Stephanie-May Ruchat

Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases

Offspring exposed to gestational diabetes mellitus (GDM) have an increased risk for chronic diseases, and one promising mechanism for fetal metabolic programming is epigenetics. Therefore, we postulated that GDM exposure impacts the offspring’s methylome and used an epigenomic approach to explore this hypothesis. Placenta and cord blood samples were obtained from 44 newborns, including 30 exposed to GDM. Women were recruited at first trimester of pregnancy and followed until delivery. GDM was assessed after a 75-g oral glucose tolerance test at 24–28 weeks of pregnancy. DNA methylation was measured at > 485,000 CpG sites (Infinium HumanMethylation450 BeadChips). Ingenuity Pathway Analysis was conducted to identify metabolic pathways epigenetically affected by GDM. Our results showed that 3,271 and 3,758 genes in placenta and cord blood, respectively, were potentially differentially methylated between samples exposed or not to GDM (p-values down to 1 × 10−06; none reached the genome-wide significance levels), with more than 25% (n = 1,029) being common to both tissues. Mean DNA methylation differences between groups were 5.7 ± 3.2% and 3.4 ± 1.9% for placenta and cord blood, respectively. These genes were likely involved in the metabolic diseases pathway (up to 115 genes (11%), p-values for pathways = 1.9 × 10−13 < p < 4.0 × 10−03; including diabetes mellitus p = 4.3 × 10−11). Among the differentially methylated genes, 326 in placenta and 117 in cord blood were also associated with newborn weight. Our results therefore suggest that GDM has epigenetic effects on genes preferentially involved in the metabolic diseases pathway, with consequences on fetal growth and development, and provide supportive evidence that DNA methylation is involved in fetal metabolic programming.

Epigenetic programming of obesity and diabetes by in utero exposure to gestational diabetes mellitus

It is now well accepted that offspring exposed to maternal undernutrition, obesity, or gestational diabetes mellitus have an increased risk for chronic diseases later in life, supporting the theory of the early origins of chronic diseases. However, the molecular mechanisms through which the exposure to an altered in utero environment translates into the development of chronic diseases are not yet well understood. Recently reported promising results help to resolve this issue. They suggest that epigenetic modifications are a potential mechanism for fetal metabolic programming. This review provides an overview of the relationship between the exposure to an altered intrauterine environment and fetal metabolic programming, focusing on gestational diabetes mellitus and epigenetic variations at adipokine candidate genes.

Timing of excessive pregnancy-related weight gain and offspring adiposity at birth.

OBJECTIVE: To evaluate whether the timing of excessive maternal weight gain in a cohort of women following current guidelines for healthy living during pregnancy affects neonatal adiposity at birth. METHODS: One hundred seventy-two healthy women who were at least 18 years old with body mass indexes (BMIs) of at least 18.5 were recruited between 16 weeks and 20 weeks of gestation. The cohort followed healthy living guidelines during pregnancy and were retrospectively grouped according to 2009 Institute of Medicine guidelines for weight gain in the first and second halves of pregnancy: 1) appropriate gestational weight gain (ie, within Institute of Medicine recommendations) in the first and second halves of pregnancy (“overall appropriate”); 2) appropriate gestational weight gain in the first half of pregnancy and excessive gestational weight gain in the second half of pregnancy (“late excessive”); 3) excessive gestational weight gain in the first half of pregnancy and appropriate gestational weight gain in the second half of pregnancy (“early excessive”); and 4) excessive gestational weight gain throughout pregnancy (“overall excessive”). Primary measures included neonatal weight, length, BMI, and body fat at birth measured 6–18 hours after delivery. Neonatal body fat greater than 14% was considered excessive. RESULTS: Neonates of women who gained excessively in the first half of pregnancy exhibited greater heel-crown length, birth weight, and excessive body fat (“early excessive” 17.5±3.1%, “overall excessive” 18.7±3.3%) compared with those born to women who gained appropriately (“overall appropriate” 13.2±4.1%; “late excessive” 14.7±3.3%; P<.01). Neonates of women who gained excessively in the first half of pregnancy had an increased risk (odds ratio [OR] 2.64, 95% confidence interval [CI] 1.35–5.17) of elevated body fat at birth compared with neonates of women with total excessive weight gain (OR 1.49, 95% CI 0.80–2.79). CONCLUSION: Timing of excessive weight gain is an important factor influencing neonatal morphometrics. Prevention of early excessive weight gain should be encouraged in the period before conception and reinforced early in pregnancy. LEVEL OF EVIDENCE: II

Improvements in glucose homeostasis in response to regular exercise are influenced by the PPARG Pro12Ala variant: results from the HERITAGE Family Study

Aims/hypothesisExercise training improves glucose homeostasis, but large inter-individual differences are reported, suggesting a role of genetic factors. We investigated whether variants either confirmed or newly identified as diabetes susceptibility variants through genome-wide association studies (GWAS) modulate changes in phenotypes derived from an IVGTT in response to an endurance training programme.MethodsWe analysed eight polymorphisms in seven type 2 diabetes genes (CDKAL1 rs7756992; CDKN2A and CDKN2B rs10811661 and rs564398; HHEX rs7923837; IGF2BP2 rs4402960; KCNJ11 rs5215; PPARG rs1801282; and TCF7L2 rs7903146) in a maximum of 481 sedentary, non-diabetic white individuals, who participated in a 20-week endurance training programme. Associations were tested between the variants and changes in IVGTT-derived phenotypes.ResultsThe only evidence of association with training response was found with PPARG rs1801282 (Pro12Ala). We observed that Ala carriers experienced greater increase in overall glucose tolerance (Δglucose disappearance index Ala/Ala 0.22 ± 0.22, Pro/Ala 0.14 ± 0.06, Pro/Pro 0.004 ± 0.03; p = 0.0008), glucose effectiveness (Ala/Ala 0.28 ± 0.41, Pro/Ala 0.44 ± 0.14, Pro/Pro 0.09 ± 0.06; p = 0.004), acute insulin response to glucose (Ala/Ala 64.21 ± 37.73, Pro/Ala −11.92 ± 40.30, Pro/Pro −46.30 ± 14.70; p = 0.03) and disposition index (Ala/Ala 551.8 ± 448.5, Pro/Ala 534.6 ± 218.3, Pro/Pro −7.44 ± 88.18; p = 0.003).Conclusions/interpretationCompared with Pro/Pro individuals, PPARG Ala carriers experienced greater improvements in glucose and insulin metabolism in response to regular endurance training. However, we did not find evidence of association between type 2 diabetes susceptibility variants recently identified through GWAS and glucose homeostasis response to exercise. Our results extend those of previous studies showing that Ala carriers appear to be more responsive to beneficial health effects of lifestyle interventions.

The important role of physical activity in the prevention and management of gestational diabetes mellitus.

The actual pathophysiology behind gestational diabetes mellitus (GDM) is still unclear, but a deterioration in insulin resistance beyond that induced by pregnancy, combined with beta cell dysfunction, plays a key role. Interventions that help improve glucose tolerance by attenuating pregnancy‐induced insulin resistance or achieve glycaemic control may therefore help in preventing and managing GDM. In non‐pregnant populations, physical activity has been associated with an improvement in glucose homeostasis and insulin sensitivity and a risk reduction for type 2 diabetes mellitus (T2DM) and is a cornerstone for T2DM treatment. However, there is still controversy regarding the benefits of physical activity in preventing and managing GDM. The objective of this review is therefore to provide a comprehensive overview of the effect of prenatal physical activity–based interventions on (1) glucose tolerance, insulin sensitivity and GDM prevention and (2) glycaemic control and insulin use in GDM women. On the basis of the available literature, there is a lack of consistent evidence regarding the benefits of physical activity on improving glucose tolerance and insulin sensitivity and preventing GDM. However, it appears that physical activity may help to achieve good glycaemic control and limit insulin use in GDM women. Compliance appears to be a major problem in physical activity–based intervention studies aimed at GDM prevention. Rigorous scientific research is still required to make an informed decision about the role of physical activity in the prevention and management of GDM and to develop evidence‐based physical activity guidelines for GDM prevention and management. Copyright

Effect of exercise intensity and duration on capillary glucose responses in pregnant women at low and high risk for gestational diabetes

Exercise may influence glucose metabolism during pregnancy. We examined the effect of exercise intensity and duration on capillary glucose responses in pregnant women at low and high risk for gestational diabetes mellitus (GDM) who followed a modified GDM meal plan.

Dexamethasone-induced insulin resistance shows no gender difference in healthy humans.

OBJECTIVE Recent reports suggest that lipid-induced insulin resistance is more pronounced in men than in women. Whether such gender difference exists for other factors known to induce insulin resistance in healthy individuals remains unknown. We therefore assessed whether glucocorticoid-induced insulin resistance differs in men and women. METHODS The insulin sensitivity and insulin secretion of 8 women and 7 men, all non obese and healthy, were evaluated with or without administration of dexamethasone (2 mg/day during 2 days) by means of a two-step hyperglycemic clamp. RESULTS Dexamethasone decreased insulin sensitivity to the same extent in men and women. The relative increases in insulin concentration observed after dexamethasone in the basal state, during the first phase of insulin release and at the two steps of hyperglycemia were similar in men and women. The hyperinsulinemia thus attained allowed to fully compensate for insulin resistance in both genders. CONCLUSIONS The effects of glucocorticoids on insulin sensitivity and insulin secretion show no gender difference in healthy humans.

Nutrition and Exercise Reduce Excessive Weight Gain in Normal-Weight Pregnant Women

PURPOSE This study aimed to evaluate the effect of an exercise program of two different intensities, with nutritional control, on gestational weight gain (GWG), infant birth weight, and maternal weight retention at 2 months postpartum (2 mopp). METHODS Pregnant women (prepregnancy body mass index = 18.5-24.9 kg·m) were randomized at study entry (16-20 wk of gestation) to a low-intensity (LI, 30% HR reserve (HRR), n = 23) or moderate-intensity (MI, 70% HRR, n = 26) exercise program, with nutritional control. The exercise program consisted of walking sessions three to four times per week, gradually increasing exercise time from 25 to 40 min per session. Forty-five normal-weight women who did not participate in any structured exercise program during pregnancy and had singleton births were used as a historical control group. RESULTS Total GWG was higher in the control group (18.3 ± 5.3 kg) compared with the LI (15.3 ± 2.9 kg, P = 0.01) and MI (14.9 ± 3.8 kg, P = 0.003) groups. During the intervention, GWG was similar in both intervention groups, with weekly rates of weight gain of 0.49 ± 0.1 and 0.47 ± 0.1 kg·wk in the LI and MI groups, respectively. Excessive GWG during the intervention was prevented in 70% of the women in the LI group and 77% of those in the MI group. Excessive GWG occurred before the intervention began. At 2 mopp, 18% and 28% of the women in the LI and MI groups, respectively, retained ≤2.0 kg compared with only 7% of those in the control group. Infant birth weight was not different between the groups. CONCLUSIONS Results suggest that a prenatal nutrition and exercise program regardless of exercise intensity, reduced excessive GWG and decreased weight retention at 2 mopp in women of normal weight before pregnancy.

Evidence of Interaction between Type 2 Diabetes Susceptibility Genes and Dietary Fat Intake for Adiposity and Glucose Homeostasis-Related Phenotypes

Background/Aims: Genome-wide association studies have led to the identification of several susceptibility genes for type 2 diabetes mellitus (T2DM). The objective of this study was to test the hypothesis that the associations between single nucleotide polymorphisms (SNPs) in these genes and adiposity and glucose homeostasis-related phenotypes are influenced by dietary fat intake. Methods: Thirty-three SNPs in 9 T2DM genes (CDKAL1, CDKN2A/B, HHEX, HNF1B, IGF2BP2, KCNJ11, SLC30A8, TCF7L2 and WFS1) were tested in a maximum of 669 subjects from the Quebec Family Study. Subjects were measured for several adiposity indices and underwent a 75-gram oral glucose tolerance test. Total fat intake was estimated from a 3-day dietary record. Results: We observed 13 significant (p ≤ 0.01) SNP-dietary fat interactions. Among them, IGF2BP2 rs4402960, alone or in interaction with dietary fat intake, influenced abdominal total fat (ATF: SNP effect, p = 0.006, interaction effect, p = 0.009) and abdominal visceral fat (AVF: SNP effect, p = 0.007, interaction effect, p = 0.01). Similarly, TCF7L2 rs12573128 alone or in interaction with dietary fat intake, influenced insulin sensitivity (SNP effect and interaction effect, p ≤ 0.008) and glucose tolerance (SNP effect p ≤ 0.009 and interaction effect, p ≤ 0.01). Conclusion: These results suggest that gene-dietary fat interactions may influence glucose homeostasis-related phenotypes and play an important role in determining the increased risk of diabetes associated with the T2DM susceptibility genes.

Associations between glucose tolerance, insulin sensitivity and insulin secretion phenotypes and polymorphisms in adiponectin and adiponectin receptor genes in the Quebec Family Study

Aims  Studies suggest that adiponectin (APM1) and its receptors 1 and 2 (AdipoR1 and AdipoR2) play an important role in the development of insulin resistance (IR). Our objective was to examine associations between APM1 (+45T>G, +276G>T and –3971A>G), AdipoR1 (−100G>T and −3882T>C) and AdipoR2 (−35361A>G and –1352G>A) genes single‐nucleotide polymorphisms (SNPs) and adiponectin plasma levels, indicators of glucose tolerance, insulin sensitivity (IS) and insulin secretion.