Normoglycemic Women Research Articles

Effects of 10 weeks of aerobic exercise training on cardiovascular function, atherosclerosis, and vascular endothelial function in elderly women

Purpose The purpose of this study was to investigate the effect of a 10-week aerobic exercise training on cardiovascular function, atherosclerosis, and vascular endothelial function in elderly women. Methods Twenty impaired fasting glucose (IFG) and normoglycemic elderly women volunteered to participate in the study. The participants in aerobic exercise training group (TR: n=9) completed 20-40 minutes of aerobic exercise program at 30-50% HRR for 3 times per week during 10 weeks. The participants in control group (CON: n=11) were asked to maintain their normal life pattern during the same intervention period. Results Main results of the study were as follows: 1) There were no significant main effect or interaction in body weight, fat-free mass, fat mass, percent body fat, and body mass index. 2) There were no significant main effect or interaction in heart rate, stroke volume, cardiac output, total peripheral resistance (TPR), systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, pulse pressure, and rate pressure product. However, interaction between group and test in TPR was close to statistically significant level (P =.054), and it tended to be decreased in TR group. 3) There was a significant main effect of test in high sensitivity C-reactive protein(hs-CRP), it tended to be decreased in TR group. There were no significant changes in total cholesterol(TC)/high density lipoprotein-cholesterol (HDL-C) ratio, triglyceride/HDL-C ratio, and low density lipoprotein-cholesterol/HDL-C ratio. 4) There were significant main effect of group, main effect of test, as well as interaction between group and test in % flow mediated dilation(FMD), and it increased significantly (P<.01) in TR group. Nitric oxide tended to be increased in TR group, even though it did not change significantly in both groups. Conclusions It was concluded that the 10-week aerobic exercise training would be beneficial for improvement of vascular endothelial function, resulting from the decrement of total peripheral resistance.

Lipoprotein(a)-activated immunity, insulin resistance and new-onset diabetes

ABSTRACTObjectives: Some evidence suggests that serum lipoprotein[Lp](a) may be inversely linked to type-2 diabetes. We aimed to determine in nondiabetic people the relationship of serum [Lp](a) with insulin resistance and new-onset diabetes (NOD).Materials and methods: Population-based middle-aged adults (n = 1685) were categorized by fasting glucose and stratified to gender, having excluded prevalent diabetic subjects. NOD (n = 90) occurred over a median 5 years’ follow-up.Results: Subjects that subsequently developed NOD, derived both from the normoglycemia and impaired fasting glucose (IFG) groups,were distinguished, among others, primarily by significantly elevated serum gamma glutamyltransferase, reduced Lp(a) (by 31%) and, compared to IFG, by low total cholesterol levels. Partial correlation of Lp(a) with homeostatic model assessment (HOMA) was inverse in normoglycemic men; such correlation, neutral in normoglycemic women, proved inverse in IFG (r = −0.17). Circulating Lp(a) in individuals with paired measures increased significantly (1.55-fold) in the period from baseline up to NOD. Multivariable-adjusted logistic regression analysis for NOD in combined sexes indicated independent and additive prediction by serum Lp(a), albeit inverse in direction (RR 0.84, [95%CI 0.72; 0.97]).Conclusion: Lp(a) is significantly reduced in the period preceding NOD and is inversely associated with HOMA index, observations consistent with underlying autoimmune activation.

The association between serum uric acid and the incidence of prediabetes and type 2 diabetes mellitus: The Rotterdam Study

BackgroundLimited evidence is available about the association between serum uric acid and sub-stages of the spectrum from normoglycaemia to type 2 diabetes mellitus. We aimed to investigate the association between serum uric acid and risk of prediabetes and type 2 diabetes mellitus.MethodsEligible participants of the Rotterdam Study (n = 8,367) were classified into mutually exclusive subgroups of normoglycaemia (n = 7,030) and prediabetes (n = 1,337) at baseline. These subgroups were followed up for incident prediabetes (n = 1,071) and incident type 2 diabetes mellitus (n = 407), respectively. We used Cox proportional hazard models to determine hazard ratios (HRs) for incident prediabetes among individuals with normoglycaemia and incident type 2 diabetes mellitus among individuals with prediabetes.ResultsThe mean duration of follow-up was 7.5 years for incident prediabetes and 7.2 years for incident type 2 diabetes mellitus. A standard deviation increment in serum uric acid was significantly associated with incident prediabetes among individuals with normoglycaemia (HR 1.10, 95% confidence interval (CI) 1.01; 1.18), but not with incident type 2 diabetes mellitus among individuals with prediabetes (HR 1.07, 95% CI 0.94; 1.21). Exclusion of individuals who used diuretics or individuals with hypertension did not change our results. Serum uric acid was significantly associated with incident prediabetes among normoglycaemic women (HR 1.13, 95% CI 1.02; 1.25) but not among normoglycaemic men (HR 1.08, 95% CI 0.96; 1.21). In contrast, serum uric acid was significantly associated with incident type 2 diabetes mellitus among prediabetic men (HR 1.23, 95% CI 1.01; 1.48) but not among prediabetic women (HR 1.00, 95% CI 0.84; 1.19).ConclusionsOur findings agree with the notion that serum uric acid is more closely related to early-phase mechanisms in the development of type 2 diabetes mellitus than late-phase mechanisms.

Identification of candidate biomarkers for the prediction of gestational diabetes mellitus in the early stages of pregnancy using iTRAQ quantitative proteomics.

Gestational diabetes mellitus (GDM) is one of the most common medical problems of pregnancy. This study is designed to identify serum biomarkers, which can predict the subsequent development of GDM at early stages. Maternal blood was obtained prospectively from pregnant women at 12-16 wk of pregnancy. Among these, 30 women were subsequently diagnosed with GDM at 24 to 28 wk and were selected as case studies along with 30 normoglycemic women as controls. Serum samples were analyzed by using iTRAQ analysis. Thirty three differentially expressed proteins were identified between case and control groups. They were involved in various signaling processes previously implied in GDM. Of which four proteins, i.e. apolipoprotein E, coagulation factor IX, fibrinogen alpha chain, and insulin-like growth factor-binding protein 5 were successfully verified by ELISA. Combinations of these four proteins, the area under the receiver operating characteristic curve, sensitivity, and specificity were 0.985, 80% and 95%, respectively. The results highlight the roles of complement system, inflammatory and immune response, and blood coagulation in the pathogenesis of GDM. The panel of four candidate proteins could distinguish women subsequently developed with GDM from controls with high sensitivity and specificity.

First Trimester Maternal Glycated Hemoglobin and Sex Hormone-Binding Globulin Do Not Predict Third Trimester Glucose Intolerance of Pregnancy.

Early pregnancy prediction of third trimester glucose intolerance may identify a population of women whose trajectory toward gestational diabetes mellitus (GDM) is modifiable. We assessed whether first trimester glycated hemoglobin (HbA1c) and sex hormone-binding globulin (SHBG), markers of insulin resistance, predicted third trimester glucose intolerance. Nondiabetic women with singleton pregnancies enrolled in a prospective observational study, 11 0/7 to 14 6/7 weeks. At enrollment, maternal characteristics, medical history, and blood samples were collected for HbA1c and SHBG. Two-step GDM screening was performed, 22 0/7 to 33 6/7 weeks. A 50 g oral glucose tolerance test ≥130 mg/dL defined screen positive, or glucose intolerance. Carpenter-Coustan criteria diagnosed GDM. Means HbA1c and SHBG were compared between glucose-intolerant versus normoglycemic women, and GDM versus no GDM women. We report unadjusted and adjusted odds ratios (OR; 95% confidence interval [CI]) of regression analyses. Adjusted models include race, enrollment body mass index, and history of GDM. Among 250 women, 29% were glucose intolerant and 6% had GDM. Among glucose-intolerant women, HbA1c was higher (5.3 ± 0.3 vs. 5.1 ± 0.3, P = .01) and associated with glucose intolerance in unadjusted, but not adjusted, models (OR: 2.9, 95% CI: 1.2-7.1; adjusted odds ratio [aOR]: 2.0, 95% CI: 0.7-5.4). Among GDM women, HbA1c was higher (5.4 ± 0.4 vs 5.2 ± 0.3, P = .002) and SHBG was lower (228 ± 72 vs 288 ± 93 mmol/L, P = .02). The HbA1c predicted GDM in unadjusted (OR: 13.2, 95% CI: 2.6-68.0) but not adjusted (aOR: 6.7, 95% CI: 0.8-55.2) models. Although metabolic alterations may well precede third trimester glucose intolerance, neither HbA1c of SHBG remained an independent predictor of glucose intolerance or GDM in adjusted models.

Circulating progenitor and angiogenic cell frequencies are abnormally static over pregnancy in women with preconception diabetes: A pilot study.

Type 1 and 2 diabetes decrease the frequencies and functional capacities of circulating angiogenic cells (CAC). Diabetes also elevates gestational complications. These observations may be interrelated. We undertook pilot studies to address the hypothesis that preconception diabetes deviates known gestational increases in CACs. Cross-sectional study of type 1 diabetic, type 2 diabetic and normoglycemic pregnant women was conducted at 1st, 2nd, and 3rd trimester and compared to a 6mo postpartum surrogate baseline. Circulating progenitor cells (CPC; CD34+CD45dimSSlow) and CACs (CD34+CD45dimSSlow expressing CD133 without or with KDR) were quantified by flow cytometry and by colony assay (CFU-Hill). In pregnant normoglycemic women, CD34+CD45dimSSlow cell frequency was greater in 1st and 3rd trimester than postpartum but frequency of these cells was static over type 1 or 2 diabetic pregnancies. Type 1 and type 2 diabetic women showed CACs variance versus normal controls. Type 1 diabetic women had more total CD34+KDR+ CACs in 1st trimester and a higher ratio of CD133+KDR+ to total CD133+ cells in 1st and 2nd trimesters than control women, demonstrating an unbalance in CD133+KDR+ CACs. Type 2 diabetic women had more CD133+KDR+ CACs in 1st trimester and fewer CD133+KDR- CACs at mid-late pregnancy than normal pregnant women. Thus, pregnancy stage-specific physiological fluctuation in CPCs (CD34+) and CACs (CD133+KDR+ and CD133+KDR-) did not occur in type 1 and type 2 diabetic women. Early outgrowth colonies were stable across normal and diabetic pregnancies. Therefore, preconception diabetes blocks the normal dynamic pattern of CAC frequencies across gestation but does not alter colony growth. The differences between diabetic and typical women were seen at specific gestational stages that may be critical for initiation of the uterine vascular pathologies characterizing diabetic gestations.

Pregnancy to postpartum transition of serum metabolites in women with gestational diabetes

ContextGestational diabetes is commonly linked to development of type 2 diabetes mellitus (T2DM). There is a need to characterize metabolic changes associated with gestational diabetes in order to find novel biomarkers for T2DM. ObjectiveTo find potential pathophysiological mechanisms and markers for progression from gestational diabetes mellitus to T2DM by studying the metabolic transition from pregnancy to postpartum. DesignThe metabolic transition profile from pregnancy to postpartum was characterized in 56 women by mass spectrometry-based metabolomics; 11 women had gestational diabetes mellitus, 24 had normal glucose tolerance, and 21 were normoglycaemic but at increased risk for gestational diabetes mellitus. Fasting serum samples collected during trimester 3 (gestational week 32±0.6) and postpartum (10.5±0.4months) were compared in diagnosis-specific multivariate models (orthogonal partial least squares analysis). Clinical measurements (e.g., insulin, glucose, lipid levels) were compared and models of insulin sensitivity and resistance were calculated for the same time period. ResultsWomen with gestational diabetes had significantly increased postpartum levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine, and their circulating lipids did not return to normal levels after pregnancy. The increase in BCAAs occurred postpartum since the BCAAs did not differ during pregnancy, as compared to normoglycemic women. ConclusionsPostpartum levels of specific BCAAs, notably valine, are related to gestational diabetes during pregnancy.

Leptin/Adiponectin Ratios Using Either Total Or High-Molecular-Weight Adiponectin as Biomarkers of Systemic Insulin Sensitivity in Normoglycemic Women

Plasma leptin/adiponectin ratio (LAR) is negatively associated with insulin sensitivity indexes. High-molecular-weight adiponectin (HMWA) was proposed as the most biologically active form of this insulin-sensitizing adipokine. There are no studies assessing the relative merits of leptin/HMWA ratio over LAR as a biomarker of systemic insulin sensitivity. A standard 2-hour oral glucose tolerance test (OGTT; 75 g of glucose) and a short minimal-model intravenous glucose tolerance test (IVGTT; 0.3 g/kg body weight) were performed in 58 Chilean normoglycemic women (age: 27 ± 6.3 years, BMI 23.6 ± 3.2 kg/m2). LAR was negatively associated with HOMA-S (r = −0.49; p < 0.0001), Matsuda-ISICOMP (r = −0.54; p < 0.0001), and the calculated sensitivity index (CSi) derived from IVGTT (r = −0.38; p = 0.007). In comparison to LAR, leptin/HMWA ratio did not increase neither the linear fit (r2) nor the magnitude of association with insulin sensitivity indexes (slope of multiple linear regression). The discriminatory capacity of both ratios to classify insulin-resistant versus insulin-sensitive subjects was similar for HOMA-S (p = 0.84), Matsuda-ISICOMP (p = 0.43), or CSi (p = 0.50). In conclusion, LAR showed consistent negative associations with different systemic insulin sensitivity indexes. The use of HMWA to generate leptin/HMWA ratio did not show any advantage over LAR as a biomarker of systemic insulin sensitivity in normoglycemic women.

Is Uric Acid a Missing Link between Previous Gestational Diabetes Mellitus and the Development of Type 2 Diabetes at a Later Time of Life?

IntroductionA high level of uric acid (UA) is a strong, independent risk factor for type 2 diabetes mellitus. The relationship between UA levels and the development of type 2 diabetes in women with previous gestational diabetes mellitus (pGDM) remains unclear. The aim of study was to evaluate the UA levels in pGDM women in relation to their current nutritional status and carbohydrate metabolism.Material and Methods199 women with pGDM diagnoses based on oral glucose tolerance tests (OGTTs) 5–12 years previously and a control group of 50 women without pGDM. The assessment included anthropometric parameters, body composition (Tanita SC-330S), current OGTT, insulin resistance index (HOMA-IR), β-cell function (HOMA-%B), HbA1c, lipids, and uric acid.ResultsNo differences between groups were found in terms of age, time from the index pregnancy, anthropometric parameters, lipids or creatinine levels. The incidences of overweight and obesity were similar. Carbohydrate abnormalities were more frequent in the pGDM group than the control group (43.2% vs 12.0% p<0.001). The women with pGDM had significantly higher fasting glucose, HbA1c, glucose and insulin levels in the OGTTs, but similar HOMA-IR values. Their UA levels were significantly higher (258±58 vs 230±50 μmol/L, p<0.005) and correlated with BMI and the severity of carbohydrate disorders. The normal weight and normoglycemic pGDM women also demonstrated higher UA levels than a similar control subgroup (232±48 vs 208±48 μmol/L, p<0.05). Multivariate analysis revealed significant correlations of UA level with BMI (β = 0.38, 95% CI 0.25–0.51, p<0.0001), creatinine level (β = 0.23, 95% CI 0.11–0.35, p<0.0005), triglycerides (β = 0.20, 95% CI 0.07–0.33, p<0.005) and family history of diabetes (β = 0.13, 95% CI 0.01–0.25, p<0.05). In logistic regression analysis, the association between higher UA level (defined as value ≥297 μmol/L) and presence of any carbohydrate metabolism disorder (IFG, IGT or diabetes) was statistically significant (odds ratio 3.62 [95% CI 1.8–7.3], p<0.001).ConclusionsHigher UA levels may be associated with the development of type 2 diabetes in pGDM women, also in these with normal body weights.

Metformin-Sustained Weight Loss and Reduced Android Fat Tissue At 12 Months In Empowir (Enhance The Metabolic Profile Of Women With Insulin Resistance): A Double Blind, Placebo-Controlled, Randomized Trial of Normoglycemic Women with Midlife Weight Gain

To assess 12-month body weight (BW) and body composition changes in normoglycemic women with midlife weight gain, after dietary and pharmacologic interventions targeting hyperinsulinemia. EMPOWIR (Enhance the Metabolic Profile of Women With Insulin Resistance; NCT00618072) was a double-blind, placebo-controlled, 12-month trial of women with >20-pound weight gain, normal glucose tolerance test, and increased area-under-the-curve insulin. Subjects (mean ± SD, 46.7 ± 6.5 years of age; body mass index, 30.8 ± 2.8 kg/m(2); 50% white) attended 4 nutrition workshops to introduce a novel carbohydrate-modified diet (CMD) and were then randomized to one of three arms for 6 months (phase 1): CMD alone (D), or in combination with metformin (M), or metformin + rosiglitazone (MR), with rerandomization of the D group to one of the active treatment arms (phase 2, months 7 through 12). Repeated measure analysis of variance was used to assess BW at baseline, 6 months, and 12 months in 32 subjects with 12-month data; paired t tests compared baseline and 12-month dual-energy X-ray absorptiometry-derived body composition. Mean (±SD) BW decreased significantly at 12 months in the M arm: 85.1 ± 8.5 kg to 79.8 ± 9.0 kg (P = .0003), with 54% of variance in weight over time explained by M treatment. Mean (±SD) percent android fat decreased significantly in the M and D arms: 53.5 ± 4.8% to 49.3 ± 7.6% (P = .010) and 52.9 ± 6.2% to 48.1 ± 8.7% (P = .021). In combination with a novel carbohydrate modified diet, metformin enhanced 12-month weight loss and improved body composition in ethnically diverse normoglycemic, hyperinsulinemic women with midlife weight gain. These findings suggest that EMPOWIR's easily implemented dietary interventions, alone and in combination with pharmacotherapies that target hyperinsulinemia, merit additional investigation in larger, long-term studies.

Differential apelin mRNA expression in placenta of women with gestational diabetes (GDM)

The percentage of pregnancies accompanied by gestational diabetes (GDM) is increasing globally. Also, GDM and the associated disturbances in maternal lipid metabolism are shown to have negative impacts on maternal and fetal long term health. In normoglycemic women (NGT), the pancreas can compensate for the reduction in insulin sensitivity being present in the 3rd trimester of pregnancy. However in GDM, the compensatory beta cell response is absent. It is proposed that adipokines, also released from the placenta might lead to reduced compensatory effects of the beta cells.

Insulin resistance is associated with altered amino acid metabolism and adipose tissue dysfunction in normoglycemic women.

Insulin resistance is associated adiposity, but the mechanisms are not fully understood. In this study, we aimed to identify early metabolic alterations associated with insulin resistance in normoglycemic women with varying degree of adiposity. One-hundred and ten young and middle-aged women were divided into low and high IR groups based on their median HOMA-IR (0.9 ± 0.4 vs. 2.8 ± 1.2). Body composition was assessed using DXA, skeletal muscle and liver fat by proton magnetic resonance spectroscopy, serum metabolites by nuclear magnetic resonance spectroscopy and adipose tissue and skeletal muscle gene expression by microarrays. High HOMA-IR subjects had higher serum branched-chain amino acid concentrations (BCAA) (p < 0.05 for both). Gene expression analysis of subcutaneous adipose tissue revealed significant down-regulation of genes related to BCAA catabolism and mitochondrial energy metabolism and up-regulation of several inflammation-related pathways in high HOMA-IR subjects (p < 0.05 for all), but no differentially expressed genes in skeletal muscle were found. In conclusion, in normoglycemic women insulin resistance was associated with increased serum BCAA concentrations, down-regulation of mitochondrial energy metabolism and increased expression of inflammation-related genes in the adipose tissue.

The mutual effect of pregestational body mass index, maternal hyperglycemia and gestational weight gain on adverse pregnancy outcomes

Objective: To investigate the mutual effect of obesity, gestational diabetes (GDM) and gestational weight gain (GWG) on adverse pregnancy outcomes.Methods: Charts of patients who delivered in our hospital between June 2001 and June 2006 singleton, live births >24 weeks gestation were reviewed. Univariate and multivariate logistic regression were used to assess pregnancy outcomes defined as large for gestational age (LGA), primary cesarean section (PCS) and a composite outcome of LGA and/or PCS.Results: A total of 8595 women were included. Frequency of composite outcome increased with increasing body mass index (BMI), increasing hyperglycemia and above-recommended GWG. In the multivariate logistic regression analysis compared to women with normal BMI, odds ratio (OR) for composite outcome was 1.23 (95% confidence interval [CI] 1.06–1.44) in overweight women, OR = 1.86 (1.51–2.31) in obese women and in severe obesity OR = 2.97 (2.15–4.11).Compared to normoglycemic women, odds for composite outcome in women with abnormal glucose challenge test OR = 1.46 (1.20–1.79), impaired glucose tolerance OR = 1.65 (1.14–2.4) and GDM OR = 1.56 (1.16–2.10). Women with GWG above recommended had OR = 1.58, (1.37–1.81) for composite outcome.Conclusions: Higher pregestational BMI, maternal hyperglycemia and above-recommended GWG independently contribute to adverse pregnancy outcomes. Furthermore, there is mutual effect between these three factors and adverse outcomes. Appropriate pregestational weight and adequate GWG might reduce risk of adverse pregnancy outcomes.

Gastrin Secretion After Bariatric Surgery-Response to a Protein-Rich Mixed Meal Following Roux-En-Y Gastric Bypass and Sleeve Gastrectomy: a Pilot Study in Normoglycemic Women.

Recent investigations have linked elevated gastrin levels to the improvement of type 2 diabetes mellitus (T2DM). Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are effective treatments for T2DM, but it is not known if this is related to postoperative alterations of gastrin secretion. Twenty women previously operated with RYGB or SG and 13 female controls were enrolled and evaluated for body mass index, lipids, C-peptide, HbA1c, and anti-H. pylori IgG. Glucose, gastrin, insulin, and glucagon-like peptide 1 (GLP-1) concentrations were measured before and 30, 60, 90, and 120min after ingestion of a protein-rich mixed meal. Six participants primarily selected were excluded due to usage of proton pump inhibitors, positive H.pylori IgG, or history of T2DM, yielding the following groups: RYGB (n = 9), SG (n = 8), and controls (n = 10). There were no differences in age, body mass index, HbA1c, or C-peptide levels between groups. RYGB had significantly lower area under the curve (AUC) for glucose during the test compared to controls (p = 0.013). RYGB showed lower serum gastrin levels compared to SG and controls (p < 0.05 for all). There was a non-significant increased gastrin release in SG compared to controls (p = 0.091). For SG and controls, there was a negative correlation between glucose and gastrin response (p = 0.0043). Gastrin secretion is diminished after RYGB. Hypergastrinemia was not present after SG, but a tendency of enhanced gastrin secretion was observed. These findings require further investigation in prospective studies.

Disturbances in insulin secretion and subclinical inflammation in normoglycemic women with a history of pregnancy complicated by gestational diabetes mellitus

Disturbances in insulin secretion and subclinical inflammation in normoglycemic women with a history of pregnancy complicated by gestational diabetes mellitus

HbA1c: A Useful Screening Test for Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is associated with adverse maternal and fetal outcomes, and the oral glucose tolerance test (OGTT) is the recommended test for its diagnosis. We evaluated the role of glycated hemoglobin (HbA1c) in screening and diagnosis of GDM and its correlation with adverse pregnancy outcomes. In this prospective observational study, OGTT and HbA1c were performed in 500 antenatal women between 24 and 28 weeks of gestation; the pregnant women were followed up thereafter. Repeat OGTT and HbA1c were done in women with GDM at 6 weeks postpartum. Among the 500 women, 45 were diagnosed with GDM, for an incidence of 9%. The mean HbA1c level in women with GDM was 6.2 ± 0.6%, whereas it was 5.4 ± 0.5% in those with normoglycemia. Women with GDM had a higher incidence of pregnancy-related complications compared with normoglycemic women. An HbA1c cutoff of 5.3% had a sensitivity of 95.6% and a specificity of 51.6% for the diagnosis of GDM and would have avoided OGTT in approximately half of antenatal women, while missing 5% of the women. However, those with an abnormal HbA1c will require a confirmatory OGTT, as 50% of normoglycemic women would be misclassified as having GDM by this approach. On repeat testing postpartum, two of 45 women (4.4%) had overt diabetes mellitus, whereas five (11.1%) had impaired glucose tolerance. Although HbA1c cannot replace OGTT in the diagnosis of GDM, it can be used as a screening test, avoiding OGTT in approximately 50% of women, if a cutoff of 5.3% is used.

Metabolic and hormonal consequencies of the "obesity risk" MC4R variant (rs12970134) in Czech women.

Although the mutations in MC4R gene became known as the most common genetic cause of human obesity, the effect of rs12970134 A/G near MC4R gene on insulin resistance has been described. The aim of this study was to determine the effect of rs12970134 on obesity, hormone levels, and glucose metabolism in a cohort of women varying in glucose tolerance: 850 normoglycemic women, 423 diagnosed with polycystic ovary syndrome (PCOS), 402 gestational diabetics (GDM), and 250 type 2 diabetic (T2D) women. We did not confirm the explicit effect of rs12970134 on obesity. However, the influence of the A-allele on body adiposity index was observed in a cohort of women diagnosed with PCOS. In normoglycemic women, the A-allele carriership was associated with lower fasting levels of glucose, insulin, C-peptide, and index of insulin resistance. Furthermore, higher levels of growth hormone, leptin and SHBG, and lower levels of fT3, testosterone, and androstenedione were recorded in normoglycemic A-allele carriers. In conclusion, the study presents the evidence of the impact of rs12970134 on complex hypothalamic regulations.

LRP1B, BRD2 and CACNA1D: new candidate genes in fetal metabolic programming of newborns exposed to maternal hyperglycemia.

To assess the associations between gestational diabetes mellitus (GDM) and DNA methylation levels at genes related to energy metabolism. Ten loci were selected from our recent epigenome-wide association study on GDM. DNA methylation levels were quantified by bisulfite pyrosequencing in 80 placenta and cord blood samples (20 exposed to GDM) from an independent birth cohort (Gen3G). We did not replicate association between DNA methylation and GDM. However, in normoglycemic women, glucose levels were associated with DNA methylation changes at LRP1B and BRD2 and at CACNA1D and LRP1B gene loci in placenta and cord blood, respectively. These results suggest that maternal glucose levels, within the normal range, are associated with DNA methylation changes at genes related to energy metabolism and previously associated with GDM. Maternal glycemia might thus be involved in fetal metabolic programming.

Hyperinsulinism and polycystic ovary syndrome (PCOS): role of insulin clearance.

Insulin resistance and compensatory hyperinsulinism are the predominant metabolic defects in polycystic ovary syndrome (PCOS). However, hyperinsulinism, as well as being compensatory, can also express a condition of reduced insulin clearance. Our aim was to evaluate the differences in insulin action and metabolism between women with PCOS (with normal glucose tolerance) and age- and BMI-matched women with prediabetes (without hyperandrogenism and ovulatory disorders). 22 women with PCOS and 21 age/BMI-matched women with prediabetes were subjected to a Hyperinsulinemic-euglycemic clamp and an Oral Glucose tolerance Test (OGTT). Insulin sensitivity was assessed by the glucose infusion rate during clamp (M value); insulin secretion by Insulinogenic index, Oral Disposition Index (DIo) and AUC(2h-insulin) during OGTT; and insulin clearance by the metabolic clearance rate of insulin (MCRI) during clamp. Women with PCOS showed significantly higher levels of AUC(2h-insulin) (p < 0.011), Insulinogenic Index (p < 0.001), DIo (p = 0.002) and significantly lower levels of AUC(2h-glucos)e (p = 0.001). No difference was found between the two groups regarding insulin sensitivity (M value). Lower levels of MCRI were found in women with PCOS [420 (IQR 227-588) vs. 743 (IQR 597-888) ml m(-2) min(-1): p < 0.001]. Furthermore, in the PCOS group, a strong independent inverse correlation was only observed between MCRI and AUC(2h-insulin) (PCOS: β:-0.878; p < 0.001; Prediabetes: β:-0.501; p = 0.019). Our study suggests that in normoglycemic women with PCOS there is peripheral insulin sensitivity similar to that of women with prediabetes. What sets PCOS apart is the hyperinsulinism, today still simplistically defined "compensatory"; actually this is mainly related to decreased insulin clearance whose specific causes and dynamics have yet to be clarified.

Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans

AimsThe common MTNR1B genetic variant rs10830963 is associated with an increased risk of type 2 diabetes (T2D). To date, no experimental study has tested the effect of the MTNR1B variant on glucose metabolism in humans during exposure of the melatonin receptors to their ligand. The aim of this study was to investigate whether this MTNR1B variant influenced the effect of melatonin (5mg) on glucose tolerance assessed by an oral glucose tolerance test (OGTT; 75g) at different times of the day (morning and evening) as compared to a placebo. MethodsSeventeen normoglycemic women (24±6years; BMI 23.0±3.3kg/m2) completed the study (11 carriers of the risk allele [CG] and 6 noncarriers [CC]). ResultsThe effect of melatonin on glucose tolerance depended on the genotype. In the morning, the effect of melatonin (melatonin-placebo) on the glucose area under the curve (AUC) above baseline differed significantly (P=0.036) between the carriers and noncarriers. This effect of melatonin in the carriers was six times as large as that in the noncarriers. The MTNR1B SNP explained over one-quarter (26%) of the inter-individual differences in the effect of melatonin on glucose AUC. However, in the evening, the effect of melatonin on glucose AUC of the carriers and noncarriers did not differ significantly (P>0.05). ConclusionsMTNR1B rs10830963 risk variant worsens the effect of melatonin on glucose tolerance, suggesting the importance of genotyping and personalized recommendations, especially in people consuming food when melatonin levels are elevated. Large-scale studies in vulnerable populations are necessary to translate these results into real-world, clinically relevant recommendations.