Higher Insulin Secretion Research Articles

Curcumin improves high glucose-induced INS-1 cell insulin resistance via activation of insulin signaling.

Curcumin is a yellow pigment isolated from Corcuma longan. This research investigates the improvement of curcumin on INS-1 cells with insulin resistance induced by high glucose. INS-1 cells were treated with high glucose (30 mmol L(-1)) for 48 h. Subsequently, the medium was replaced with curcumin for 24 h. Curcumin effectively increased insulin gene expression and glucose stimulated insulin secretion (GSIS) in a dose-dependent manner. Furthermore, the molecular mechanism of curcumin-induced insulin expression and secretion in high glucose-induced INS-1 cells was investigated in this study. Curcumin increased the expression of glucose transporter 2 (GLUT2) and phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS1), phosphatidylinositol-3-kinase (PI3K) and AKT in the INS-1 cells. Moreover, curcumin stimulation increased the expression of PDX-1 and GCK. This investigation suggests that curcumin prevented high glucose-reduced insulin expression and secretion through activation of the PI3K/Akt/GLUT2 pathway in INS-1 cells.

Enhanced or reduced fetal growth induced by embryo transfer into smaller or larger breeds alters post-natal growth and metabolism in pre-weaning horses.

In equids, placentation is diffuse and nutrient supply to the fetus is determined by uterine size. This correlates with maternal size and affects intra-uterine development and subsequent post-natal growth, as well as insulin sensitivity in the newborn. Long-term effects remain to be described. In this study, fetal growth was enhanced or restricted through ET using pony (P), saddlebred (S) and draft (D) horses. Control P-P (n = 21) and S-S (n = 28) pregnancies were obtained by AI. Enhanced and restricted pregnancies were obtained by transferring P or S embryos into D mares (P-D, n = 6 and S-D, n = 8) or S embryos into P mares (S-P, n = 6), respectively. Control and experimental foals were raised by their dams and recipient mothers, respectively. Weight gain, growth hormones and glucose homeostasis were investigated in the foals from birth to weaning. Fetal growth was enhanced in P-D and these foals remained consistently heavier, with reduced T3 concentrations until weaning compared to P-P. P-D had lower fasting glucose from days 30 to 200 and higher insulin secretion than P-P after IVGTT on day 3. Euglycemic clamps in the immediate post-weaning period revealed no difference in insulin sensitivity between P-D and P-P. Fetal growth was restricted in S-P and these foals remained consistently lighter until weaning compared to S-D, with elevated T3 concentrations in the newborn compared to S-S. S-P exhibited higher fasting glycemia than S-S and S-D from days 30 to 200. They had higher maximum increment in plasma glucose than S-D after IVGTT on day 3 and clamps on day 200 demonstrated higher insulin sensitivity compared to S-D. Neither the restricted nor the enhanced fetal environment affected IGF-1 concentrations. Thus, enhanced and restricted fetal and post-natal environments had combined effects that persisted until weaning. They induced different adaptive responses in post-natal glucose metabolism: an early insulin-resistance was induced in enhanced P-D, while S-P developed increased insulin sensitivity.

An improved method for murine islet isolation and subcapsular kidney transplantation

Objective To present a series of islet transplantation in mice by improve the method of islet isolation and subcapsular kidney transplantation.Methods Islet isolation was completed by end of the common bile duct ligation,Perfusion of the pancreas by 3 ml collagenase V (2 g/L),filtration by 100 μm filter and purification by picking islets under microscopy.Islets' yield,purity,function of insulin secretion and effect of islet transplantation were evaluated compared with islets isolated by Ficoll density gradient separation method.Results Purification by filtration increased islet yield (P ＜ 0.01),and resulted in higher insulin secretion in vitro (P ＜ 0.01).Moreover,when syngeneic diabetic hosts were transplanted with a marginal islet mass,the number of islets purified by filtration which restore normoglycemia significantly was less than those isolated by Ficoll.Conclusion Islet filtration is a simple and rapid procedure for purification of islets that demonstrate improved functional mass.The islet transplantation model consisted by Islet filtration and subcapsular kidney transplantation might be widely used in the research of islet transplantation. Key words: Islet isolation; Subcapsular kidney transplantation; Filtration

Culturing Free-Floating and Fibrin-Embedded Islets with Endothelial Cells: Effects on Insulin Secretion and Apoptosis

There is a need to develop methods to culture isolated endocrine pancreatic islets in vitro, as their capacity to secrete insulin typically declines following isolation and they usually undergo apoptosis. In this study, the effects on insulin secretion and apoptosis were tested for two co-culture systems of endocrine porcine islets (1) embedded in fibrin with porcine liver microvascular endothelial cells (PLMEC) and (2) seeded on PLMEC monolayers. The addition of endothelial cells in fibrin resulted in better preserved islet integrity, higher insulin secretion over 7 days, improved glucose-stimulated insulin secretion (GSIS), less loss of insulin-expressing cells over 7 days, and reduced apoptosis, the latter only for 2 days. Seeding islets on PLMEC monolayers had marginal improvement of the insulin secretion over 7 days. It improved GSIS for 2 days, but not over 7 days, as it did not affect the loss of insulin-expressing cells over 7 days. When compared to freely-floating islets in tissue culture polystyrene, the apoptosis level of islets seeded on PLMEC monolayers was on par and slightly decreased over 2 and 7 days, respectively. For both islets co-seeded with PLMEC in fibrin and those cultured on PLMEC monolayers, insulin secretion decreased over 7 days.

Abstract P455: Insulin Resistance, Secretion and Risk of Incident Coronary Heart Disease in Non-diabetic Japanese Population: The Circulatory Risk in Communities Study

Background: Both high insulin resistance and low insulin secretion are the causes of diabetes mellitus. Japanese level of insulin secretion said to be lower than Western people. However, the association between insulin resistance, secretion and risk of coronary heart disease (CHD) or stroke in non-diabetic population remains unknown. Hypothesis: We assessed the hypothesis that each higher insulin resistance and lower insulin secretion is associated with increased risk of CHD even in non-diabetic population. Methods: A prospective study of Japanese subjects aged 40-79 years was undertaken using data collected from 5,639 participants (1,971 men and 3,668 women) who had no past history of cardiovascular disease or diabetes mellitus in cardiovascular risk surveys conducted in three communities of the Circulatory Risk in Communities Study (CIRCS) in 2000 and 2001. Insulin resistance was calculated on the basis of fasting glucose (mg/dL) and insulin levels (μU/mL) according to the homeostasis model assessment (HOMA-r) method: glucose x insulin / 405. The HOMA-beta cell function (HOMA-b) was calculated by using the following formula: 360 x fasting insulin (μU/mL) / (fasting glucose (mg/dL) - 63). Each incidence of CHD and stroke was ascertained by systematic surveillance. The hazard ratios (HRs) of incidence of CHD and 95% confidence intervals (CI) associated with a 1 standard deviation (SD) increase in log(HOMA-r) and in log(HOMA-b) were calculated with adjustment for age and other potential confounding factors using the Cox proportional hazards model. Results: During an average follow up of 9.8-years, 39 incident CHD (including 23 myocardial infarction) and 123 incident stroke occurred. Higher insulin resistance tended to increase risk of CHD or myocardial infarction, but all HRs did not reach statistical significance. The multivariable HRs in log(HOMA-r) for risk of CHD were 1.30(95% CI: 0.23 to 7.42) for men, 2.84(0.60 to 13.56) for women, and 1.56(0.40 to 6.04) for total subjects. The corresponding HRs of myocardial infarction were 3.73(0.31 to 44.87) for men, 2.45(0.46 to 12.98) for women, and 2.71(0.48 to 15.36) for total subjects. Lower insulin secretion associated with risk of CHD or myocardial infarction, and some of HRs reached statistical significance. The multivariable HRs in log(HOMA-b) for risk of CHD were 1.17(0.56 to 2.45) for men, 0.31(0.10 to0.96, p=0.042) for women, and 0.75(0.40 to1.42) for total subjects. The corresponding HRs of myocardial infarction were 0.53(0.18 to1.53) for men, 0.31(0.07 to 1.35) for women, and 0.42(0.18 to1.00, p=0.049) for total subjects. There was no interaction between HOMA-r and HOMA-b. HOMA-r and HOMA-b did not associated with incidence of stroke. Conclusions: Lower insulin secretion may be associated with increased risk of coronary heart disease among non-diabetic Japanese population.

Beneficial effects of liraglutide on adipocytokines, insulin sensitivity parameters and cardiovascular risk biomarkers in patients with Type 2 diabetes: A prospective study

AimsTo evaluate the effects of liraglutide after 14 weeks of treatment on serum adipokines, insulin resistance index and cardiovascular risk biomarkers in overweight or obese T2DM patients unable to achieve glycemic control with metformin alone or in association with a sulfonylurea in daily clinical practice. MethodsProspective study in 59 consecutive overweight or obese (BMI≥25kg/m2) T2DM patients unable to achieve glycemic control (HbA1c>7%, 53mmol/mol) with metformin alone or in association with sulfonylurea that require initiation of liraglutide in progressive dose increase up to 1.8mg/day subcutaneously. Weight, body composition, blood pressure, glucose, HbA1c, C-peptide, insulin, plasma lipids, adipokines (leptin, adiponectin, resistin and visfatin) as well as cardiovascular biomarkers (IL-6 and TNF-a) levels were measured fasting at baseline and 14 weeks after liraglutide initiation. Results14 weeks of liraglutide treatment significantly reduced HbA1c, BMI and total body fat mass by 0.9%, 1.4kg/m2 and 0.5% respectively. Statistically significant lower insulin resistance and higher insulin secretion was found by HOMA-IR 8.4 (1.6) vs 4.6 (0.9)molmIU/L2 and HOMA-B 48.2 (9.0) vs 87.6 (16.3)μIU/mmol. Statistically significantly higher levels of visfatin 6.3 (2.1) vs 6.8 (2.1)ng/ml and resistin 3.6 (2.0) vs 4.3 (2.3)ng/ml were also observed after treatment. Baseline visfatin was negatively correlated with basal fasting plasma glucose r=−0.360 (p<0.05). ConclusionsLiraglutide treatment for 14 weeks in daily clinical practice led to reduction of BMI and improvement of glucose control and insulin sensitivity and resistance parameters. Additionally, circulating levels of adipokines and pro-inflammatory factors could play an important role in GLP-1 treatment response.

Gender and glycaemia: Insulin sensitivity and secretion in premature neonates

The inability to regulate blood glucose concentration (BG) is a common complication of prematurity and stress in neonatal intensive care, particularly in very low birth weight (VLBW) neonates. Model-based glycaemic control requires quantification of glucose and insulin appearance, clearance, and action. In the VLBW neonates plasma insulin concentration is often used to reflect insulin secretion due to sampling limitations. In this study, C-peptide concentrations are used to more accurately analyse insulin secretion in a VLBW neonatal cohort, and a comparison of insulin secretion and sensitivity is made between male and female sub cohorts. The retrospective analysis is made of a cohort comprises 88 extremely pre-term (median age 26 [25–27] weeks) and very low birth-weight infants (median birth weight 793 [691-901 g]). In 41 of the infants, C-Peptide plasma concentrations were used in conjunction with C-peptide models to estimate insulin secretion. Time varying model-based insulin sensitivity values are also fit across dense clinical data from the entire 88 patients. Female infants had higher insulin secretion than males (P<0.005) for comparable BG and plasma insulin concentrations. Females also had a higher correlation of increasing insulin secretion with increasing BG (R2=0.51) than males (R2=0.13), and were more insulin sensitive (P<0.005), and had greater hour to hour variability in this sensitivity (P<0.005). The results suggest female neonates are better able to clear insulin, and probably reflect the worsened outcomes and increased complications in male neonates, reported in the literature.

Insulin Oversecretion in MSG-Obese Rats is Related to Alterations in Cholinergic Muscarinic Receptor Subtypes in Pancreatic Islets

Background/ Aims: Impaired pancreatic beta cell function and insulin secretion/action are a link between obesity and type 2 diabetes, which are worldwide public health burdens. We aimed to characterize the muscarinic acetylcholine receptor (mAChR) M₁-M₄ subtypes in isolated pancreatic islets from pre-diabetic obese rats that had been treated neonatally with monosodium L-glutamate (MSG). Methods: At 90 days of age, both the MSG and the control groups underwent biometric and biochemical evaluation. Anti-muscarinic drugs were used to study mAChR function either in vivo or in vitro. Results: The results demonstrated that atropine treatment reduced insulin secretion in the MSG-treated and control groups, whereas treatment with an M₂mAChR-selective antagonist increased secretion. Moreover, the insulinostatic effect of an M₃mAChR-selective antagonist was significantly higher in the MSG-treated group. M₁mAChR and M₃mAChR expression was increased in the MSG-obese group by 55% and 73%, respectively. In contrast, M₂mAChR expression decreased by 25% in the MSG group, whereas M₄mAChR expression was unchanged. Conclusions: Functional changes in and altered content of the mAChR (M₁-M₄) subtypes are pivotal to the demand for high pancreatic beta cell insulin secretion in MSG-obese rats, which is directly associated with vagal hyperactivity and peripheral insulin resistance.

Prediction of Diabetes Based on Baseline Metabolic Characteristics in Individuals at High Risk

OBJECTIVEIndividuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM versus maintenance of IGT or conversion to normal glucose tolerance.RESEARCH DESIGN AND METHODSWe studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years.RESULTSIn a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, ∆G0–120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln ∆I0–120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [∆I0–120/∆G0–120]) during the OGTT was associated with decreased risk of diabetes. Higher β-cell function (insulin secretion/insulin resistance or disposition index; ln [∆I0–120/∆G0–120 × Matsuda index of insulin sensitivity]; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes.CONCLUSIONSIn a stepwise multiple-variable analysis, only HbA1c and β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).

β-Cell Lipotoxicity in Response to Free Fatty Acid Elevation in Prepubertal Youth

Prepubertal African American (AA) youth compared with their Caucasian (C) peers have higher insulin secretion, which correlates positively with free fatty acid (FFA) concentration. In our continued efforts to explain the racial disparity in insulinemia, and because FFAs modulate insulin secretion, we hypothesized that AA youth would have a greater response to FFA-induced β-cell insulin secretion than C youth. We compared the short-term effects of FFA elevation on fasting and glucose-stimulated C-peptide–modeled insulin secretion in prepubertal normal-weight AA versus C peers during a 2-h hyperglycemic clamp (12.5 mmol/L) on two occasions: 1) infusion of normal saline and 2) infusion of 20% intralipid (IL). During IL infusion, insulin sensitivity (IS) declined comparably in AA and C youth. Glucose sensitivity of first- and second-phase insulin secretion showed a significant condition × race interaction being higher in AA youth. Disposition index, β-cell function relative to IS, declined with IL infusion in AA and C youth, with a significantly greater decrease in Cs compared with AAs. In conclusion, AA and C prepubertal youth both demonstrated a decline in β-cell function relative to IS during IL infusion, indicative of acute lipotoxicity. The greater decline in C youth compared with AAs may suggest that C youth are more susceptible to β-cell lipotoxicity than AA youth, or alternatively, that AA youth are hypersensitive to FFA stimulation of β-cell insulin secretion, consistent with our theory.

Normal Weight Obesity Is Associated with Metabolic Syndrome and Insulin Resistance in Young Adults from a Middle-Income Country

ObjectiveThis population-based birth cohort study examined whether normal weight obesity is associated with metabolic disorders in young adults in a middle-income country undergoing rapid nutrition transition.Design and MethodsThe sample involved 1,222 males and females from the 1978/79 Ribeirão Preto birth cohort, Brazil, aged 23–25 years. NWO was defined as body mass index (BMI) within the normal range (18.5–24.9 kg/m2) and the sum of subscapular and triceps skinfolds above the sex-specific 90th percentiles of the study sample. It was also defined as normal BMI and % BF (body fat) >23% in men and >30% in women. Insulin resistance (IR), insulin sensitivity and secretion were based on the Homeostasis Model Assessment (HOMA) model.ResultsIn logistic models, after adjusting for age, sex and skin colour, NWO was significantly associated with Metabolic Syndrome (MS) according to the Joint Interim Statement (JIS) definition (Odds Ratio OR = 6.83; 95% Confidence Interval CI 2.84–16.47). NWO was also associated with HOMA2-IR (OR = 3.81; 95%CI 1.57–9.28), low insulin sensitivity (OR = 3.89; 95%CI 2.39–6.33), and high insulin secretion (OR = 2.17; 95%CI 1.24–3.80). Significant associations between NWO and some components of the MS were also detected: high waist circumference (OR = 8.46; 95%CI 5.09–14.04), low High Density Lipoprotein cholesterol (OR = 1.65; 95%CI 1.11–2.47) and high triglyceride levels (OR = 1.93; 95%CI 1.02–3.64). Most estimates changed little after further adjustment for early and adult life variables.ConclusionsNWO was associated with MS and IR, suggesting that clinical assessment of excess body fat in normal-BMI individuals should begin early in life even in middle-income countries.

Glycemia, Insulin Resistance, Insulin Secretion, and Risk of Depressive Symptoms in Middle Age

OBJECTIVEThe extent to which abnormal glucose metabolism increases the risk of depression remains unclear. In this study, we investigated prospective associations of levels of fasting glucose and fasting insulin and indices of insulin resistance and secretion with subsequent new-onset depressive symptoms (DepS).RESEARCH DESIGN AND METHODSIn this prospective cohort study of 3,145 adults from the Whitehall II Study (23.5% women, aged 60.6 ± 5.9 years), baseline examination included fasting glucose and insulin level, the homeostasis model assessment of insulin resistance (HOMA2-%IR), and the homeostasis model assessment of β-cell insulin secretion (HOMA2-%B). DepS (Center for Epidemiologic Studies Depression Scale ≥16 or use of antidepressive drugs) were assessed at baseline and at 5-year follow-up.RESULTSOver the 5-year follow-up, DepS developed in 142 men and 84 women. Women in the lowest quintile of insulin secretion (HOMA2-%B ≤55.3%) had 2.18 (95% CI 1.25–3.78) times higher odds of developing DepS than those with higher insulin secretion. This association was not accounted for by inflammatory markers, cortisol secretion, or menopausal status and hormone replacement therapy. Fasting insulin measures were not associated with DepS in men, and fasting glucose measures were not associated with new-onset DepS in either sex.CONCLUSIONSLow insulin secretion appears to be a risk factor for DepS in middle-aged women, although further work is required to confirm this finding.

Induction of receptor for advanced glycation end products by insufficient leptin action triggers pancreatic β‐cell failure in type 2 diabetes

Glucolipotoxicity, which is exerted by free fatty acids (FFA) and prolonged hyperglycemia, is implicated in pancreatic β-cell failure in diabetes. Pattern recognition receptors such as receptor for advanced glycation end products (RAGE) and toll-like receptors 2 and 4 could mediate danger signals in β-cells. We examined whether RAGE contributes to β-cell failure in a type 2 diabetes mouse model. Pancreatic islets were isolated from ob/ob, db/db, diet-induced obesity (DIO), RAGE-null (RAGE(-/-) ), and RAGE(+/+) wild-type (WT) control mice and dispersed into single cells for flow cytometry. RAGE expression was detected in insulin-positive β-cells of ob/ob and db/db mice, but not of WT, DIO, or RAGE(-/-) mice: thus, inadequate leptin receptor signaling and RAGE expression may be linked. Compared with RAGE(+/+) db/db mice, RAGE(-/-) db/db mice showed higher β-cell number and mass with less apoptosis as well as glucose tolerance with higher insulin secretion without any differences in serum levels of FFA and adiponectin. Palmitate or oleate pretreatment combined with a leptin antagonist induced RAGE expression, AGE-elicited apoptosis, and impaired glucose-stimulated insulin secretion by advanced glycation end products (AGE) in MIN6 cells. FFA elevation with concomitant AGE formation during prolonged hyperglycemia could cause β-cell damage through insufficient leptin action and subsequent RAGE induction in type 2 diabetes.

Neuroendocrine tumor presenting as metastatic carcinoid and later as insulinoma: a rare metamorphosis

We describe a very rare case of a neuroendocrine tumor, which initially presented as metastatic carcinoid with lesions in the liver and bones. Diagnosis was made by an elevated blood serotonin level and 24 hour urine 5HIAA. Liver biopsy confirmed the presence of a well differentiated neuroendocrine tumor (NET) staining positive for Chromogranin and negative for insulin. Two years after the initial diagnosis, the patient started to experience neuroglycopenic symptoms. Insulin and C-peptide levels were markedly elevated along with severe and recurrent hypoglycemic episodes. Due to extremely high insulin secretion from a large tumor burden, the patient’s clinical condition rapidly deteriorated in spite of maximal medical treatment. Shortly after the diagnosis of metastatic Insulinoma with unknown primary was made, the patient developed multiple organ system failure which limited invasive diagnostic techniques for localization. It appears that this patient’s neuroendocrine tumor had undergone a partial or complete change in its humoral function from a carcinoid or indolent neuroendcorine tumor to an Insulinoma or that the tumor started to co-secrete insulin along with serotonin. Less likely, he may have developed a separate tumor in the pancreas which was unable to be visualized by conventional imaging. Excess secretion of both Serotonin and Insulin from a single tumor is extremely rare and very few cases have been reported in the literature where a gastroenteopancreatic NET was found to secrete both insulin and serotonin.

Role of glycemic variability in gestational diabetes mellitus (GDM): still an uphill climb

Insulin resistance tends to increase in physiological pregnancy because of the gradually rising levels of feto-placental hormones such as progesterone, cortisol, growth hormone, prolactin, and human placental lactogen. In response to this imbalance, the pancreas normally compensates with a higher insulin secretion. When this compensatory mechanism fails, glucose intolerance develops and, in pregnancy, this is called gestational diabetes mellitus (GDM) [1]. The resulting maternal hyperglycemia gives rise to a concomitant fetal hyperinsulinemia via the placenta, leading primarily to fetal macrosomia, which is the main cause of well-known complications relating to the fetus’s development (e.g., shoulder dystocia, Erb’s paralysis, hypoxia, and acidosis) and to the course of labor (e.g., perineal laceration, cesarean section) [2]. Clinical evidence has confirmed that the main goal of glycemic management in GDM is to keep the mother’s blood glucose levels as close as possible to the normal range. A number of studies have demonstrated that macrosomia correlate with glycemic control in pregnancy complicated by diabetes [3]. It has recently been suggested that glucose variability, characterized by significant glucose excursions, may overlap with HbA1c levels in determining the risk of diabetes-related complications [4]. Oscillating blood sugar levels have been shown to increase free radicals and endothelial dysfunction, which are the links between hyperglycemia and the activation of pathological pathways that lead to tissue damage [5], and it has been reported that containing these hyperglycemic spikes coincides with a reduction in some markers of oxidative stress. In pregnancy complicated by diabetes even transient periods of hyperglycemia may lead to accelerated fetal growth, resulting in macrosomic infants. These peaks are difficult to capture using common glucose monitoring methods based on six to eight glucose measurements a day, whereas continuous glucose monitoring (CGM) systems are more revealing because they enable glucose levels to be monitored constantly throughout the day [6]. Despite recent opportunities to shed further light on the subject, glucose variability is still a poorly understood factor in GDM patients, especially its link with maternal and fetal complications. In one study, 48-h CGM was performed in all three trimesters in 31 women with GDM, and showed a close relationship between babies’ ponderal index and their mothers’ glucose variability indicators and mean glycemia in the 2nd trimester, irrespective of their HbA1c levels. This study emphasized that fetal growth in the early stages of gestation could be affected even in patients whose glycemic variability indices were only slightly higher than in controls [7]. In this issue of Endocrine, Su et al. [8] set out to use 72-h CGM to analyze several glycemic variability parameters in 30 patients with GDM, as compared with 20 healthy pregnant women and 20 healthy non-pregnant women, seeking a possible association with markers of beta-cell function. As indicators of glucose variability, they took into account the mean amplitude of glycemic excursion (MAGE), the mean of daily differences (MODD), and the standard deviation of blood glucose (SDBG); the HOMA-IR index was calculated to assess insulin resistance. The early insulinogenic index (DI30/DG30) and the area under the curve of insulin (AUCI 180) derived from 75 g oral glucose tolerance test (OGTT) were calculated to A. Lapolla (&) N. C. Chilelli Department of Medicine (DIMED), University of Padua, Via Giustiniani n 2, 35128 Padua, Italy e-mail: annunziata.lapolla@unipd.it

Glucose Response Curve and Type 2 Diabetes Risk in Latino Adolescents

OBJECTIVEIn adults, the shape of the glucose response during an oral glucose tolerance test (OGTT) prospectively and independently predicts type 2 diabetes. However, no reports have described the utility of this indicator in younger populations. The purpose of this study was to compare type 2 diabetes risk factors in Latino adolescents characterized by either a monophasic or biphasic glucose response during an OGTT.RESEARCH DESIGN AND METHODSA total of 156 nondiabetic Latino adolescents completed a 2-h OGTT. Monophasic and biphasic groups were compared for the following type 2 diabetes risk factors: fasting and 2-h glucose, HbA1c, glucose area under the curve (AUC), insulin sensitivity (Matsuda index), insulin secretion (insulinogenic index), and β-cell function as measured by the disposition index (insulin sensitivity × insulin secretion).RESULTSOf the participants, 107 youth were categorized as monophasic and 49 were biphasic. Compared with the monophasic group, participants with a biphasic response exhibited lower HbA1c (5.4 ± 0.3 vs. 5.6 ± 0.3%, P < 0.01) and lower glucose AUC (14,205 ± 2,382 vs. 16,230 ± 2,537 mg ⋅ dL−1 ⋅ h−1, P < 0.001) with higher insulin sensitivity (5.4 ± 3.2 vs. 4.6 ± 3.4, P ≤ 0.05), higher insulin secretion (2.1 ± 1.3 vs. 1.8 ± 1.3, P = 0.05), and better β-cell function (10.3 ± 7.8 vs. 6.0 ± 3.6, P < 0.001). Differences persisted after adjusting for age, sex, and BMI.CONCLUSIONSThese data suggest that the glycemic response to an OGTT may differentiate risk for type 2 diabetes in youth. This response may be an early marker of type 2 diabetes risk among high-risk youth.

Early maternal undernutrition programs increased feed intake, altered glucose metabolism and insulin secretion, and liver function in aged female offspring

Insulin resistance and obesity are components of the metabolic syndrome that includes development of cardiovascular disease and diabetes with advancing age. The thrifty phenotype hypothesis suggests that offspring of poorly nourished mothers are predisposed to the various components of the metabolic syndrome due to adaptations made during fetal development. We assessed the effects of maternal nutrient restriction in early gestation on feeding behavior, insulin and glucose dynamics, body composition, and liver function in aged female offspring of ewes fed either a nutrient-restricted [NR 50% National Research Council (NRC) recommendations] or control (C: 100% NRC) diet from 28 to 78 days of gestation, after which both groups were fed at 100% of NRC from day 79 to lambing and through lactation. Female lambs born to NR and C dams were reared as a single group from weaning, and thereafter, they were fed 100% NRC recommendations until assigned to this study at 6 yr of age. These female offspring were evaluated by a frequently sampled intravenous glucose tolerance test, followed by dual-energy X-ray absorptiometry for body composition analysis prior to and after ad libitum feeding of a highly palatable pelleted diet for 11 wk with automated monitoring of feed intake (GrowSafe Systems). Aged female offspring born to NR ewes demonstrated greater and more rapid feed intake, greater body weight gain, and efficiency of gain, lower insulin sensitivity, higher insulin secretion, and greater hepatic lipid and glycogen content than offspring from C ewes. These data confirm an increased metabolic "thriftiness" of offspring born to NR mothers, which continues into advanced age, possibly predisposing these offspring to metabolic disease.

Acceleration of autoimmune diabetes in Rheb-congenic NOD mice with β-cell-specific mTORC1 activation

The protein Ras homolog enriched in brain (Rheb) is a Ras-like small GTPase that activates the mechanistic target of rapamycin complex 1 (mTORC1), which promotes cell growth. We previously generated transgenic C57BL/6 mice overexpressing Rheb in β-cells (B6 Rheb), which exhibited increased β-cell size and improved glucose tolerance with higher insulin secretion than wild type C57BL/6 mice. The mice also showed resistance to obesity-induced hyperglycemia, a model of type 2 diabetes, and to multiple low-dose-streptozotocin (MLDS)-induced hyperglycemia, a model of type 1 diabetes (T1D). To investigate whether the effects of mTORC1 activation by Rheb in B6 Rheb mice would also be evident in NOD mice, a spontaneous autoimmune T1D model, we created two NOD mouse lines overexpressing Rheb in their β-cells (NOD Rheb; R3 and R20). We verified Rheb overexpression in β-cells, the relative activation of mTORC1 and β-cell enlargement. By 35 weeks of age, diabetes incidence was significantly greater in the R3 line and tended to be greater in the R20 line than in NOD mice. Histological analysis demonstrated that insulitis was significantly accelerated in 12-week-old R3 NOD Rheb mice compared with NOD mice. Furthermore, serum insulin autoantibody (IAA) expression was significantly higher than that of NOD mice. We also examined whether complete Freund’s adjuvant (CFA) treatment alone or with glucagon-like peptide-1 (GLP-1) analog would reverse the hyperglycemia of NOD Rheb mice; unexpectedly, almost none achieved normoglycemia. In summary, diabetes progression was significantly accelerated rather than prevented in NOD Rheb mice. Our results suggest that the β-cell enlargement might merely enhance the autoimmunity of pathogenic T-cells against islets, leading to acceleration of autoimmune diabetes. We conclude that not only enlargement but also regeneration of β-cells in addition to the prevention of β-cell destruction will be required for the ideal therapy of autoimmune T1D.

Effects of Sleeve Gastrectomy and Medical Treatment for Obesity on Glucagon-like Peptide 1 Levels and Glucose Homeostasis in Non-diabetic Subjects

The effects of medical and surgical treatments for obesity on glucose metabolism and glucagon-like peptide 1 (GLP-1) levels independent of weight loss remain unclear. This study aims to assess plasma glucose levels, insulin sensitivity and secretion, and GLP-1 levels before and after sleeve gastrectomy (SG) or medical treatment (MED) for obesity. This study is a prospective, controlled, non-randomised study. Two groups of non-diabetic obese patients with similar BMIs, including a SG group (BMI, 35.5 ± 0.9 kg/m(2); n = 6) and a MED group (BMI, 37.7 ± 1.9 kg/m(2); n = 6) and a group of lean subjects (BMI, 21.7 ± 0.7 kg/m(2); n = 8). Plasma glucose, insulin, and total GLP-1 levels at fasting and after the intake of a standard liquid meal at baseline and at 2 months post-intervention. At baseline, total GLP-1 levels were similar, but obese patients had lower insulin sensitivity and higher insulin secretion than lean subjects. At 2 months post-intervention, SG and MED patients achieved similar weight loss (14.4 ± 0.8%, 15.3 ± 0.9%, respectively). Insulin sensitivity increased in SG and MED patients; however, postprandial insulin secretion decreased after MED, but not after SG. The incremental area under the curve of GLP-1 increased after SG (P = 0.04), but not after MED. Weight loss by medical or surgical treatment improved insulin sensitivity. However, only MED corrected the hyperinsulinemic postprandial state associated to obesity. Postprandial GLP-1 levels increased significantly after SG without duodenal exclusion, which may explain why insulin secretion did not decrease following this surgery.

Increased prevalence of non-alcoholic fatty liver disease in European women with a history of gestational diabetes

Non-alcoholic fatty liver disease (NAFLD) is common in type 2 diabetes but it is unknown whether NAFLD is prevalent in European women at risk of type 2 diabetes. We studied the prevalence of, and risk factors for, NAFLD in European women with previous gestational diabetes (GDM) at high risk of type 2 diabetes. A total of 110 women with previous GDM and 113 without previous GDM, with non-diabetic glucose tolerance were recruited retrospectively from antenatal databases. Participants underwent liver ultrasound scan examination, anthropometry and blood sampling for liver function tests and to determine levels of fasting lipids, NEFA and insulin and glucose concentrations in order to derive insulin sensitivity and insulin secretion indices (HOMA%S and HOMA%B, respectively). There was no significant difference in BMI in women with previous GDM compared with those without previous GDM (28.9 ± 0.6 vs. 27.9 ± 0.6kg/m(2), respectively; p = 0.12). Women with previous GDM had higher fasting and 2h glucose concentrations following a 75g OGTT ([mean ± SEM] fasting glucose 5.3 ± 0.1 vs. 5.1 ± 0.1mmol/l, p = 0.02; 2h glucose 6.8 ± 0.2 vs. 5.8 ± 0.3mmol/l, p = 0.02), dyslipidaemia (LDL-cholesterol 3.3 ± 0.1 vs. 2.8 ± 0.1mmol/l; HDL-cholesterol [median {interquartile range}] 1.3 [1.2-1.6] vs. 1.8 [1.5-1.9] mmol/l; triacylglycerol 1.3 [0.9-1.6] vs. 1.0 [0.7-1.7] mmol/l, all p ≤ 0.03), higher insulin secretion and lower insulin sensitivity. NAFLD prevalence was greater in women with previous GDM compared with those without previous GDM: 38% (95% CI 28-47%) vs. 17% (95% CI 10-24%), p = 0.001. In multiple logistic regression analysis, lower insulin sensitivity and raised serum alanine transaminase concentrations were associated with NAFLD. NAFLD is prevalent in European women with previous GDM. Impaired insulin sensitivity and increased liver transaminase activity are closely associated with NAFLD in these women.