First-phase Insulin Response Research Articles

Acute intravenous glucose load impairs early insulin secretion and insulin content in islet β cells in mice.

To investigate insulin secretion and content in islet β cells after intravenous glucose load in mice. Acute hyperglycemia (≥16.7 mmol/L) in C57BL/J6 mice was achieved by hyperglycemic clamp. Mice were divided into four groups: a 2-hour and a 4-hour high glucose-infusion (2 h-HG and 4 h-HG) with 25% dextrose groups and control groups with saline infusion of the same duration. Insulin levels and response were measured using intraperitoneal glucose tolerance test (IPGTT) in mice and glucose-stimulated insulin secretion (GSIS) for isolated islets after overnight culture. Immunohistochemistry and electron microscopy (EM) for islet β cells were used after the hyperglycemic clamp to study morphologic changes of insulin granules and to assess the impact of acute glucose load on islet histology. Blood glucose at 15, 30, 60 and 120 min was significantly higher in 4 h-HG compared with the other groups. Serum plasma insulin significantly decreased only at 15 min as a first-phase insulin response (FPIR). Insulin secretion at 2.8 and 16.7 mmol/L glucose stimulus in 4 h-HG group decreased 77% and 64% more than those in 2 h-HG, respectively (P<0.05). Similarly, residual insulin content in islet β cells after 2.8 and 16.7 mmol/L glucose challenge decreased 30% and 43% more than those in 2 h-HG, respectively (P<0.05). EM showed decreased insulin granules in islet cells and swollen mitochondria only in 4 h-HG. Short time intravenous glucose load blunted FPIRs and decreased insulin content of islet β cells.

Weight Loss Decreases Excess Pancreatic Triacylglycerol Specifically in Type 2 Diabetes.

This study determined whether the decrease in pancreatic triacylglycerol during weight loss in type 2 diabetes mellitus (T2DM) is simply reflective of whole-body fat or specific to diabetes and associated with the simultaneous recovery of insulin secretory function. Individuals listed for gastric bypass surgery who had T2DM or normal glucose tolerance (NGT) matched for age, weight, and sex were studied before and 8 weeks after surgery. Pancreas and liver triacylglycerol were quantified using in-phase, out-of-phase MRI. Also measured were the first-phase insulin response to a stepped intravenous glucose infusion, hepatic insulin sensitivity, and glycemic and incretin responses to a semisolid test meal. Weight loss after surgery was similar (NGT: 12.8 ± 0.8% and T2DM: 13.6 ± 0.7%) as was the change in fat mass (56.7 ± 3.3 to 45.4 ± 2.3 vs. 56.6 ± 2.4 to 43.0 ± 2.4 kg). Pancreatic triacylglycerol did not change in NGT (5.1 ± 0.2 to 5.5 ± 0.4%) but decreased in the group with T2DM (6.6 ± 0.5 to 5.4 ± 0.4%; P = 0.007). First-phase insulin response to a stepped intravenous glucose infusion did not change in NGT (0.24 [0.13-0.46] to 0.23 [0.19-0.37] nmol ⋅ min(-1) ⋅ m(-2)) but normalized in T2DM (0.08 [-0.01 to -0.10] to 0.22 [0.07-0.30]) nmol ⋅ min(-1) ⋅ m(-2) at week 8 (P = 0.005). No differential effect of incretin secretion was observed after gastric bypass, with more rapid glucose absorption bringing about equivalently enhanced glucagon-like peptide 1 secretion in the two groups. The fall in intrapancreatic triacylglycerol in T2DM, which occurs during weight loss, is associated with the condition itself rather than decreased total body fat.

Reduced β-cell function in early preclinical type 1 diabetes.

ObjectiveWe aimed to characterize insulin responses to i.v. glucose during the preclinical period of type 1 diabetes starting from the emergence of islet autoimmunity.Design and methodsA large population-based cohort of children with HLA-conferred susceptibility to type 1 diabetes was observed from birth. During regular follow-up visits islet autoantibodies were analysed. We compared markers of glucose metabolism in sequential intravenous glucose tolerance tests between 210 children who were positive for multiple (≥2) islet autoantibodies and progressed to type 1 diabetes (progressors) and 192 children testing positive for classical islet-cell antibodies only and remained healthy (non-progressors).ResultsIn the progressors, the first phase insulin response (FPIR) was decreased as early as 4–6 years before the diagnosis when compared to the non-progressors (P=0.001). The difference in FPIR between the progressors and non-progressors was significant (P<0.001) in all age groups, increasing with age (at 2 years: difference 50% (95% CI 28–75%) and at 10 years: difference 172% (95% CI 128–224%)). The area under the 10-min insulin curve showed a similar difference between the groups (P<0.001; at 2 years: difference 36% (95% CI 17–58%) and at 10 years: difference 186% (95% CI 143–237%)). Insulin sensitivity did not differ between the groups.ConclusionsFPIR is decreased several years before the diagnosis of type 1 diabetes, implying an intrinsic defect in β-cell mass and/or function.

Insulin secretion and sensitivity in healthy adults with low vitamin D are not affected by high-dose ergocalciferol administration: a randomized controlled trial

Epidemiologic data suggest that low serum 25-hydroxyvitamin D [25(OH)D] increases insulin resistance and the risk of type 2 diabetes. Few interventional trials have assessed the effect of vitamin D on insulin metabolism, and published results are discordant. The goal of this study was to perform a detailed assessment of the effect of ergocalciferol administration on glucose and insulin metabolism in healthy people with low total 25(OH)D(total). This was a 12-wk, double-blinded, randomized controlled trial. We enrolled 90 healthy volunteers aged 18-45 y with serum 25(OH)D ≤20 ng/mL (by immunoassay) and administered 50,000 IU ergocalciferol/wk or placebo for 12 wk. Primary endpoints were change in first-phase insulin response and insulin sensitivity as measured by intravenous glucose tolerance test. Secondary endpoints included change in homeostasis model assessment of insulin resistance; fasting glucose, insulin, and lipids; body mass index (BMI); and blood pressure. On-study 25(OH)D(total) was assessed by liquid chromatography-tandem mass spectrometry. In the treated group, 25(OH)D(total) rose from 18 ± 7 to 43 ± 12 ng/mL (P < 0.001) with no change in the placebo group. Despite this increase, at 12 wk, there were no between-group differences in either insulin response or insulin sensitivity; nor were there differences in any measured secondary endpoints. There was no evidence of effect modification by sex, race, glucose tolerance status, baseline 25(OH)D(total), or BMI. In healthy persons with low 25(OH)D(total), ergocalciferol administration for 12 wk normalizes 25(OH)D(total) but does not improve insulin secretion, insulin sensitivity, or other markers of metabolic health.

Experimental evaluation and computational modeling of the effects of encapsulation on the time-profile of glucose-stimulated insulin release of pancreatic islets.

BackgroundIn type 1 diabetic patients, who have lost their ability to produce insulin, transplantation of pancreatic islet cells can normalize metabolic control in a manner that is not achievable with exogenous insulin. To be successful, this procedure has to address the problems caused by the immune and autoimmune responses to the graft. Islet encapsulation using various techniques and materials has been and is being extensively explored as a possible approach. Within this framework, it is of considerable interest to characterize the effect encapsulation has on the insulin response of pancreatic islets.MethodsTo improve our ability to quantitatively describe the glucose-stimulated insulin release (GSIR) of pancreatic islets in general and of micro-encapsulated islets in particular, we performed dynamic perifusion experiments with frequent sampling. We used unencapsulated and microencapsulated murine islets in parallel and fitted the results with a complex local concentration-based finite element method (FEM) computational model.ResultsThe high-resolution dynamic perifusion experiments allowed good characterization of the first-phase and second-phase insulin secretion, and we observed a slightly delayed and blunted first-phase insulin response for microencapsulated islets when compared to free islets. Insulin secretion profiles of both free and encapsulated islets could be fitted well by a COMSOL Multiphysics model that couples hormone secretion and nutrient consumption kinetics with diffusive and convective transport. This model, which was further validated and calibrated here, can be used for arbitrary geometries and glucose stimulation sequences and is well suited for the quantitative characterization of the insulin response of cultured, perifused, transplanted, or encapsulated islets.ConclusionsThe present high-resolution GSIR experiments allowed for direct characterization of the effect microencapsulation has on the time-profile of insulin secretion. The multiphysics model, further validated here with the help of these experimental results, can be used to increase our understanding of the challenges that have to be faced in the design of bioartificial pancreas-type devices and to advance their further optimization.Electronic supplementary materialThe online version of this article (doi:10.1186/s12938-015-0021-9) contains supplementary material, which is available to authorized users.

L-glutamine and whole protein restore first-phase insulin response and increase glucagon-like peptide-1 in type 2 diabetes patients.

l-glutamine triggers glucagon-like peptide-1 (GLP-1) release from L cells in vitro and when ingested pre-meal, decreases postprandial glycaemia and increases circulating insulin and GLP-1 in type 2 diabetes (T2D) patients. We aimed to evaluate the effect of oral l-glutamine, compared with whole protein low in glutamine, on insulin response in well-controlled T2D patients. In a randomized study with a crossover design, T2D patients (n = 10, 6 men) aged 65.1 ± 5.8, with glycosylated hemoglobin (HbA1c) 6.6% ± 0.7% (48 ± 8 mmol/mol), received oral l-glutamine (25 g), protein (25 g) or water, followed by an intravenous glucose bolus (0.3 g/kg) and hyperglycemic glucose clamp for 2 h. Blood was frequently collected for analyses of glucose, serum insulin and plasma total and active GLP-1 and area under the curve of glucose, insulin, total and active GLP-1 excursions calculated. Treatments were tested 1–2 weeks apart. Both l-glutamine and protein increased first-phase insulin response (p ≤ 0.02). Protein (p = 0.05), but not l-glutamine (p = 0.2), increased second-phase insulin response. Total GLP-1 was increased by both l-glutamine and protein (p ≤ 0.02). We conclude that oral l-glutamine and whole protein are similarly effective in restoring first-phase insulin response in T2D patients. Larger studies are required to further investigate the utility of similar approaches in improving insulin response in diabetes.

Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance.

We evaluated the insulinotropic properties of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in healthy individuals at risk of developing type 2 diabetes before and after glucocorticoid-induced insulin resistance. Nineteen healthy, glucose tolerant, first-degree relatives of type 2 diabetic patients underwent OGTT and 7mmol/l and 15mmol/l glucose clamps with concomitant infusions of GLP-1, GIP or NaCl and a final infusion of arginine for determination of maximum beta cell capacity before and after treatment with dexamethasone. In addition, first-phase insulin responses were determined at 7mmol/l and 15mmol/l and second-phase insulin responses at 7mmol/l. After dexamethasone treatment, all 19 participants had increased insulin resistance (HOMA-IR and insulin sensitivity index [M/I] values) and 2h plasma glucose concentrations, while beta cell function indices generally increased according to the increased resistance. First-phase insulin responses induced by GLP-1 and GIP at 7mmol/l and maximal beta cell secretory capacity did not differ before and after dexamethasone, while second-phase responses to 7mmol/l and first-phase responses to 15mmol/l glucose were reduced equally for both hormones. Glucocorticoid-induced insulin resistance in individuals at risk of type 2 diabetes leads to a reduced insulinotropic effect of the incretin hormones. This reduction was not associated with a decrease in the maximal beta cell secretory capacity, indicating that the reduced incretin effect in the developing dysglycaemia of the present experimental model is due to a specific early reduction of the insulinotropic effects of the incretin hormones. Clinicaltrials.gov NCT02235584.

Immediate enhancement of first-phase insulin secretion and unchanged glucose effectiveness in patients with type 2 diabetes after Roux-en-Y gastric bypass.

Roux-en-Y gastric bypass surgery (RYGB) in patients with type 2 diabetes often leads to early disease remission, and it is unknown to what extent this involves improved pancreatic β-cell function per se and/or enhanced insulin- and non-insulin-mediated glucose disposal (glucose effectiveness). We studied 30 obese patients, including 10 with type 2 diabetes, 8 with impaired glucose tolerance, and 12 with normal glucose tolerance before, 1 wk, and 3 mo after RYGB, using an intravenous glucose tolerance test (IVGTT) to estimate first-phase insulin response, insulin sensitivity (Si), and glucose effectiveness with Bergman's minimal model. In the fasting state, insulin sensitivity was estimated by HOMA-S and β-cell function by HOMA-β. Moreover, mixed-meal tests and oral GTTs were performed. In patients with type 2 diabetes, glucose levels normalized after RYGB, first-phase insulin secretion in response to iv glucose increased twofold, and HOMA-β already improved 1 wk postoperatively, with further enhancements at 3 mo. Insulin sensitivity increased in the liver (HOMA-S) at 1 wk and at 3 mo in peripheral tissues (Si), whereas glucose effectiveness did not improve significantly. During oral testing, GLP-1 responses and insulin secretion increased regardless of glucose tolerance. Therefore, in addition to increased insulin sensitivity and exaggerated postprandial GLP-1 levels, diabetes remission after RYGB involves early improvement of pancreatic β-cell function per se, reflected in enhanced first-phase insulin secretion to iv glucose and increased HOMA-β. A major role for improved glucose effectiveness after RYGB was not supported by this study.

Profound defects in β-cell function in screen-detected type 2 diabetes are not improved with glucose-lowering treatment in the Early Diabetes Intervention Program (EDIP).

Few studies have measured the ability of interventions to affect declining β-cell function in screen-detected type 2 diabetes. The Early Diabetes Intervention Programme (ClinicalTrials.gov NCT01470937) was a randomized study based on the hypothesis that improving postprandial glucose excursions with acarbose would slow the progression of fasting hyperglycaemia in screen-detected type 2 diabetes. In the Early Diabetes Intervention Programme, the effect of acarbose plus lifestyle advice on progression of fasting hyperglycaemia over a 5-year period was not greater than that of placebo. However, there was an early glucose-lowering effect of the trial. The objective of the current secondary analysis was to describe β-cell function changes in response to glucose lowering. Participants were overweight adult subjects with screen-detected type 2 diabetes. β-cell function was measured using hyperglycaemic clamps and oral glucose tolerance testing. The primary outcome was the change in β-cell function from baseline to year 1, the time point where the maximal glucose-lowering effect was seen. At baseline, participants exhibited markedly impaired first-phase insulin response. Despite significant reductions in weight, fasting plasma glucose (PG) and 2-h PG, there was no clinically significant improvement in the first-phase insulin response. Late-phase insulin responses declined despite beneficial glycaemic effects of interventions. Insulin secretion is already severely impaired in early, screen-detected type 2 diabetes. Effective glucose-lowering intervention with acarbose was not sufficient to improve insulin secretion or halt the decline of β-cell function.

Effects of short-term very-low calorie diet on islet β-cell function, glucose and lipid metabolism in type 2 diabetic patients

Objective To study the effects of short-term caloric restriction (CR) on insulin secretion and glucose and lipid metabolism in type 2 diabetic patients.Methods Oral glucose tolerance test,insulin releasing test,and other biochemical tests were performed in 20 type 2 diabetic patients whose body mass index(BMI) was less than 40 kg/m2before and after 9 days with CR(300-600 kcal/d).Results (1) After short-term CR,the patients' mean body weight was reduced from (70.5 ± 11.0) kg to (65.9 ± 10.5) kg(P＜0.01),and their waist circumference from (86.68 ± 10.26) cm to (81.03 ± 9.77) cm (P＜0.001).Moreover,BM1 was reduced from (25.99 ± 2.78) kg/m2 to (23.89 ± 2.66) kg/m2 (P＜0.01),the visceral fat mass area decreased from (104.79 ± 29.65) cm2 to (97.44 ± 29.14) cm2 (P =0.015),and the weight of body fat mass was reduced from (22.8 ± 4.9) kg to (20.9 ± 4.5) kg(P＜ 0.01).(2) After 9 days of CR,there were significant reductions in fasting blood glucose [from (8.47 ± 1.77) mmol/L to (6.30± 1.82) mmol/L,P＜0.01],fasting insulin [from (10.8±4.0) mIU/L to (7.1 ±4.2) mIU/L,P＜ 0.01),and blood triglyceride [from (2.36 ± 1.71) mmol/L to (1.28 ± 0.50) mmol/L,P＜0.05),as well as lowering of systolic blood pressure[from (127 ± 11) mmHg(1 mmHg=0.133 kPa) to (117 ± 10) mmHg,P＜0.01),and diastolic blood pressure [from (80 ± 7) mmHg to (73 ± 10) mmHg,P＜0.01],though,no significant difference was found in total eholesterol and low density lipoprotein levels before and after CR.(3) The first-phase insulin response,which was represented by acute insulin response,was increased from (62.37 ± 40.28) mIU/L to (98.1 8 ± 77.17) mIU/L(P＜0.05) during the study period,while changes in insulin area under the curve showed no significant differences before and after CR.HOMA-IR,which was a parameter of insulin resistance,was decreased from 4.12 ± 1.87 to 2.02 ± 1.25 (P＜0.01).Conclusion Short-term CR can effectively improve islet β cell function,glucose and lipid metabolism in patients with type 2 diabetes. Key words: Caloric restriction ; Diabetes mellitus, type 2 ; Insulin secretion ; Glucose ; Lipid

Physical Activity in Overweight and Obese Pregnant Women Is Associated With Higher Levels of Proinflammatory Cytokines and With Reduced Insulin Response Through Interleukin-6

OBJECTIVE Previously, we reported the positive association of moderate-to-vigorous physical activity (MVPA) with insulin sensitivity in overweight and obese pregnant women. We sought to assess whether these MVPA-induced changes in insulin sensitivity are mediated by changes in interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and IL-1β. RESEARCH DESIGN AND METHODS A prospective longitudinal study was conducted in 46 overweight and obese women at risk for gestational diabetes mellitus. Objective physical activity measurements and fasting blood samples were taken at 15, 24, and 32 weeks of pregnancy. At 24 and 32 weeks, a 100-g oral glucose test was performed in addition. Cytokines, C-reactive protein, and glucose and insulin levels were measured, and insulin sensitivity and first-phase insulin response were calculated. Relationships between the different parameters were assessed using linear regression models, adjusting for maternal age and BMI. RESULTS All cytokines were elevated in women with higher levels of MVPA at 15 weeks of gestation. Higher IL-6 was related to a lower first-phase insulin response (β -810.5 [95% CI -1,524.5 to -96.5]; P = 0.03). TNF-α and IL-1β had different effects in women with low MVPA (with low IL-6 levels) compared with more active women. CRP was not related to MVPA. CONCLUSIONS The association of MVPA with insulin sensitivity and first-phase insulin response may be (partly) mediated by IL-6, since this cytokine was related to reduced first-phase insulin response. The possible positive effects of the elevated cytokine profile in active obese pregnant women warrant further study.

Maternal history of diabetes is associated with increased cardiometabolic risk in Chinese

Objective:Positive family history is associated with increased type 2 diabetes (T2D) risk, and reflects both genetic and environmental risks. Several studies have suggested an excess maternal transmission of T2D, although the underlying mechanism is unknown. We aimed to examine the association between maternal diabetes and cardiometabolic risk in the offspring.Methods:Parental history of diabetes and clinical data including anthropometric traits, fasting plasma glucose and insulin (FPG, FPI), blood pressure and lipid profile were collected from 2581 unrelated Chinese offspring (2026 adolescents from a population-based school survey and 555 adults from a community-based health screening programme). A subset of subjects (n=834) underwent oral glucose tolerance test to measure the glucose and insulin concentrations at 0, 15, 30, 60 and 120 min for evaluation of the areas under the curve (AUC) of glucose and insulin at 0–120 min, homoeostasis model assessment of insulin resistance (HOMA-IR) and bell-cell function, insulinogenic index, insulin sensitivity index (ISI) and oral disposition index (DI).Results:A positive parental history of diabetes was associated with increased risk of obesity (odd ratios (OR) (95% confidence interval (CI))=1.48 (1.10–2.00)), central obesity (OR (95% CI)=1.67 (1.21–2.32)), higher FPI, HOMA-IR, 2-h insulin, AUC of glucose at 0–120 min, triglycerides, reduced ISI and DI. Compared with individuals without parental diabetes, offspring with diabetic mother had significantly increased risk of obesity (OR (95% CI)=1.59 (1.07–2.35)), central obesity (OR (95% CI)=1.88 (1.23–2.88)), higher glucose levels and BP, were more insulin resistant but also had impaired first-phase insulin response and worse lipid profile. However, paternal history of diabetes had no effect on any of the studied traits, except higher body mass index, waist circumference in females and FPG.Conclusions:Our findings suggested that maternal history of diabetes conferred increased risk of cardiometabolic abnormalities, and was associated with both insulin resistance and impaired first-phase insulin secretion. Further investigation into the mechanism of transgenerational diabetes is warranted.

Acceleration of the loss of the first-phase insulin response during the progression to type 1 diabetes in diabetes prevention trial-type 1 participants.

We studied the change in the first-phase insulin response (FPIR) during the progression to type 1 diabetes (T1D). Seventy-four oral insulin trial progressors to T1D from the Diabetes Prevention Trial–Type 1 with at least one FPIR measurement after baseline and before diagnosis were studied. The FPIR was examined longitudinally in 26 progressors who had FPIR measurements during each of the 3 years before diagnosis. The association between the change from the baseline FPIR to the last FPIR and time to diagnosis was studied in the remainder (n = 48). The 74 progressors had lower baseline FPIR values than nonprogressors (n = 270), with adjustments made for age and BMI. In the longitudinal analysis of the 26 progressors, there was a greater decline in the FPIR from 1.5 to 0.5 years before diagnosis than from 2.5 to 1.5 years before diagnosis. This accelerated decline was also evident in a regression analysis of the 48 remaining progressors in whom the rate of decline became more marked with the approaching diagnosis. The patterns of decline were similar between the longitudinal and regression analyses. There is an acceleration of decline in the FPIR during the progression to T1D, which becomes especially marked between 1.5 and 0.5 years before diagnosis.

Following the Fate of the Failing β-Cell: New Insights From First-Phase Insulin Responses

The benefits of residual endogenous insulin secretion in improving metabolic control and reducing complications in patients with type 1 diabetes (T1D) (1) have highlighted the need for early intervention to preserve β-cell mass. However, the time course of β-cell destruction in T1D is still poorly understood (2). Islet autoantibodies indicative of ongoing autoimmunity often appear in early infancy and may be present for many years before diabetes develops (3). Thus, autoantibodies are very useful for identifying individuals at high risk of progression but do not provide precise estimates of time to diabetes onset. Current tests of T-cell activity are poor guides to the rate of progression. Imaging methods for tracking β-cell loss are in development, but are unlikely to be available for several years (4). Metabolic testing is therefore the best approach for monitoring the decline in β-cell capacity (5,6) (Fig. 1). FIG. 1. Schematic showing potentially informative tests for tracking the loss of β-cell mass and function. Deterioration of FPIR in the IVGTT and of OGTT responses are currently the best indicators of impending diabetes. Imaging methods for monitoring β-cell mass are still in development. Little is known about the pattern of insulitis and decline in β-cell mass in humans during the prediabetic prodrome. PI/C-peptide, proinsulin-to-C-peptide ratio; Teff, effector T cells. Several tests have been used to assess β-cell function. These vary in complexity and differ in what …

Plasma Metabolomics Reveal Alterations of Sphingo- and Glycerophospholipid Levels in Non-Diabetic Carriers of the Transcription Factor 7-Like 2 Polymorphism rs7903146

Aims/HypothesisPolymorphisms in the transcription factor 7-like 2 (TCF7L2) gene have been shown to display a powerful association with type 2 diabetes. The aim of the present study was to evaluate metabolic alterations in carriers of a common TCF7L2 risk variant.MethodsSeventeen non-diabetic subjects carrying the T risk allele at the rs7903146 TCF7L2 locus and 24 subjects carrying no risk allele were submitted to intravenous glucose tolerance test and euglycemic-hyperinsulinemic clamp. Plasma samples were analysed for concentrations of 163 metabolites through targeted mass spectrometry.ResultsTCF7L2 risk allele carriers had a reduced first-phase insulin response and normal insulin sensitivity. Under fasting conditions, carriers of TCF7L2 rs7903146 exhibited a non-significant increase of plasma sphingomyelins (SMs), phosphatidylcholines (PCs) and lysophosphatidylcholines (lysoPCs) species. A significant genotype effect was detected in response to challenge tests in 6 SMs (C16:0, C16:1, C18:0, C18:1, C24:0, C24:1), 5 hydroxy-SMs (C14:1, C16:1, C22:1, C22:2, C24:1), 4 lysoPCs (C14:0, C16:0, C16:1, C17:0), 3 diacyl-PCs (C28:1, C36:6, C40:4) and 4 long-chain acyl-alkyl-PCs (C40:2, C40:5, C44:5, C44:6).DiscussionPlasma metabolomic profiling identified alterations of phospholipid metabolism in response to challenge tests in subjects with TCF7L2 rs7903146 genotype. This may reflect a genotype-mediated link to early metabolic abnormalities prior to the development of disturbed glucose tolerance.

Insulin secretion and sensitivity in the prediction of type 1 diabetes in children with advanced β-cell autoimmunity

Reduced early insulin response has been shown to predict type 1 diabetes (T1D) in first-degree relatives of diabetic patients, while its role, as well as that of insulin resistance, has remained poorly defined in young children representing the general population. The predictive values of these markers and their relation to other risk factors of T1D were assessed in children with advanced β-cell autoimmunity, i.e. persistent positivity for two or more autoantibodies. Intravenous glucose tolerance tests (IVGTTs) were carried out in 218 children with HLA-DQB1-conferred disease susceptibility and advanced β-cell autoimmunity. Baseline, metabolic and growth data were compared between children progressing to diabetes and those remaining unaffected. Hazard ratios for the disease predictors and the progression rate of T1D were assessed. Children developing T1D were younger at seroconversion, progressed more rapidly to advanced β-cell autoimmunity and had lower first-phase insulin response (FPIR) and homeostasis model assessment index for insulin resistance (HOMA-IR) than those remaining non-diabetic. The levels of HOMA-IR/FPIR, islet cell antibodies, insulin autoantibodies (IAA) and islet antigen 2 antibodies (IA-2A) were higher in progressors. BMI SDS, FPIR, age at IVGTT and levels of IAA and IA-2A were predictive markers for T1D. Young age, higher BMI SDS, reduced FPIR and higher levels of IAA and IA-2A predicted T1D in young children with HLA-DQB1-conferred disease susceptibility and advanced β-cell autoimmunity. Disease risk estimates were successfully stratified by the assessment of metabolic status and BMI. The role of insulin resistance as an accelerator of the disease process was minor.

Incretin-Based Therapy for Type 2 Diabetes Mellitus

The prevalence of type 2 diabetes mellitus has increased at an alarming rate in recent years. Recent estimations project that 366 million people could have diabetes by 2030. The incretin system emerges as a new target for type 2 diabetes therapy, and new molecules are being approved for its use in humans since the year 2005. These agents could be divided into 2 main groups, glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors. Endogenous GLP-1 is an incretin hormone composed by a 30-amino acid peptide and is secreted from L-cells in distal small intestine in response to calorie intake, causing a glucose-dependent β-cell response resulting in a restoration of the first-phase insulin response. Additionally, GLP-1 regulates glucagon production, which leads to inhibition of glucogenolysis and gluconeogenesis in the liver. Synthetic molecules such as exenatide and liraglutide have been developed to bind GLP-1 receptor and mimic GLP-1 effects in pancreatic cells and other target organs.

Impact of embryo donor adiposity, birthweight and gender on early postnatal growth, glucose metabolism and body composition in the young lamb

Intrauterine growth restriction (IUGR) is a risk factor for metabolic syndrome, notably when associated with rapid postnatal catch-up growth. A sheep paradigm was used to assess relationships between prenatal and early postnatal growth trajectories, metabolism and body composition. Singletons (single-sire embryo transfer from obese and control donors) were gestated and suckled by overnourished adolescent dams and categorised by birthweight as IUGR or normal (N). Gestation length was equivalent in both categories and all lambs were delivered spontaneously preterm (PT; mean (±s.e.m.) 139.8±1.7 days; term=145-147 days). The IUGR lambs were smaller at birth, but fractional growth rates (FGR) for eight anthropometry parameters were higher and independent of gender (except thorax girth; males (M)<females (F)). At Day 48, fasting glucose (IUGR>N; M>F) and first-phase insulin response (to 20min; IUGR<N; M<F) after glucose were influenced by prenatal growth and gender. Embryo donor adiposity influenced glucose tolerance only. Plasma insulin, insulin-like growth factor-1 (M>F) and leptin (M<F) were influenced by gender but not prenatal growth. At necropsy (Day 77), IUGR plus PT lambs had decreased carcass and visceral organ weights, but carcass composition was not different from N plus PT. In contrast, M were heavier, with lower internal fat mass, carcass fat percentage and perirenal fat leptin mRNA than F. Therefore, IUGR was associated with increased postnatal FGR and altered glucose handling, but, without absolute catch-up growth, gender had the predominant influence on postnatal leptinaemia and adiposity.

Screening for Type 1 and Type 2 Diabetes

Screening for Type 1 and Type 2 Diabetes

Glucose tolerance and beta-cell function in islet autoantibody-positive children recruited to a secondary prevention study

Children with type 1 diabetes (T1D) risk and islet autoantibodies are recruited to a secondary prevention study. The aims were to determine metabolic control in relation to human leukocyte antigen (HLA) genetic risk and islet autoantibodies in prepubertal children. In 47 healthy children with GADA and at least one additional islet autoantibody, intravenous glucose tolerance test (IvGTT) and oral glucose tolerance test (OGTT) were performed 8-65 d apart. Hemoglobin A1c, plasma glucose as well as serum insulin and C-peptide were determined at fasting and during IvGTT and OGTT. All children aged median 5.1 (4.0-9.2) yr had autoantibodies to two to six of the beta-cell antigens GAD65, insulin, IA-2, and the three amino acid position 325 variants of the ZnT8 transporter. In total, 20/47 children showed impaired glucose metabolism. Decreased (≤ 30 μU/mL insulin) first-phase insulin response (FPIR) was found in 14/20 children while 11/20 had impaired glucose tolerance in the OGTT. Five children had both impaired glucose tolerance and FPIR ≤ 30 μU/mL insulin. Number and levels of autoantibodies were not associated with glucose metabolism, except for an increased frequency (p = 0.03) and level (p = 0.01) of ZnT8QA in children with impaired glucose metabolism. Among the children with impaired glucose metabolism, 13/20 had HLA-DQ2/8, compared to 9/27 of the children with normal glucose metabolism (p = 0.03). Secondary prevention studies in children with islet autoantibodies are complicated by variability in baseline glucose metabolism. Evaluation of metabolic control with both IvGTT and OGTT is critical and should be taken into account before randomization. All currently available autoantibody tests should be analyzed, including ZnT8QA.