after the control diet, and the total ceramide level was in addition positively associated with hepatic insulin resistance. Further studies are needed to determine if lipotoxicity contributes to insulin resistance in LBW individuals.

Background (and Purpose). The aim of this study was to investigate the importance of including the measurement of bone mineral density (BMD) in reliable fracture risk assessment for women diagnosed with early nonmetastatic breast cancer (EBC) before AI treatment if zoledronic acid is not an option. Material and Methods. One hundred and sixteen women with EBC were included in the study before initiating AI treatment. Most participants were osteopenic. The 10-year probability of hip fracture and major osteoporotic fracture was calculated with and without BMD based on clinical information collected at baseline using the fracture risk assessment (FRAX) tool. To compare data, the nonparametric tests were used. Results. There was a significant difference (p Conclusions. Our data support that DXA scanning of women with EBC should be performed to avoid overestimation of osteoporosis before AI treatment. It is particularly important in patients older than 65 years of age and when zoledronic acid is not an option.

ObjectiveThe World Health Organization (WHO) has in 2013 changed the diagnostic criteria for gestational diabetes mellitus (GDM) to acknowledge the putative effect of mildly elevated fasting plasma glucose (FPG) levels on pregnancy outcomes. We aimed to determine the prevalence and risk factors of GDM comparing the previous WHO 1999 criteria to the WHO 2013 criteria in North India.MethodsIn a population-based screening programme, 5100 randomly selected North Indian women were studied using a cross-sectional design with a questionnaire, venous FPG and 2-h capillary plasma glucose (PG) after a 75 g oral glucose tolerance test performed between 24 and 28 weeks of pregnancy.ResultsThe prevalence of GDM was 35% using WHO 2013 criteria vs 9% using WHO 1999 criteria. FPG measurements identified 94% of WHO 2013 GDM cases as opposed to 11% of WHO 1999 GDM cases. In contrast, 2-h PG measurements identified only 13% of WHO 2013 GDM cases compared with 96% of the WHO 1999 GDM cases. Using logistic regression with backward elimination, urban habitat, illiteracy, non-vegetarianism, increased BMI, Hindu religion and low adult height were all independent risk factors of GDM using the 1999 criteria, whereas only urban habitat, low adult height and increased age were independent risk factors of GDM using the 2013 criteria.ConclusionsIntervention studies are needed to justify the WHO 2013 GDM criteria increasing the prevalence four fold to include more than one third of North Indian pregnant women.

Low birthweight (LBW) individuals and offspring of women with gestational diabetes mellitus (GDM) exhibit increased risk of developing type 2 diabetes (T2D) and associated cardiometabolic traits in adulthood, which for both groups may be mediated by adverse events and developmental changes in fetal life. T2D is a multifactorial disease occurring as a result of complicated interplay between genetic and both prenatal and postnatal nongenetic factors, and it remains unknown to what extent the increased risk of T2D associated with LBW or GDM in the mother may be due to, or confounded by, genetic factors. Indeed, it has been shown that genetic changes influencing risk of diabetes may also be associated with reduced fetal growth as a result of reduced insulin secretion and/or action. Similarly, increased risk of T2D among offspring could be explained by T2D susceptibility genes shared between the mother and her offspring. Epigenetic mechanisms may explain the link between factors operating in fetal life and later risk of developing T2D, but so far convincing evidence is lacking for epigenetic changes as a prime and direct cause of T2D. This review addresses recent literature on the early origins of adult disease hypothesis, with a special emphasis on the role of genetic compared with nongenetic and epigenetic risk determinants and disease mechanisms.

The association between low birthweight (LBW) and risk of developing type 2 diabetes may involve epigenetic mechanisms, with skeletal muscle being a prime target tissue. Differential DNA methylation patterns have been observed in single genes in muscle tissue from type 2 diabetic and LBW individuals, and we recently showed multiple DNA methylation changes during short-term high-fat overfeeding in muscle of healthy people. In a randomised crossover study, we analysed genome-wide DNA promoter methylation in skeletal muscle of 17 young LBW men and 23 matched normal birthweight (NBW) men after a control and a 5 day high-fat overfeeding diet.DNA methylation was measured using Illumina's Infinium BeadArray covering 27,578 CpG sites representing 14,475 different genes.After correction for multiple comparisons, DNA methylation levels were found to be similar in the LBW and NBW groups during the control diet. Whereas widespread DNA methylation changes were observed in the NBW group in response to high-fat overfeeding, only a few methylation changes were seen in the LBW group (χ(2), p 0.001).Our results indicate lower DNA methylation plasticity in skeletal muscle from LBW vs NBW men, potentially contributing to understanding the link between LBW and increased risk of type 2 diabetes.

Objective Increased DNA methylation of the metabolic regulator peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) has been reported in skeletal muscle from type 2 diabetes (T2D) subjects and from low birth weight (LBW) subjects with an increased risk of T2D. High-fat overfeeding increases PPARGC1A DNA methylation in muscle in a birth weight dependent manner. However, PPARGC1A DNA methylation in subcutaneous adipose tissue (SAT) in LBW subjects has not previously been investigated. Our objective was to determine PPARGC1A DNA methylation and mRNA expression in basal and insulin-stimulated SAT from LBW and matched normal birth weight (NBW) subjects during control and high-fat overfeeding. Materials/Methods Nineteen young healthy men with LBW and 26 NBW controls were studied after both a 5-day high-fat overfeeding and a control diet in a randomized crossover setting. DNA methylation was assessed with bisulfite sequencing and mRNA expression with quantitative real-time PCR. Results Following high-fat overfeeding, increased SAT PPARGC1A DNA methylation was observed in LBW subjects but not in NBW controls. Basal SAT PPARGC1A mRNA expression was unaffected by diet and similar in the two groups. However, LBW subjects showed an increased SAT PPARGC1A mRNA expression during insulin-stimulation. SAT PPARGC1A methylation correlated inversely with mRNA expression during insulin-stimulation. Conclusions The study adds to the increasing awareness of PPARGC1A DNA methylation being flexible and influenced by high-fat overfeeding in a birth weight dependent manner with muscle and fat responding differently. Further data are needed to understand the role of PPARGC1A DNA methylation in insulin resistance and developmental programming of T2D.

Objective Low birth weight (LBW), a marker of disturbed fetal growth, is associated with adiposity and increased risk of type 2 diabetes (T2D). The aim of the study was to investigate whether LBW is associated with changes in 24-h energy expenditure (EE) and/or substrate utilization rates, potentially contributing to the development of adiposity and/or T2D compared to matched control subjects. Materials/Methods Forty-six young, healthy men were included in the study; 20 with LBW (≤ 10th percentile) and 26 control subjects with normal birth weight (NBW) (50th–90th percentile). The subjects were fed a weight maintenance diet and 24-h energy expenditure (EE), respiratory quotient (RQ), and substrate oxidation were assessed in a respiratory chamber. Results No differences in 24-h EE, RQ or substrate oxidation were observed between LBW and controls. Interestingly, the LBW group exhibited lower nocturnal RQ compared to controls (0.81 ± 0.01 vs. 0.85 ± 0.01 (mean ± SE), P = 0.01), and hence higher nocturnal fat oxidation (2.55 ± 0.13 vs. 2.09 ± 0.12 kJ/min (mean ± SE), P = 0.02). Conclusions Young LBW men do not exhibit reductions in 24-h EE. However, LBW subjects display increased nocturnal fat oxidation at the expense of reduced glucose oxidation. We speculate that this may be associated with insufficient capability to retain fat in subcutaneous adipose tissue after meals during day time, with an increased rate of nocturnal and morning lipolysis, and potentially with subtle elevations of gluconeogenesis and of fasting glucose levels in the LBW subjects.

Low-grade inflammation in obesity is associated with accumulation of the macrophage-derived cytokine osteopontin (OPN) in adipose tissue and induction of local as well as systemic insulin resistance. Since glucose-dependent insulinotropic polypeptide (GIP) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate OPN expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13 ± 0.04 vs. 0.04 ± 0.01, P < 0.05) and correlated inversely with measures of insulin sensitivity (r = −0.24, P = 0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with a lower amount of the exon 9–containing isoform required for transmembrane activity. Carriers of the A allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of the GIPR rs10423928 A allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions.

Prevention of multi-morbidities following non-communicable diseases requires a systematic registration of adverse modifiable risk factors, including low physical fitness. The aim of the study was to establish criterion validity and reliability of a smartphone app (InterWalk) delivered fitness test in patients with type 2 diabetes. Patients with type 2 diabetes (N = 27, mean (SD) age 64.2 (5.9) years, BMI 30.0 (5.1) kg/m2, (30 % male)) completed a 7-min progressive walking protocol twice (with and without encouragement). VO2 during the test was assessed using indirect calorimetry and the acceleration (vector magnitude) from the smartphone was obtained. The vector magnitude was used to predict VO2peak along with the co-variates weight, height and sex. The validity of the algorithm was tested when the smartphone was placed in the right pocket of the pants or jacket. The algorithm was validated using leave-one-out cross validation. Test-retest reliability was tested in a subset of participants (N = 10). The overall VO2peak prediction of the algorithm (R2) was 0.60 and 0.45 when the smartphone was placed in the pockets of the pants and jacket, respectively (p < 0.001). The mean bias (limits of agreement) in the cross validation was−0.4 (38) % (pants) and−0.1 (46) % (jacket). When the smartphone was placed in the jacket a significant intensity dependent bias (r = 0.5, p = 0.02) was observed. The test-retest intraclass correlations were 0.85 and 0.86 (p < 0.001), for the pants and jacket, respectively. No effects of encouragement were observed on test performance. In conclusion, the InterWalk Fitness Test is accurate and reliable for persons with type 2 diabetes when the smartphone is placed in the side pocket of the pants for. The test could give a fair estimate of the CRF in absence of a progressive maximal test during standardized conditions with the appropriate equipment. www.clinicaltrials.org ( NCT02089477 ), first registered (prospectively) on March 14th 2014

We hypothesized that an increased, incomplete fatty acid beta‐oxidation in mitochondria could be part of the metabolic events leading to insulin resistance and thereby an increased type 2 diabetes risk in low birth weight (LBW) compared with normal birth weight (NBW) individuals. Therefore, we measured fasting plasma levels of 45 acylcarnitine species in 18 LBW and 25 NBW men after an isocaloric control diet and a 5‐day high‐fat, high‐calorie diet. We demonstrated that LBW men had higher C2 and C4‐OH levels after the control diet compared with NBW men, indicating an increased fatty acid beta‐oxidation relative to the tricarboxylic acid cycle flux. Also, they had higher C6‐DC, C10‐OH/C8‐DC, and total hydroxyl‐/dicarboxyl‐acylcarnitine levels, which may suggest an increased fatty acid omega‐oxidation in the liver. Furthermore, LBW and NBW men decreased several acylcarnitine levels in response to overfeeding, which is likely a result of an upregulation of fatty acid oxidation due to the dietary challenge. Moreover, C10‐OH/C8‐DC and total hydroxyl‐/dicarboxyl‐acylcarnitine levels tended to be negatively associated with the serum insulin level, and the total hydroxyl‐/dicarboxyl‐acylcarnitine level additionally tended to be negatively associated with the hepatic insulin resistance index. This indicates that an increased fatty acid omega‐oxidation could be a compensatory mechanism to prevent an accumulation of lipid species that impair insulin signaling.

Mathias Ried-Larsen,1–3 Reimar W Thomsen,2,4 Klara Berencsi,4 Cecilie F Brinkløv,1,5 Charlotte Brøns,1,5 Laura S Valentiner,1,6 Kristian Karstoft,1,3 Henning Langberg,1,6 Allan A Vaag,1,2,5 Bente K Pedersen,1,3 Jens S Nielsen7 1Department of Infectious Diseases, Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, 2The Danish Diabetes Academy, Odense University Hospital, Odense, 3Department of Infectious Diseases, Centre of Inflammation and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus Nord, 5Department of Endocrinology (Diabetes and Metabolism), Rigshospitalet, University of Copenhagen, 6CopenRehab, Department of Public Health, Section of Social Medicine, University of Copenhagen, Copenhagen, 7Department of Endocrinology, Odense University Hospital, Odense, Denmark Abstract: Promoting physical activity is a first-line choice of treatment for patients with type 2 diabetes (T2D). However, there is a need for more effective tools and technologies to facilitate structured lifestyle interventions and to ensure a better compliance, sustainability, and health benefits of exercise training in patients with T2D. The InterWalk initiative and its innovative application (app) for smartphones described in this study were developed by the Danish Centre for Strategic Research in T2D aiming at implementing, testing, and validating interval walking in patients with T2D in Denmark. The interval walking training approach consists of repetitive 3-minute cycles of slow and fast walking with simultaneous intensity guiding, based on the exercise capacity of the user. The individual intensity during slow and fast walking is determined by a short initial self-conducted and audio-guided fitness test, which combined with automated audio instructions strives to motivate the individual to adjust the intensity to the predetermined individualized walking intensities. The InterWalk app data are collected prospectively from all users and will be linked to the unique Danish nationwide databases and administrative registries, allowing extensive epidemiological studies of exercise in patients with T2D, such as the level of adherence to InterWalk training and long-term effectiveness surveys of important health outcomes, including cardiovascular morbidity and mortality. Currently, the InterWalk app has been downloaded by >30,000 persons, and the achieved epidemiological data quality is encouraging. Of the 9,466 persons providing personal information, 80% of the men and 62% women were overweight or obese (body mass index ≥25). The InterWalk project represents a contemporary technology-driven public health approach to monitor real-life exercise adherence and to propagate improved health through exercise intervention in T2D and in the general population. Keywords: exercise, telemedicine, cell phones

Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men, where 592,794 single nucleotide polymorphisms (SNPs) were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs) in cis and 5,342 SNP-CpG pairs in trans showing significant associations between genotype and DNA methylation in adipose tissue after correction for multiple testing, where cis is defined as distance less than 500 kb between a SNP and CpG site. These mQTLs include reported obesity, lipid and type 2 diabetes loci, e.g. ADCY3/POMC, APOA5, CETP, FADS2, GCKR, SORT1 and LEPR. Significant mQTLs were overrepresented in intergenic regions meanwhile underrepresented in promoter regions and CpG islands. We further identified 635 SNPs in significant cis-mQTLs associated with expression of 86 genes in adipose tissue including CHRNA5, G6PC2, GPX7, RPL27A, THNSL2 and ZFP57. SNPs in significant mQTLs were also associated with body mass index (BMI), lipid traits and glucose and insulin levels in our study cohort and public available consortia data. Importantly, the Causal Inference Test (CIT) demonstrates how genetic variants mediate their effects on metabolic traits (e.g. BMI, cholesterol, high-density lipoprotein (HDL), hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR)) via altered DNA methylation in human adipose tissue. This study identifies genome-wide interactions between genetic and epigenetic variation in both cis and trans positions influencing gene expression in adipose tissue and in vivo (dys)metabolic traits associated with the development of obesity and diabetes.

Objective Sleep disturbances and alterations of diurnal endocrine rhythms are associated with increased risk of type 2 diabetes (T2D). We previously showed that young men born small for gestational age (SGA) and with increased risk of T2D have elevated fat and decreased glucose oxidation rates during nighttime. In this study, we investigated whether SGA men have an altered diurnal profile of hormones, substrates and inflammatory markers implicated in T2D pathophysiology compared with matched individuals born appropriate for gestational age (AGA). Methods We collected hourly blood samples for 24 h, to measure levels of glucose, free fatty acids (FFA), triglycerides (TG), insulin, C-peptide, leptin, resistin, ghrelin, plasminogen activator inhibitor-1 (PAI-1), incretins (GLP-1 and GIP), and inflammatory markers (TNF-α and IL-6) in 13 young men born SGA and 11 young men born AGA. Results Repeated measurements analyses were used to analyze the diurnal variations and differences between groups. The SGA subjects had increased 24-h glucose (P=0.03), glucagon (P=0.03) and resistin (P=0.003) levels with no difference in diurnal rhythms compared with AGA controls. We found significant diurnal variations in levels of blood glucose, plasma TG, FFA, insulin, C-peptide, GLP-1, GIP, leptin, visfatin, TNF-α, IL-6 and PAI-1. The variation in FFA levels differed between the groups during the evening. Plasma ghrelin and glucagon levels did not display diurnal variations. Conclusions Young men born SGA exhibit elevated 24-h blood glucose, and plasma glucagon and resistin levels with no major differences in diurnal rhythms of these or other key metabolic hormones, substrates or inflammatory markers implicated in the origin of adiposity and T2D.