Low levels of Sex-Hormone-Binding Globulin predict insulin requirement in patients with gestational diabetes mellitus.

Low Sex-Hormone-Binding Globulin (SHBG) levels--indicating a state of hyperandrogenicity--are associated with a higher risk for the development of non-insulin dependent diabetes (NIDDM) in women and are accepted as a marker of muscular insulin resistance. To analyze whether low SHBG values are also present in patients with gestational diabetes, we investigated levels of SHBG in 42 patients with gestational diabetes mellitus (GDM) in comparison with 48 pregnant women with normal glucose tolerance (NGT). Beside maternal parameters like body-mass index (BMI), HbA1c, fasting, 1- and 2-hour blood glucose and insulin concentrations, parameters of the new-borns (head-circumference, body weight, height and sex) were recorded. Maternal and neonatal variables were then related to SHBG levels. Both groups showed no differences in BMI, height, weight or age of gestation. Patients with GDM revealed significantly lower levels of SHBG than pregnant women with NGT(512 +/- 249 nmol/l vs. 643 +/- 137 nmol/l; p < 0.01). In patients with severe GDM and insulin therapy significantly lower levels of SHBG than in those with dietary treatment only were found (223 +/- 210 nmol/l vs. 592 +/- 102 nmol/l; p < 0.001). SHBG was inversely correlated to BMI (r = - 0.30; p < 0.01), 1-hour (r = - 0.20; p < 0.05) and 2-hour blood glucose levels (r = - 0.30; p <0.01). In summary, we found significantly lower levels of SHBG in patients with GDM, especially in those who developed severe GDM and required insulin therapy during the last months of pregnancy.     

Relative hypoleptinaemia in women with mild gestational diabetes mellitus.

AIMS: There is increasing evidence suggesting that leptin plays a major role in the regulation of energy homeostasis, as well as in the neuroendocrine and reproductive systems. Leptin is synthesized in the human placenta. The aim of this study was to relate serum leptin levels during pregnancy to glucose tolerance, body mass index (BMI) and specific metabolic variables, such as specific insulin and proinsulin. METHODS: A 2-h 75 g oral glucose tolerance test was performed in 221 pregnant women at 22-29 weeks of gestation (median 25th week). Serum leptin was measured using a radioimmunoassay. In 49 women, sequential leptin measurements were performed (during pregnancy and post partum (median 5 months)). RESULTS: During pregnancy serum leptin was significantly related to body weight (r = 0.49), BMI (r = 0.51), fasting immunoreactive insulin (r = 0.46), specific insulin (r = 0.43) and proinsulin (r = 0.29) (all P-values <0.0001). In women with mild gestational diabetes (GDM, n = 55), leptin levels were lower compared to women with normal glucose tolerance (n = 166) after adjusting for BMI and fasting insulin (26.9 vs. 19.4 ng/ml, P = 0.0001). Leptin was significantly higher during pregnancy compared to post partum (mean +/- SE: 24.3+/-1.5 vs. 19.6+/-1.6 ng/ml, P = 0.0003), even after adjustment for changes in BMI and changes in fasting insulin (P = 0.013). CONCLUSIONS: Leptin levels are elevated in pregnancy. Women with mild GDM presented with relative hypoleptinaemia compared to women with normal glucose tolerance.     

Reduced pancreatic B cell compensation to the insulin resistance of aging: impact on proinsulin and insulin levels

Type 2 diabetes mellitus is associated with insulin resistance, reduced B cell function, and an increase in the proinsulin (PI) to immunoreactive insulin (IRI) ratio (PI/IRI); the latter is thought to be an indication of B cell dysfunction. Normal aging is associated with insulin resistance and reduced B cell function, but it is not known whether changes in PI and the PI/IRI ratio are also a feature of the aging-associated B cell dysfunction. Therefore, we tested whether the aging-associated changes in insulin sensitivity and B cell function result in changes in PI and IRI levels that are proportionate or whether they are disproportionate as in type 2 diabetes. Twenty-six healthy older (mean +/- SEM age, 67 +/- 1 yr) and 22 younger (28 +/- 1 yr) subjects with similar body mass indexes (27.9 +/- 0.6 vs. 26.3 +/- 1.0 kg/m2) were studied. PI was measured by a RIA recognizing both intact PI and its conversion intermediates. The insulin sensitivity index (SI) was quantified using the minimal model, and B cell function was measured as fasting insulin levels, the acute insulin response to glucose (AIRglucose), and as the acute insulin response to arginine at maximal glycemic potentiation (AIRmax). B cell function was also adjusted for SI based on the known hyperbolic relationship between these two variables. Older and younger subjects had similar fasting glucose (5.3 +/- 0.1 vs. 5.2 +/- 0.1 mmol/L), IRI (83 +/- 8 vs. 76 +/- 9 pmol/L), PI (8.9 +/- 0.8 vs. 10.6 +/- 2.0 pmol/L), and PI/IRI ratio (12.3 +/- 1.3% vs. 13.9 +/- 1.6%; all P = NS) despite a 50% reduction of insulin sensitivity (SI, 1.94 +/- 0.21 vs. 3.88 +/- 0.38 x 10(-5) min(-1)/pmol x L; P < 0.001) and in B cell function [SI x fasting IRI, 139 +/- 18 vs. 244 +/- 24 x 10(-5)(P < 0.001); SI x AIRglucose, 0.75 +/- 0.13 vs. 1.70 +/- 0.15 x 10(-2) min(-1) (P < 0.001); SI x AIRmax, 3.63 +/- 0.53 vs. 6.81 +/- 0.70 x 10(-2) min(-1) (P < 0.001)] in the older subjects. These findings suggest that the B cell dysfunction in older subjects is not associated with disproportionate proinsulinemia. However, in older subjects the B cell response to the insulin resistance of aging is reduced whether measured as fasting levels of PI or IRI or as the acute response to secretagogues. Thus, when examined in terms of the degree of insulin sensitivity, the lower fasting IRI levels in older subjects suggest that the utility of fasting insulin levels as a surrogate measure of insulin resistance in older individuals may be limited.     

Relative hyperproinsulinemia as a sign of islet dysfunction in women with impaired glucose tolerance.

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.     

Evidence against a rate-limiting role of proinsulin processing for maximal insulin secretion in subjects with impaired glucose tolerance and beta-cell dysfunction

In subjects with impaired glucose tolerance (IGT) insulin secretion is impaired. Increased proinsulin/insulin (PI/I) ratios suggest that there is also reduced processing of proinsulin to insulin in this condition. The PI/I ratio in the insulin secretory granule is ideally assessed by plasma measurements in response to acute stimulation of insulin secretion. In the present study we tested the hypothesis that maximal stimulation of insulin secretion results in exhaustion of the proinsulin conversion pathway to insulin. We therefore determined the PI/I ratio in 11 normal glucose-tolerant subjects (NGT) and 11 subjects with IGT in response to glucose (squarewave hyperglycemic clamp, 10 mmol/L), glucagon-like peptide-1 (GLP-1; primed-continuous infusion), and arginine given during the continued GLP-1 infusion. In IGT, insulin levels were significantly lower during the first phase (144 +/- 20 vs. 397 +/- 119 pmol/L; P = 0.02), at the end of the GLP infusion (2142 +/- 350 vs. 5430 +/- 1091 pmol/L; P: = 0.002), and in response to arginine (3983 +/- 375 vs. 8663 +/- 1430 pmol/L; P = 0.005). In response to glucose, the minimum PI/I ratio was significantly higher in IGT (3.4 +/- 0.6%) than in NGT (1.4 +/- 0.5%; P = 0.02), suggesting defective proinsulin processing in this condition. In subjects with IGT, the PI/I ratio decreased significantly after GLP-1 priming (1.7 +/- 0.2%; P = 0.02) and after arginine given during GLP-1 (1.4 +/- 0.2%; P = 0.007) and was not significantly different from those values in NGT (1.3 +/- 0.2% and 1.3 +/- 0.2%, respectively; both P = NS). In conclusion, during maximal stimulation of insulin secretion in subjects with IGT, the PI/I ratio in plasma decreased significantly and was not different from that in normal controls. This strongly argues against the hypothesis that defective processing of proinsulin to insulin represents a major component of the beta-cell dysfunction in IGT.     

Hyperproinsulinemia is not a characteristic feature in the offspring of patients with different phenotypes of type II diabetes

OBJECTIVE: The purpose of this work was to study whether there are differences in plasma proinsulin levels and proinsulin-to-specific insulin ratio in the offspring of patients with different phenotypes of type II diabetes. DESIGN: Eleven glucose-tolerant offspring of type II diabetic patients with deficient insulin secretion phenotype (IS group), nine glucose-tolerant offspring of patients with insulin-resistant phenotype (IR group), and fourteen healthy control subjects without a family history of diabetes were studied. METHODS: Plasma specific insulin, plasma proinsulin, and plasma C-peptide levels were measured during a 2-h oral glucose tolerance test and during hyperglycemic clamp. RESULTS: Plasma proinsulin levels during the oral glucose tolerance test and the hyperglycemic clamp did not differ among the study groups. The IR group had a lower fasting plasma proinsulin-to-specific insulin ratio (10.3+/-1.7%) than the control group (15.4+/-1.4%; P<0.05) and the IS group (18.6+/-2.7%; P<0.05). Furthermore, the IR group had lower plasma proinsulin-to-specific insulin ratio at 30, 60 and 90 min after the oral glucose load than the IS group. However, there were no significant differences in proinsulin-to-C-peptide ratio during the oral glucose tolerance test among the study groups. In stepwise multiple regression analysis, hepatic specific insulin extraction in the fasting state (beta =0.65; P<0.001) and fasting blood glucose (beta =0.32; P<0.05) together explained 52% of the variation in fasting plasma proinsulin-to-specific insulin ratio. CONCLUSIONS: Hyperproinsulinemia is not a characteristic finding in glucose-tolerant offspring of type II diabetic probands with deficient insulin secretion or insulin-resistant phenotype. The differences in proinsulin-to-specific insulin ratios were most likely explained by different hepatic extraction among the study groups.     

Association of proinsulin and insulin resistance with coronary artery disease in non-diabetic south Indian men.

AIMS: To evaluate the association of plasma proinsulin and insulin resistance (IR) with coronary artery disease (CAD) in non-diabetic subjects. METHODS: In this case control study, 41 normoglycaemic men with angiographic evidence of CAD were compared with 41 control men matched for age and glycaemia and with no history or evidence of cardiac diseases. Estimations of plasma glucose, lipids, fasting plasma specific insulin (SI) and proinsulin (PI) were performed. IR was calculated by the homeostasis model assessment (HOMA) method. Multiple logistic regression analysis was performed to test the association of the variables with the prevalence of CAD. RESULTS: Subjects with CAD had a higher body mass index (BMI) (25.4 +/- 4.3 vs. 22.9 +/- 3.2 kg/m2, P = 0.003) and waist to hip ratio (WHR) (0.95 +/- 0.05 vs. 0.89 +/- 0.09, P = 0.001) and a lower high-density lipoprotein (HDL) cholesterol level (0.97 +/- 0.2 vs. 1.1 +/- 0.2 mmol/l, P = 0.002). They also had higher mean SI values (107.5 vs. 62.3 pmol/l, P = 0.002), PI values (19.3 vs. 5.7 pmol/l, P < 0.0001), PI/SI ratios (21.4 vs. 10.3, P < 0.0001) and HOMA IR (4.2 vs. 2.4, P = 0.004) compared with non-CAD subjects. These variables were associated with CAD in the unadjusted multiple regression analysis. In the multiple regression with the forward entry of the variables, WHR and PI only showed independent association with CAD. CONCLUSIONS: Subjects with CAD had higher levels of obesity and WHR. CAD showed an association with low HDL cholesterol, circulating PI, PI/SI ratios and IR.     

Lack of relationship between beta3-adrenergic receptor gene polymorphism and gestational diabetes mellitus in a Taiwanese population

The Trp64Arg polymorphism of beta(3)-adrenergic receptor (ADRB3) has been reported to be associated with insulin resistance and gestational diabetes mellitus (GDM). The objective of this study is to investigate whether the ADRB3 Arg variant confers susceptibility to GDM in a Taiwanese population. A total of 299 pregnant women (mean +/- SD, 31.1 +/- 4.2 years) was recruited. Two-hour, 75-g oral glucose tolerance tests (OGTT) were conducted at 24 to 31 weeks gestation (28.3 +/- 1.6 weeks). Forty-one GDM subjects and 258 controls with normal glucose tolerance (NGT) level were genotyped for the ADRB3 Trp64Arg polymorphism. The genotype distribution and allele frequency of ADRB3 did not significantly differ between GDM and NGT subjects (9.8% v 14.5%). Body weight gain during pregnancy was not different between ADRB3 genotypes. However, the GDM subjects with the Arg64 variant had higher fasting (P =.04) and postload 120 minutes (P =.03) insulin levels as compared with the GDM subjects with the Trp64Trp allele. In all subjects, the women with the Arg64 allele (n = 76) had significantly higher level of insulin secretion (the ratio of Deltainsulin(60)/Deltaglucose(60)) during OGTT than those without (n = 223) (P =.03) despite similar plasma levels of glucose and insulin in both genotypes. Our results indicated that the ADRB3 Trp64Arg variant is not related to the development of GDM and has no effect on obesity during pregnancy in a Taiwanese population. However, ADRB3 polymorphism might be a possible determinant of insulin resistance.     

不同糖耐量个体血清瘦素水平与特异胰岛素、胰岛素原及胰岛素敏感性的关系探讨

目的　研究不同糖耐量人群空腹瘦素水平与特异胰岛素、胰岛素原及胰岛素敏感性之间的关系。方法　用放射免疫法测量 5 4例正常糖耐量 (NGT)、33例糖耐量低减 (IGT)、4 7例新发 2型糖尿病 (DM )的空腹瘦素水平、口服葡萄糖耐量试验 (OGTT) 0、1/2、1、2h的特异胰岛素 (SI)和胰岛素原 (PI)。结果　 (1)多元逐步回归分析显示 ,性别、体重指数 (BMI)、胰岛素敏感性指数是影响空腹瘦素水平最重要的因素 (校正的R2 分别为 0 .2 5 1、0 .4 19、0 .4 38,P值分别为 <0 .0 0 1、<0 .0 0 1、<0 .0 5 ) ;空腹血清瘦素水平与OGTT各时间点PI、SI、PI/SI值无相关性。 (2 )在校正性别、BMI等影响因素后 ,空腹血清瘦素水平在不同糖耐量组差异无显著性 ;DM组OGTT各时间点PI/SI值明显高于IGT组和NGT组 (P <0 .0 1) ;胰岛素敏感性 (ISI)为NGT组 >IGT组 >DM组 (P <0 .0 0 1)。结论　在测定特异胰岛素、胰岛素原时 ,血清瘦素水平除了与性别、BMI相关外 ,尚与胰岛素敏感性 (按SI水平计算 )相关 ;不同糖耐量状态对血清瘦素水平无明显影响 ;DM组存在胰岛素不敏感、PI/SI失调     

Do adiponectin,TNFα, leptin and CRP relate to insulin resistance in pregnancy? Studies in women with and without gestational diabetes,during and after pregnancy

BACKGROUND: The role of adiponectin, tumour necrosis factor alpha (TNFalpha), leptin and C-reactive protein in the insulin resistance of pregnancy is not clear. We measured their levels in women with gestational diabetes (GDM) and in controls, during and after pregnancy, and related them to insulin secretion and action. METHODS: Nineteen women with GDM and 19 BMI-matched healthy pregnant women underwent intravenous glucose tolerance tests in the third trimester of pregnancy and 4 months postpartum to determine insulin sensitivity (SI) and insulin secretion. Adiponectin, TNFalpha, leptin and high sensitivity CRP (hsCRP) were measured in fasted blood. RESULTS: Of the circulating factors, only leptin (r = -0.41, p = 0.01) correlated with SI in pregnancy. Leptin and hsCRP levels were elevated in pregnancy compared to postpartum (leptin (mean +/- SEM): 27.8 +/- 2.4 vs 19.3 +/- 2.1 ng/mL, p < 0.001; hsCRP: 5.2 +/- 0.7 vs 3.2 +/- 0.6 mg/L, p < 0.001). Adiponectin levels did not change from pregnancy to postpartum, despite a marked increase in SI. All four factors correlated with SI postpartum (adiponectin: r = 0.38, p = 0.01; TNFalpha: r = -0.48, p = 0.002; Leptin: r = -0.61, p = 0.001; hsCRP: r = -0.48, p = 0.002). TNFalpha correlated inversely with insulin secretion in pregnancy (r = -0.35, p = 0.03) and was significantly higher in the GDM group (2.62 +/- 0.3 vs 1.88 +/- 0.3 pg/mL, p = 0.01) in pregnancy. CONCLUSION: In our study, the influence of adiponectin, TNFalpha and hsCRP upon SI is overwhelmed by other factors in pregnancy. While leptin and SI correlated in pregnancy, it is unclear whether this represents cause or effect. Finally, TNFalpha may exert an inhibitory effect on insulin secretion in GDM, contributing to the associated hyperglycaemia.     

Visfatin concentration is decreased in women with gestational diabetes mellitus in the third trimester

Our aim is to investigate visfatin concentration and its relationship to glycated hemoglobin (HbA1c), insulin resistance, lipid parameters, and neonatal birth weight in women with gestational diabetes mellitus (GDM). In our study group, there were 47 women with GDM and 31 women with normal glucose tolerance (NGT) between 33-39 weeks of gestation. Plasma visfatin levels were significantly decreased in pregnant women with GDM compared to those with NGT (p=0.001). Homeostasis model assessment-insulin resistance (HOMA-IR) levels were higher in the GDM group than in the NGT group (p=0.006). In all subjects, plasma visfatin levels were negatively correlated with HOMA-IR, post-prandial blood glucose, triglycerides, and VLDL cholesterol (p<0.05). We did not observe any statistically significant correlation between the plasma visfatin levels and the selected parameters in the GDM group, but in the NGT group plasma visfatin levels were negatively correlated with HOMA-IR (r=-0.36, p=0.04). There was no correlation between visfatin concentrations and fetal birth weight in either group (p>0.05). By regression analysis, having GDM was found to be the only significant determinant (t=3.5, p=0.001) of visfatin concentration (R=0.39, r2=0.15). We conclude that women with GDM have significantly decreased visfatin concentrations in the third trimester. Future studies are required to establish the exact role of visfatin in the pathogenesis of GDM.     

Fibrinolytic dysfunction after gestation is associated to components of insulin resistance and early type 2 diabetes in latino women with previous gestational diabetes

Among patients with metabolic syndrome (MS), atherosclerosis and abnormal fibrinolytic function are frequently present, mostly owing to an increase in plasminogen activator inhibitor-1(PAI-1). We analyze PAI-1 in pregnant women, both normal and with gestational diabetes (GDM) and postpartum regarding its correlation to MS surrogates. Clinical characteristics, glucose tolerance (100g-OGTT), lipids, PAI-1 antigen, insulin sensitivity (HOMA-S), and pancreatic beta-cell function (HOMA-B) were investigated in 34 women. Eleven had normal glucose tolerance (NGT) during pregnancy and 23 had GDM (all GAD antibodies-negative). All patients were studied at 28-34 weeks of gestation and 16-24 weeks after delivery (75 g-OGTT). Parameters of interest were determined using commercial test systems. During pregnancy, PAI-1 was not statistically different between NGT and GDM (47+/-25 ng/ml versus 47+/-28 ng/ml, p=0.9). After gestation, 19 (56%) women had NGT (11 of them from previous NGT group) and 15 (44%) had impaired glucose tolerance (IGT) or DM. The IGT (IGT+DM) group had higher PAI-1 (p=0.01), which did not decreased after delivery NGT-NGT before and after delivery (47+/-25 ng/ml versus 6+/-5 ng/ml; p<0.001), GDM-NGT (62+/-36 ng/ml versus 14+/-15 ng/ml; p=0.001) and GDM-IGT (39+/-20 ng/ml versus 27+/-23 ng/ml; p=0.15). PAI-1 levels were positively correlated (p<0.05) to total cholesterol (r(s)=0.37), triglycerides (r(s)=0.48), fasting plasma glucose (r(s)=0.52), 2-h plasma glucose in the OGTT (r(s)=0.58) and were negatively correlated (p<0.05) with HOMA-S (r(s)=-0.42) and HOMA-B (r(s)=-0.38). Fibrinolytic dysfunction is still present in GDM women and is associated with early development of IGT or T2DM. PAI correlated with surrogate markers of MS levels and may identify a group of women at risk for macroangiopathy.     

Abnormalities in fasting circulating proinsulin concentration in mild gestational diabetes

Fasting plasma proinsulin, insulin and glucose concentrations were measured in ten women with mild gestational diabetes and ten controls matched for race, age (32 +/- 6 vs 31 +/- 6 years), body mass index (28 +/- 8 vs 27 +/- 6) and gestational week (24 +/- 4 vs 25 +/- 4 weeks). There was no significant difference in fasting plasma glucose between these gestational diabetics and their controls (median 4.7, range 3.7-6.0 mmol/l vs 4.5, range 3.4-5.3 mmol/l). The fasting proinsulin levels were significantly higher in the gestational diabetics compared with the controls (median 12.2, range less than 4-14.8 pmol/l vs 5.8, range less than 4-12.8 pmol/l, P less than or equal to 0.02, Wilcoxon Summed Rank Test), while the calculated intact insulin levels (immunoreactive insulin minus proinsulin) were significantly lower (median 14.5, range 6.3-81.8 pmol/l vs 51.6, range 11.7-312 pmol/l, P less than or equal to 0.01). The ratio of proinsulin to calculated intact insulin was significantly higher in the gestational diabetics than the controls (median 0.66, range 0.16-2.04 vs 0.12, range 0.03-0.62), P less than or equal to 0.01). These results demonstrate that gestational diabetics, with normal fasting plasma glucose values, have abnormalities in pancreatic beta-cell secretion, which are likely to be important both in the aetiology of gestational diabetes and non-insulin dependent diabetes.     

不同糖耐量水平人群血清真胰岛素和胰岛素原水平的临床意义

目的 探讨不同糖耐量者血清真胰岛素（ＴＩ）及胰岛素原（ＰＩ）水平的变化及临床意义。方法 用特异的单克隆抗体夹心放大酶联免疫分析法（ＢＡ－ＥＬＩＳＡ）检测１３５例正常糖耐量（ＮＧＴ）、８６例糖耐量低减（ＩＧＴ）及１０１例Ⅱ型糖尿病（ＤＭ）者口服葡萄糖耐量试验（ＯＧＴＴ）各点血清ＴＩ及ＰＩ水平。结果 ３组血清空腹ＴＩ差异无显著性（Ｐ〉０．０５）,免疫反应胰岛素（ＩＲＩ）Ⅱ型ＤＭ组明显升高（Ｐ〈０．０１     

The serum levels of proinsulin and their relationship with IGFBP-1 in obese children

AIM: Serum proinsulin (PI) levels were investigated in obese children to determine whether PI is a sensitive indicator of insulin resistance, as previously shown in adults with type 2 diabetes mellitus (DM), and to evaluate their relationship with insulin-like growth factor-binding protein-1 (IGFBP-1) known as a predictor of the development of cardiovascular disease in diabetic adults. SUBJECTS AND METHODS: Forty-two obese children without DM (age, 12.1 +/- 1.5 year) and 42 age-matched control children were included in the study. The serum levels of PI, immunoreactive insulin (IRI), IGFBP-1 and free insulin-like growth factor-1 (IGF-1) were measured in the fasting state. RESULTS: The fasting levels of serum PI and IRI were significantly higher in obese children than in controls (PI, 10.5 +/- 6.8 vs. 5.6 +/- 2.0 pmol/l, p < 0.001; IRI, 72.0 +/- 41.8 vs. 32.7 +/- 19.5 pmol/l, p < 0.001). Serum IGFBP-1 levels were significantly lower in obese children than in controls (37.7 +/- 24.6 vs. 76.3 +/- 26.5 microg/l, p < 0.001). The ratio of PI to IRI (calculated as molar ratios) did not differ significantly between obese and control subjects (0.16 +/- 0.08 vs. 0.19 +/- 0.11, p = 0.08). For the whole group, serum PI levels correlated positively with IRI and inversely with IGFBP-1 (IRI, r = 0.67, p < 0.001; IGFBP-1, r = -0.49, p < 0.001). Serum IGFBP-1 levels correlated inversely with both BMI and IRI (BMI, r = -0.73, p < 0.001; IRI, r = -0.60, p < 0.001). Multiple regression analysis revealed that the best predictive parameters for IGFBP-1 were BMI and PI (R2 = 0.57, p < 0.001 and p < 0.05, respectively). CONCLUSION: These findings suggest that fasting serum PI levels may be a better predictor than fasting insulin levels for the future development of type 2 DM and cardiovascular disease in obese children, and PI, in addition to insulin, contributes to the suppression of hepatic IGFBP-1 production.     

Insulin resistance has no impact on ghrelin suppression in pregnancy

Ghrelin is reduced in various states of insulin resistance. The aim of this study was to examine the relationship between ghrelin and glucose metabolism during pregnancy - a natural insulin-resistant state - in women with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or gestational diabetes mellitus (GDM) and potential changes 3 months after delivery. A total of 54 women, 37 pregnant and with various degrees of insulin resistance and 24 postpartum (PP, seven of them also studied during pregnancy) were studied. Ghrelin plasma concentrations at fasting and 60' following glucose loading (75 g-2 h-oral glucose tolerance test), area under the curve of plasma glucose (G-AUC(OGTT)) and insulin sensitivity [homeostatic model assessment (HOMA) and oral glucose sensitivity index (OGIS) indices, respectively] were determined. Both baseline and 60' ghrelin concentrations were to a comparable degree ( approximately by 65%) suppressed in NGT, IGT and GDM as compared to the PP group (the latter being indistinguishable from NGT regarding glucose tolerance and insulin sensitivity). In all women studied both during and after pregnancy, ghrelin levels rose from pregnancy to PP (mean increase 313.8%; P < 0.03). There was no correlation between baseline ghrelin and insulin sensitivity as estimated from both baseline (HOMA) and dynamic (OGTT:OGIS) glucose and insulin data. Ghrelin is substantially decreased during pregnancy, but glucose-induced ghrelin suppression is preserved at a lower level. There is apparently no relation to the degree of insulin resistance.     

C-reactive protein and gestational diabetes: the central role of maternal obesity

Acute-phase biomarkers such as C-reactive protein (CRP) and IL-6 have emerged as predictors of incident type 2 diabetes mellitus, implicating chronic subclinical inflammation as a factor in the pathophysiology of diabetes. Gestational diabetes (GDM) identifies a population of women at high risk of subsequent type 2 diabetes mellitus, representing an early stage in the natural history of the disease. In this context, we performed a cross-sectional study to determine whether markers of subclinical inflammation are elevated in patients with GDM. We studied 180 healthy pregnant women undergoing oral glucose tolerance testing in the late second or early third trimester. Based on oral glucose tolerance testing and prepregnancy body mass index (BMI), participants were stratified into four groups: 1) normal glucose tolerance (NGT) lean (BMI, <25 kg/m(2)) (n = 65); 2) NGT overweight (n = 28); 3) impaired glucose tolerance (n = 39); and 4) GDM (n = 48). Median CRP level was highest in overweight NGT subjects (8.8 mg/liter), followed by GDM (5.5 mg/liter), impaired glucose tolerance (4.4 mg/liter), and lean NGT (4.4 mg/liter) (overall P = 0.0297). CRP was significantly correlated with prepregnancy BMI (r = 0.38, P < 0.0001), followed by fasting insulin (r = 0.27, P = 0.0002) and fasting blood glucose (r = 0.18, P = 0.016). In multivariate linear regression analysis, prepregnancy BMI emerged as the most important determinant of CRP concentration, whereas glycemic tolerance status was not a significant factor. Furthermore, the observed stepwise increase in CRP per tertile of prepregnancy BMI was not significantly attenuated by glycemic tolerance status or factors known to be associated with GDM. In summary, we demonstrate that maternal serum levels of CRP are not related to GDM but rather correlate significantly with prepregnancy obesity. An independent contribution of CRP to risk of GDM could not be confirmed. These data suggest a model in which obesity mediates a systemic inflammatory response, with possible downstream metabolic sequelae, including insulin resistance and glucose dysregulation.     

Insulin secretion during and after pregnancy in patients with gestational diabetes mellitus

We have determined prehepatic insulin secretion rates (ISRs) in seven patients with gestational diabetes mellitus (GDM) and in eight age- and weight-matched nondiabetic pregnant women during late gestation (third trimester) and again postpartum. Plasma glucose concentrations were raised to approximately 8.9 mM with iv glucose (hyperglycemic clamping), and ISRs were determined by deconvolution of peripheral C-peptide concentrations using C-peptide kinetic parameters that were obtained in every patient during late gestation and again postpartum. Plasma insulin levels were measured by RIA with an antibody with minimal (<0.2%) cross-reactivity with proinsulin. During late gestation, women with GDM were more insulin resistant than nondiabetic controls and had significantly lower ISRs (689 vs. 849 pmol/min, P < 0.05) and glucose uptake rates (30.6 vs. 49.4 micromol/kg.min, P < 0.05) in response to hyperglycemia. Postpartum, ISRs and insulin resistance decreased in women with GDM and controls (ISR by 43% and 43%, respectively, and insulin resistance by 75% and 118%, respectively), and both groups had similar ISRs (352 vs. 408 pmol/min, nonsignificant). Women with GDM, however, continued to be more insulin resistant than controls. In summary, patients with GDM during late pregnancy not only had severe deficiencies in ISR but, in addition, were more insulin resistant than controls. Postpartum, insulin resistance and ISRs (and plasma insulin levels) improved in both groups, and ISRs (and plasma insulin levels) were no longer significantly different in patients with GDM and controls. Insulin resistance, however, remained higher in women with GDM, and their glucose uptake remained lower. We concluded that the women with GDM had a major ss-cell defect that made it impossible for them to compensate for their increased level of insulin resistance, which occurred during late pregnancy.     

Plasma leptin is not associated with insulin resistance and proinsulin in non-diabetic South Asian Indians

In an earlier study, we observed only a weak association between plasma insulin (non-specific assay) and leptin in South Asian Indians. This was in contrast to the observations in many other ethnic groups. With the availability of measurements of specific insulin (SI) and proinsulin (PI) in the same study group, we have reanalysed the data to look for possible correlation of leptin with proinsulin and with insulin resistance calculated from the fasting values of specific insulin and glucose using the HOMA model. Subjects with normoglycaemia (n = 117) and impaired glucose tolerance (n = 27, WHO criteria) were included in the analysis. Leptin values were higher in women. Multiple linear regression analysis showed that the variations in leptin concentrations in men were associated with BMI, WHR, and 2 h SI values (R² = 56.2 %) while fasting SI and proinsulin concentrations had no significant association. In women BMI and age showed a significant association with serum leptin values (R² = 40.1 %). Univariate and multivariate analyses using insulin resistance as the dependent variable showed that it had no association with leptin in both genders. Leptin had no correlation with proinsulin also. This study confirmed that in Asian Indians the association between plasma leptin and insulin concentrations is weak and that leptin has no influence on insulin resistance. Proinsulin and leptin are also not correlated in this population. Insulin resistance shows correlation with the β-cell function both in men and women. © 1998 John Wiley & Sons, Ltd.     

A DIRECT ASSAY FOR PROINSULIN IN PLASMA AND ITS APPLICATIONS IN HYPOGLYCAEMIA

A direct radioimmunoassay in unextracted plasma is described. The assay has a sensitivity of 4 pmol/l (2 standard deviation from zero). The proinsulin antiserum was immuno-adsorbed against human C-peptide and insulin coupled to glass beads. Cross-reactivity of the antiserum was assessed and shown to be less than 0.01% with both peptides. In normal healthy fasting subjects the plasma proinsulin level was 6.7 +/- 1.7 pmol/l (n = 17) (mean +/- SD). Fasting proinsulin levels in non-insulin dependent diabetics were significantly elevated compared with non diabetics (14.2 +/- 2 pmol/l (n = 11) vs 6.7 +/- 1.7 (n = 17) P less than 0.005). The insulin/proinsulin ratio was 3.4:1 in the non-insulin dependent diabetic compared with 6:1 in non-diabetics. Samples from 21 insulinoma patients were assayed and mean fasting plasma proinsulin level was 255 pmol/l +/- 479 when the patients were hypoglycaemic. The range in pro-insulin levels was large (30-2300 pmol/l). Mean fasting proinsulin level in three hypoglycaemic subjects due to sulphonylurea overdose was 15.7 +/- 2.3 pmol/l. The molar ratio of proinsulin to insulin was 1:6 in healthy subjects, 1:1 in insulinoma patients and 10:1 in sulphonylurea induced hypoglycaemic patients.