Normal Glucose Tolerance Women Research Articles

Fasting hyperinsulinemia associates with increased sub‐clinical inflammation in first‐degree relatives normal glucose tolerant women independently of the metabolic syndrome

To evaluate the influence of gender on the relationship between inflammation and hyperinsulinemia in first-degree relatives of type 2 diabetic patients independently of metabolic syndrome. Study group consisted in 217 first-degree relatives with normal glucose tolerance after an oral glucose tolerance test. A logistic analysis, adjusted for age, sex and all the components of the metabolic syndrome, was used to determine the relationship between interleukin-6 (IL-6) and leptin and tertiles of fasting insulin, and to take into account the influence of gender. In the whole cohort, IL-6 and leptin were significantly higher and adiponectin significantly lower in the III tertile when corrected for age, body mass index (BMI) and metabolic syndrome components. In women, but not in men, IL-6 and leptin remained significantly higher when corrected for metabolic syndrome. In the whole cohort and in women, univariate correlations between IL-6 concentrations and the parameters under evaluation showed that IL-6 and leptin were positively correlated with age, BMI, waist, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose, fasting insulin, Delta AUC insulin area, triglyceride (TG), free fatty acids (FFA) and monocyte chemoattractant protein-1 (MCP-1) and inversely correlated with HDL cholesterol (HDL-C) and adiponectin. In women a forward stepwise linear regression analysis in a model including age, BMI, features of metabolic syndrome, fasting insulin, Delta AUC insulin and insulin sensitivity index (ISI) index revealed that only IL-6 and leptin were independently associated with fasting insulin levels. In first-degree relatives normal glucose tolerant women, fasting hyperinsulinemia, independently of the presence of metabolic syndrome, is associated with elevated IL-6 and leptin levels, suggesting an increased cardiovascular risk.

Assessment of insulin sensitivity/resistance and their relations with leptin concentrations and anthropometric measures in a pregnant population with and without gestational diabetes mellitus

Fifty-six pregnant women with gestational diabetes mellitus (GDM) and 42 normal glucose tolerant (NGT) pregnant women between 26 and 36 gestational weeks were included in the study prospectively. The body fat percentage (BFP) was calculated using the Siri formula from skinfold thickness (SFT) measurements. Both groups were comparable for gestational age, height, weight, and body mass index ( P>.05). Insulin resistance assessed by homeostasis model assessment for insulin resistance (HOMA-IR) method was significantly higher in GDM patients compared to their NGT weight-matched control group. In contrast, the insulin sensitivity calculated from quantitative insulin sensitivity check index (QUICKI-IS) equation was significantly lower in GDM group. Calculated lean body mass was found to be similar in between both groups. Body fat percentage derived from SFT parameters was significantly higher in women with GDM. Women with GDM had significantly higher levels of serum insulin and leptin concentrations when compared with the NGT group. All SFT measurements were higher in GDM group when compared to those in NGT women. We did not find any correlation between leptin levels and insulin resistance; we found negative correlation between leptin levels and insulin sensitivity. Thus, we observed that leptin may contribute development of GDM by decreasing insulin sensitivity but not increasing insulin resistance. Also, we observed that the BFP estimated by the Siri formula from SFT measurements correlated significantly with HOMA-IR and QUICKI-IS and leptin concentrations in pregnant women. We suggest that by simply evaluating SFT, we may hold a view about BFP and leptin concentrations and insulin sensitivity in pregnant women.

Circulating asymmetric dimethylarginine, endothelin-1 and cell adhesion molecules in women with gestational diabetes

We measured plasma concentrations of asymmetric dimethylarginine (ADMA), endothelin-1 (ET-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and E-selectin in 56 patients with gestational diabetes (GDM), 68 pregnant women with normal glucose tolerance (NGT) and 36 healthy non-pregnant women. ADMA concentrations were markedly lower in NGT [0.48 (0.42-0.55) micromol/l] than in GDM subjects [0.50 (0.43-0.67) micromol/l] and healthy controls [0.57 (0.46-0.72) micromol/l, P = 0.005]. ET-1 levels were comparable between GDM [0.76 (0.58-0.90) pg/ml] and NGT women [0.75 (0.63-0.92) pg/ml] and significantly higher than in the non-pregnant subjects [0.62 (0.52-0.72) pg/ml, P = 0.007 and P = 0.005, respectively]. There were no differences in sVCAM-1 and E-selectin levels between the groups studied. ADMA levels were significantly associated with fasting glucose (beta = 0.23, P = 0.02) and gestational age (beta = 0.24, P = 0.01). Our results suggest that physiological adaptation to pregnancy is associated with a fall in circulating ADMA and an elevation of ET-1 concentrations, irrespective of the disturbances of glucose tolerance.

Glycemic excursions in Indian pregnant women monitored by continuous glucose monitoring system—A pilot study

Summary Objective To assess the glycemic profile in pregnant women consuming south Indian diet by continuous glucose monitoring system (CGMS) and to ascertain the time to monitor peak post-prandial plasma glucose. Research design and methods This study included 12 women with gestational diabetes mellitus (GDM) and an equal number with normal glucose tolerance (NGT) at entry. Minimed sylmer (CA, USA) CGMS system was used. They were advised to continue their usual diet and lifestyle during the study period. Results There was no difference in the time to peak between the two groups with all three meals (p > 0.05) but there was a significant increase in the peak plasma glucose (PG) in the GDM compared to NGT women (p 0.05). Conclusions Flexibility in the monitoring time between 60 and 90 min is an ethically convenient option for a pregnant woman.

Detection and care of women with gestational diabetes mellitus from early weeks of pregnancy results in birth weight of newborn babies appropriate for gestational age

The policy of screening for gestational diabetes mellitus (GDM) between 24 and 28 weeks of gestation and care has resulted in a few women delivering big babies despite good glycemic control. Hence we undertook a study to assess the merits of care given to women in whom GDM was diagnosed in different weeks of gestation and to find out the ideal period of screening in women with history of high-risk pregnancies. A total of 207 consecutive pregnant women irrespective of trimester referred to our referral clinic for diabetes in pregnancy, underwent a 75 g oral glucose tolerance test (OGTT) and GDM was diagnosed if 2 h plasma glucose (PG) ≥140 mg/dl. A1c was estimated in all of them. Women who failed to respond to medical nutrition therapy were advised insulin and the dose titrated to maintain fasting PG (FPG) <90 mg/dl and 2 h PG <120 mg/dl. The mean age of the population screened was 28.38 ± 4.31 years and the mean gestational age of screening was 20.05 ± 10.71 weeks. Among them, 87 were diagnosed as GDM. The gestational week at diagnosis was ≤12 in 36 (41.4%) women (group 1), between 13 and 23 in 18 (20.7%) (group 2), between 24 and 30 in 15 (17.2%) (group 3) and beyond 30 weeks of gestation in 18 (20.7%) (group 4). The A1c was 5.34 ± 0.43% in normal glucose tolerance (NGT) women, while it was 6.93 ± 1.62% in group 1, 6.03 ± 0.79% in group 2, 6.14 ± 0.93% in group 3 and 6.20 ± 0.31% in group 4, respectively. The birth weight of babies born to women with NGT was 3.28 ± 0.50 kg. The birth weight of babies born to GDM women in group 1, group 2, group 3 and group 4 was 3.15 ± 0.48, 3.09 ± 0.68, 3.32 ± 0.51 and 3.51 ± 0.63 kg, respectively. Group 1 women in spite of the history of high-risk pregnancies, delivered babies appropriate for gestational age like NGT women. Screening in the first trimester of pregnancy and institution of therapy is advisable in women with high-risk pregnancies.

Insulin sensitivity and resistin levels in gestational diabetes mellitus and after parturition

Resistin is expressed and secreted by the placenta during pregnancy. Increased serum resistin levels have been found in the second half of normal pregnancy, but its role in the pathogenesis of the insulin resistance of pregnancy is undetermined. The objective of the study was to assess the relationship between circulating resistin levels and insulin sensitivity in gestational diabetes mellitus (GDM). A case (n=23)-control (n=35) study was performed at the obstetrics and endocrinology clinic of a university hospital. In total, 58 Caucasian women with a singleton pregnancy who had been referred for a 100 g oral glucose tolerance test were enrolled between the weeks 26 and 30, and 22 women with GDM were also evaluated after pregnancy. Serum resistin and insulin sensitivity in GDM during and after pregnancy. The relationship of resistin to metabolic abnormalities was evaluated. Resistin levels were lower in GDM women than in pregnant women with normal glucose tolerance (NGT) (4.32+/-1.56 vs 9.30+/-1.32 ng/ml, P<0.001), and experienced a further decrease after parturition (4.24+/-1.56 vs 3.11+/-1.63 ng/ml, P=0.003). The association between low serum resistin levels and the diagnosis of GDM was independent of the degree of insulin sensitivity. Lower resistin levels were observed in GDM than in NGT women and decreased after parturition, suggesting a role for resistin in the development of this disease. But we have failed to find an independent relationship between resistin levels and insulin sensitivity during pregnancy.

Increased Skeletal Muscle Tumor Necrosis Factor-α and Impaired Insulin Signaling Persist in Obese Women With Gestational Diabetes Mellitus 1 Year Postpartum

Women with gestational diabetes mellitus (GDM) demonstrate chronic and progressive insulin resistance and a markedly increased risk of converting to type 2 diabetes after pregnancy. However, the cellular mechanisms underlying this insulin resistance are unknown. We investigated the progression of insulin resistance in nine obese women with GDM during late pregnancy (30-36 weeks) and 1 year postpartum. Skeletal muscle biopsies were obtained at each visit, and insulin resistance was determined by the hyperinsulinemic-euglycemic clamp technique. Insulin resistance was not significantly improved in GDM women (4.1 +/- 0.4 vs. 5.8 +/- 1.1 10(-2) mg x kg FFM x min(-1)/microU x ml(-1)). Subjects did not experience significant weight loss postpartum. Body weight, fat mass, fasting glucose, and plasma tumor necrosis factor (TNF)-alpha remained higher 1 year postpartum than seen in previously studied normal glucose-tolerant women. Skeletal muscle TNF-alpha mRNA was elevated five- to sixfold in GDM women and remained higher 1 year postpartum. While levels of insulin receptor (IR), IR substrate (IRS)-1, and p85 alpha improved postpartum, insulin-stimulated IR tyrosine phosphorylation and receptor tyrosine kinase activity did not significantly improve postpartum in GDM. The levels of (312)Ser-IRS-1 also did not improve postpartum and correlated with TNF-alpha mRNA (r(2) = 0.19, P < 0.03), consistent with a state of subclinical inflammation and chronic skeletal muscle insulin resistance. These results suggest the mechanisms underlying chronic insulin resistance in GDM women may be driven by increased inflammation that impinges on the IR and IRS-1 signaling cascade in skeletal muscle. These findings have important implications for the health of GDM women during subsequent pregnancies and their risk for progression to type 2 diabetes.

Relationship between Gestational Diabetes Mellitus and Type 2 Diabetes: Evidence of Mitochondrial Dysfunction

We examined the pathogenesis of gestational diabetes mellitus (GDM) in a large Dutch multiethnic cohort. We used a 2-step testing procedure to stratify 2031 consecutive pregnant women into 4 groups according to American Diabetes Association criteria: (a) normal glucose tolerance (NGT), (b) mild gestational hyperglycemia (MGH), (c) GDM without early postpartum diabetes within 6 months of delivery (GDM1), and (d) GDM with early postpartum diabetes (GDM2). Antepartum and postpartum clinical characteristics and measures of glucose tolerance were documented. Overall, 1627 women had NGT, 237 had MGH, 156 had GDM1, and 11 had GDM2. Prepregnancy body mass index values progressively increased from NGT to MGH to GDM1. The fasting plasma glucose concentration, the 100-g oral glucose tolerance test (OGTT) area under the curve, and the mean glucose concentration during the OGTT all increased progressively among the 4 groups. The fasting C-peptide concentration displayed an inverted-U pattern, with a maximum at a mean plasma glucose concentration during the OGTT of 9.6 mmol/L in the transition from GDM1 to GDM2. The fasting C-peptide/glucose concentration ratio decreased by 42% in GDM patients compared with NGT patients, whereas the ratios in MGH and NGT women were similar. Progressive metabolic derangement of glucose tolerance 1st detected during pregnancy mimics the pathogenesis of type 2 diabetes. In addition, our results imply an impaired basal glucose effectiveness in the early prediabetic state. To explain the parallel in both metabolic derangements, we postulate that GDM, like type 2 diabetes, is attributable to the same inherited mitochondrial dysfunction.

Tumor Necrosis Factor Alpha System and Plasma Adiponectin Concentration in Women with Gestational Diabetes

Plasma concentrations of adiponectin, tumor necrosis factor-alpha (TNF-alpha) and its soluble receptors sTNFR-1 and sTNFR-2 were measured in 80 patients with gestational diabetes (GDM) (mean age 29.0 +/- 4.9 years) and 30 pregnant women with normal glucose tolerance (NGT) (mean age 28.2 +/- 6.0 years). We found that GDM patients had significantly lower concentrations of adiponectin (11.28 +/- 5.91 vs. 16.31 +/- 6.04 microg/ml, p = 0.00009) and elevated levels of TNF-alpha (1.71 +/- 0.92 vs. 1.27 +/- 0.42 pg/ml, p = 0.0175) in comparison to NGT women. The differences remained statistically significant after adjusting for BMI. Plasma levels of sTNFR-1 and sTNFR-2 also tended to be higher in GDM patients. In the GDM group TNF-alpha concentrations correlated significantly with sTNFR-1 (r = 0.444, p = 0.00008), sTNFR-2 (r = 0.364, p = 0.0016) and with C-peptide concentrations (r = 0.318, p = 0.016), whereas in women with NGT TNF-alpha correlated only with TG levels (r = 0.50, p = 0.024). Multivariate linear regression analysis revealed that prepregnant BMI was the most predictive indicator of TNF-alpha concentrations in GDM women. TG concentrations as well as BMI before pregnancy and at the time of sampling in pregnant NGT women were significant predictors, explaining 62% of the variance in TNF-alpha concentration. There were also negative correlations between adiponectin concentrations and a pregestational BMI (r = - 0.298, p = 0.009), BMI at the time of sampling (r = - 0.239, p = 0.034) and TG concentrations (r = - 0.379, p = 0.039) in GDM patients, whereas women with NGT showed only a negative correlation between adiponectin and TG concentrations (r = - 0.488, p = 0.025). In a multivariate regression analysis, prepregnancy BMI and TG levels remained significant predictors, explaining 39% of the variation in plasma adiponectin concentration in GDM women. In conclusion, our results suggest that decreased adiponectin concentration in GDM may not simply reflect maternal adiposity and insulin resistant state, but may contribute to the impaired glucose metabolism during pregnancy, with potential implications for screening and prevention of the disease.

Impaired fasting glucose vs. glucose intolerance in pre-menopausal women: distinct metabolic entities and cardiovascular disease risk?

Impaired glucose tolerance (IGT) is associated with an increased cardiovascular disease risk. Less is known about cardiovascular disease risk among subjects with impaired fasting glucose (IFG) or with combined IFG and IGT. To compare body composition, body fat distribution, plasma glucose-insulin homeostasis and plasma lipid-lipoprotein profile between pre-menopausal women having either a normal glucose tolerance (NGT), isolated IFG, isolated IGT or combined IFG and IGT. Three hundred and thirty-four women with NGT, 11 women with IFG, 35 women with IGT and 10 women with both IFG and IGT were studied. Women with IFG were characterized by a higher visceral adipose tissue (AT) accumulation than women with NGT (P < 0.05). Also, they were characterized by a higher subcutaneous AT area and by higher body fat mass than NGT and IGT women (P < 0.05). However, their lipid-lipoprotein profile was comparable with that of NGT women, except for reduced HDL-cholesterol concentrations (P < 0.05). After adjustment for visceral AT, women with IFG had lower total cholesterol, LDL-cholesterol and apolipoprotein B (apoB) levels than the three other groups. They also had lower HDL(2)-cholesterol than NGT women and lower total cholesterol/HDL-cholesterol ratio than IGT women. Women with IGT showed higher triglyceride and apoB concentrations and a higher total cholesterol/HDL-cholesterol ratio than women with NGT (P < 0.05). Overall, women with combined IFG and IGT showed body fatness characteristics and alterations in their metabolic risk profile which were essentially similar to women with isolated IGT. These results indicate that there are significant differences in anthropometric and metabolic variables between pre-menopausal women with IFG vs. IGT and that the association between body fatness-body fat distribution indices and the metabolic profile may differ between IFG and IGT women.

Pancreatic β-cell defects in women at risk of type 2 diabetes

We evaluated insulin release and insulin sensitivity in women with basal and/or postprandial hyperglycemia but normal oral glucose tolerance test (OGTT) in previous pregnancy (GHG). These women were individually matched with females without previous hyperglycemia (NGT). Both groups consisted of normal glucose-tolerant women at the time of this study. They underwent OGTT (75 g; n=32 pairs) and hyperglycemic clamp experiments (10 mmol l −1; n=27 pairs) with plasma glucose, insulin, and C-peptide measurements and calculation of insulinogenic index, first- and second-phase insulin release, and insulin sensitivity index (ISI). The GHG group showed higher glycosylated hemoglobin levels (6.2±0.6% versus 5.8±0.8%; P<0.05); lower insulinogenic index at 30 min (134.03±62.69 pmol mmol −1 versus 181.59±70.26 pmol mmol l −1; P<0.05) and diminished C-peptide response in relation to glucose (4.05±0.36 nmol mmol −1 versus 4.23±0.36 nmol mmol −1; P<0.05) at OGTT. Both groups did not show difference in insulin secretion and ISI by hyperglycemic clamp technique. We concluded that in up to 12 years from index pregnancy, women with previous GHG, presenting normal glucose tolerance and well-matched with their controls, showed β-cell dysfunction without change in ISI. As women with previous GHG are at risk of type 2 diabetes, β-cell dysfunction may be its primary defect.

Plasma Adiponectin and Leptin Levels, Body Composition, and Glucose Utilization in Adult Women With Wide Ranges of Age and Obesity

The purpose of this study was to determine the relationships between plasma adiponectin and leptin levels, total and central obesity, and glucose utilization across the adult age span. We studied 148 women aged 18-81 years with a BMI range of 17.2-44.3 kg/m(2). Total percent body fat was determined by dual-energy X-ray absorptiometry and abdominal fat by computed tomography. Glucose tolerance in non-type 2 diabetic volunteers was determined with an oral glucose tolerance test. Glucose utilization (M) was measured during the last 60 min of hyperinsulinemic-euglycemic clamps (240 pmol x m(-2) x min(-1)). Plasma adiponectin levels were measured by radioimmunoassay. The women were separated into three age-groups: young, middle, and old (<40, 40-59, and >or=60 years, respectively), as well as by glucose tolerance status. Adiponectin concentrations did not differ by age-groups. There were significant age effects for BMI, percent body fat, visceral fat, subcutaneous abdominal fat, VO(2max), and M. Adiponectin levels were lower in the prediabetic women (n = 18) than in the normal glucose-tolerant women (n = 108) and the women with type 2 diabetes (n = 22) (both P < 0.05). Univariate correlations revealed significant negative relationships between plasma adiponectin levels and BMI, percent body fat, visceral fat, subcutaneous abdominal fat, fasting leptin, and fasting insulin and positive relationship with M (all P < 0.05). In a multiple stepwise regression model to predict adiponectin, only M remained in the model at P < 0.001. Multivariate analyses revealed a significant relation for M as a function of adiponectin, insulin, and VO(2max). The data suggest that plasma adiponectin does not change with age but levels are negatively associated with percent body fat, visceral fat, subcutaneous abdominal fat, insulin, and leptin levels in women. Adiponectin is positively associated with M across the age span in women.

Global fibrinolytic capacity is decreased in polycystic ovary syndrome, suggesting a prothrombotic state.

The polycystic ovary syndrome (PCOS) is associated with an increased risk of cardiovascular disease (CVD). Insulin resistance (IR), hyperandrogenism, and dyslipidemia are well-known cardiovascular risk factors in PCOS. Impaired fibrinolysis could also contribute to the development of CVD in PCOS. Global fibrinolytic capacity (GFC) is a recently developed method, which is reflected by the amount of generated D-dimer when the fibrinolysis of a freeze-dried fibrin clot is stopped by introducing aprotinin. GFC is sensitive to all the factors involved in the process of fibrinolysis. We evaluated whether women with PCOS have any alterations in the GFC and other essential hemostatic parameters. Fifty-nine nonobese, normal glucose-tolerant women with PCOS (age, 22.9 +/- 4.4 yr; body mass index, 23.0 +/- 2.4 kg/m(2) ) and 23 age- and body mass index-matched healthy controls participated. We measured GFC and triglycerides; total cholesterol; HDL-cholesterol (HDL-C); lipoprotein-a; prothrombin time; partial thromboplastin time; thrombin time; antithrombin III; factors II, V, VII, and X; fibrinogen; plasminogen; antiplasmin; and D-dimer. Serum glucose and insulin (at baseline and during a 75-g 2-h oral glucose tolerance test) were also measured, and IR was assessed by homeostatic model assessment. GFC was significantly lower in the PCOS group, compared with the control group (2.49 +/- 1.6 vs. 5.95 +/- 2.43 microg/ml, P < 0.001). All the other coagulation and fibrinolysis parameters were comparable between the two groups. The PCOS group had lower HDL-C and higher IR values. GFC was correlated with testosterone and free testosterone negatively and with HDL-C positively. There was no correlation between GFC and any of the IR parameters. Our results suggest that women with PCOS have impaired fibrinolysis, as reflected by the decreased GFC. This impairment is not related to the IR and may increase the risk of CVD in PCOS.

Relative Hyperproinsulinemia as a Sign of Islet Dysfunction in Women with Impaired Glucose Tolerance1

Proinsulin release is increased relative to insulin secretion in subjects with type 2 diabetes, indicative of islet dysfunction. However, it has not been conclusively shown whether there is an increased relative proinsulin release in subjects with impaired glucose tolerance (IGT), i.e. whether it precedes the development of diabetes. We therefore determined the proinsulin to insulin ratios in the fasting state and after acute stimulation of insulin secretion in 23 postmenopausal women, aged 61-62 yr (mean +/- SD, 61.7 +/- 0.5 yr). Ten women had normal glucose tolerance (NGT), and 13 had IGT. The groups were matched for insulin sensitivity and did not differ in body mass index. Proinsulin and insulin secretion were measured after arginine stimulation (5 g, i.v.) at three glucose levels (fasting, 14 mmol/L, and >25 mmol/L), and the acute insulin (AIR(arg)) and proinsulin responses (APIR(arg)) were calculated as the mean 2-5 min postload increase. At fasting glucose, levels of insulin, proinsulin, or the proinsulin/insulin ratio (13.6 +/- 5.0% vs. 11.1 +/- 2.7%; P = NS) did not differ between NGT and IGT. Although the AIR(arg) values were decreased in the IGT group at all glucose levels (P < 0.05), the absolute proinsulin levels and the APIRs(arg) were similar between IGT and NGT women. Therefore, the IGT women had higher proinsulin/insulin ratios at 14 mmol/L (10.7 +/- 4.4% vs. 6.4 +/- 1.8%; P = 0.006) and more than 25 mmol/L glucose (11.4 +/- 5.2% vs. 6.7 +/- 2.1%; P = 0.007). The IGT group had increased APIR(arg)/AIR(arg) at fasting (2.2 +/- 1.4% vs. 1.3 +/- 0.6%; P = 0.047) and more than 25 mmol/L glucose (3.5 +/- 1.6% vs. 2.3 +/- 0.7%; P = 0.037). We conclude that women with IGT exhibit increased relative proinsulin secretion, suggesting a defect in the intracellular proinsulin processing before diabetes develops.