HPI-15K Sigma-AldrichHuman Proinsulin RIA

The aim was to study the effect of family history of type 2 diabetes mellitus (T2DM) on insulin sensitivity and ?-cell function in normoglycemic offspring.

Heterozygous mutations in the human preproinsulin (INS) gene are a cause of nonsyndromic neonatal or early-infancy diabetes. Here, we sought to identify INS mutations associated with maturity-onset diabetes of the young (MODY) or nonautoimmune diabetes in mid-adult life, and to explore the molecular mechanisms involved.

OBJECTIVE: Noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS), characterized by postprandial neuroglycopaenia, negative prolonged fasts and negative perioperative localization studies for insulinoma, but positive selective arterial calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas, is a rare hypoglycaemic disorder of undetermined aetiology. We analysed the clinical, morphological and immunohistological features to further clarify the aetiology and pathogenesis of this rare disease. PATIENTS: Ten consecutive patients with NIPHS (nine men and one woman, aged 29-78 years) were included in the study. Six of the 10 received a gradient-guided subtotal (70%) or distal (50%) pancreatectomy. In the remaining four patients, diazoxide treatment was initiated and the precise mechanism of its action was assessed by meal tests. RESULTS: All of the patients showed a combination of postprandial neuroglycopaenia, negative prolonged fasts (except one patient) and negative localization studies for insulinoma, but positive calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas. Immunohistological studies of the resected pancreatic tissues revealed neither an increased rate of proliferation of beta-cells nor an abnormal synthesis and/or processing of either proinsulin or amylin. Evidence of overexpression of the two pancreatic differentiation factors, PDX-1 and Nkx-6.1, as well as the calcium sensing receptor (CaSR) was absent. Nevertheless, abnormal expression of islet neogenesis-associated protein (INGAP), a human cytokine expressed only in the presence of islet neogenesis, in ducts and/or islets, was identified in three of the five patients studied. All of the six patients who received a surgical operation were relieved of further neuroglycopaenic attacks, but one patient who received a subtotal pancreatectomy developed diabetes. In the remaining four patients who received diazoxide treatment, hypoglycaemic episodes were satisfactorily controlled with an attenuated response of beta-cell peptides to meal stimulation. CONCLUSIONS: Our results strengthen the existence of this unique clinical hypoglycaemic syndrome from beta-cell hyperfunction as well as the value of the selective arterial calcium stimulation test in its correct diagnosis and localization. The mechanisms underlying beta-cell hyperfunction and release of insulin to calcium, however, remain poorly characterized. Nevertheless, in a subset of patients with NIPHS, there exists some, as yet undefined, pancreatic humoral/paracrine factor(s) other than proinsulin, amylin, PDX-1, Nkx-6.1 and possibly glucagon-like peptide-1 (GLP-1) that are capable of inducing the INGAP gene and, if activated, will initiate ductal proliferation and islet neogenesis. As for the treatment, we recommend that diazoxide be tried first in each patient and, should it fail, a gradient-guided subtotal or distal pancreatectomy be attempted.

CONTEXT: Women of Asian and South Asian descent are at increased risk of developing gestational diabetes mellitus compared with Caucasians, despite lower body mass index (BMI). Nevertheless, there has been limited study of insulin action during pregnancy in these ethnic groups. OBJECTIVE: The objective of the study was to compare insulin sensitivity in pregnancy in Asian, South Asian, and Caucasian subjects and to determine whether the impact of obesity on insulin action is modified by ethnicity. DESIGN AND PARTICIPANTS: A cross-sectional study was performed in outpatients undergoing oral glucose tolerance testing in late pregnancy. Participants were stratified into three groups: 1) Caucasian (n = 116); 2) South Asian (n = 31); and 3) Asian (n = 28). MAIN OUTCOME MEASURE: Insulin sensitivity was measured using the oral glucose tolerance test (IS(OGTT)) index of M. Matsuda and R. DeFronzo, previously validated in pregnancy. Results: There were no significant ethnic differences in insulin sensitivity despite variation in prepregnancy BMI (Caucasians, 25.2 kg/m(2); South Asians, 23.3 kg/m(2); Asians, 21.4 kg/m(2); overall P = 0.0001). On multiple linear regression analysis, the strongest independent determinants of IS(OGTT) were gestational diabetes mellitus (t = -5.71; P 0.0001) and BMI (t = -5.43; P 0.0001). Importantly, both Asian (t = -2.87; P = 0.0047) and South Asian (t = -2.46; P = 0.015) ethnicity also emerged as negative, independent determinants of IS(OGTT). Furthermore, Asian ethnicity significantly modified the association of prepregnancy BMI with IS(OGTT) (interaction term, t = -2.29; P = 0.0231). CONCLUSIONS: Asian and South Asian ethnicity are both independently associated with increased insulin resistance in late pregnancy. Prepregnancy BMI has a much greater effect on insulin resistance in pregnancy in Asian women than in Caucasians. Ethnicity thus emerges as a factor that modulates the effect of obesity on insulin resistance in pregnancy.

OBJECTIVE: Excessive secretion of the insulin precursor proinsulin, as manifested by an increased serum proinsulin-to-insulin ratio, has been associated with beta-cell dysfunction. In women with gestational diabetes mellitus (GDM), previous studies of the proinsulin-to-insulin ratio have yielded conflicting results, despite the presence of beta-cell dysfunction. The interpretation of the proinsulin-to-insulin ratio, however, may be confounded by the variable effects of hepatic insulin extraction. Thus, we sought to determine whether GDM is characterized by relative hyperproinsulinemia as measured by the proinsulin-to-C-peptide ratio, an alternate measure of proinsulin secretion that is not affected by hepatic insulin extraction. RESEARCH DESIGN AND METHODS: Serum proinsulin, C-peptide, and insulin were measured in a cross-sectional study of 180 women undergoing oral glucose tolerance tests (OGTTs) in the late second or early third trimester. Based on the OGTT, participants were stratified into three groups: 1) normal glucose tolerance (NGT; n = 93), 2) impaired glucose tolerance (IGT; n = 39), and 3) GDM (n = 48). Insulin sensitivity (IS) was measured using the IS(OGTT) index of Matsuda and DeFronzo, which has been previously validated in pregnant women. RESULTS: There were no significant differences in mean fasting proinsulin-to-C-peptide ratio between the three glucose tolerance groups (NGT, 0.024; IGT, 0.022; GDM, 0.019; P = 0.4). Furthermore, adjustment for age, weeks' gestation, prepregnancy BMI, ethnicity, previous GDM, and family history of diabetes did not reveal any association between the proinsulin-to-C-peptide ratio and glucose tolerance status. Using Spearman univariate correlation analysis, fasting proinsulin-to-C-peptide ratio was significantly correlated with IS(OGTT) (r = 0.29, P 0.0001) and inversely related to the homeostasis model assessment of insulin resistance (r = -0.36, P 0.0001) and prepregnancy BMI (r = -0.23, P 0.005). On multiple linear regression analysis, IS(OGTT) emerged as the strongest independent correlate of the dependent variable proinsulin-to-C-peptide ratio. Furthermore, after adjustment for potential covariates, a stepwise decrease in proinsulin-to-C-peptide ratio was observed per decreasing tertile of IS(OGTT) (trend P = 0.0019), consistent with enhanced efficiency of proinsulin processing (i.e., reduced proinsulin-to-C-peptide ratio) as insulin resistance increases. CONCLUSIONS: GDM is not independently associated with hyperproinsulinemia as measured by the proinsulin-to-C-peptide ratio. Instead, in pregnant women, increased insulin resistance is associated with decreased proinsulin-to-C-peptide ratio, independently of glucose tolerance status. These data suggest that relative proinsulin secretion in late pregnancy is primarily related to insulin resistance and does not necessarily reflect beta-cell function.

Offspring of type 2 diabetics have an increased risk of dyslipidemia, glucose intolerance and obesity. The aim of this study was to assess the lipid levels in the offspring of diabetics with normal glucose tolerance and normal body weight.