Recent studies have provided new insights into nonlinearities of insulin action in the hypoglycemic range and into glucagon kinetics as it relates to response to hypoglycemia. Based on these data, we developed a new version of the UVA/PADOVA Type 1 Diabetes Simulator, which was submitted to FDA in 2013 (S2013). The model of glucose kinetics in hypoglycemia has been improved, implementing the notion that insulin-dependent utilization increases nonlinearly when glucose decreases below a certain threshold. In addition, glucagon kinetics and secretion and action models have been incorporated into the simulator: glucagon kinetics is a single compartment; glucagon secretion is controlled by plasma insulin, plasma glucose below a certain threshold, and glucose rate of change; and plasma glucagon stimulates with some delay endogenous glucose production. A refined statistical strategy for virtual patient generation has been adopted as well. Finally, new rules for determining insulin to carbs ratio (CR) and correction factor (CF) of the virtual patients have been implemented to better comply with clinical definitions. S2013 shows a better performance in describing hypoglycemic events. In addition, the new virtual subjects span well the real type 1 diabetes mellitus population as demonstrated by good agreement between real and simulated distribution of patient-specific parameters, such as CR and CF. S2013 provides a more reliable framework for in silico trials, for testing glucose sensors and insulin augmented pump prediction methods, and for closed-loop single/dual hormone controller design, testing, and validation.

The contribution of elevated glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism after Roux-en-Y gastric bypass (RYGB) has been the subject of uncertainty. We used exendin-9,39, a competitive antagonist of GLP-1, to examine glucose metabolism, islet hormone secretion, and gastrointestinal transit in subjects after RYGB and in matched control subjects. Subjects were studied in the presence or absence of exendin-9,39 infused at 300 pmol/kg/min. Exendin-9,39 resulted in an increase in integrated postprandial glucose concentrations post-RYGB (3.6 ± 0.5 vs. 2.0 ± 0.4 mol/6 h, P = 0.001). Exendin-9,39 decreased insulin concentrations (12.3 ± 2.2 vs. 18.1 ± 3.1 nmol/6 h, P = 0.002) and the β-cell response to glucose (ϕTotal, 13 ± 1 vs. 11 ± 1 × 10−9 min−1, P = 0.01) but did not alter the disposition index (DI). In control subjects, exendin-9,39 also increased glucose (2.2 ± 0.4 vs. 1.7 ± 0.3 mol/6 h, P = 0.03) without accompanying changes in insulin concentrations, resulting in an impaired DI. Post-RYGB, acceleration of stomach emptying during the first 30 min by exendin-9,39 did not alter meal appearance, and similarly, suppression of glucose production and stimulation of glucose disappearance were unaltered in RYGB subjects. These data indicate that endogenous GLP-1 has effects on glucose metabolism and on gastrointestinal motility years after RYGB. However, it remains uncertain whether this explains all of the changes after RYGB.

OBJECTIVEGlucagon-like peptide (GLP)-1 receptor is encoded by GLP1R. The effect of genetic variation at this locus on the response to GLP-1 is unknown. This study assessed the effect of GLP1R polymorphisms on insulin secretion in response to hyperglycemia and to infused GLP-1 in nondiabetic subjects.RESEARCH DESIGN AND METHODSEighty-eight healthy individuals (aged 26.3 ± 0.6 years, fasting glucose 4.83 ± 0.04 mmol/l) were studied using a hyperglycemic clamp. GLP-1 was infused for the last 2 h of the study (0.75 pmol/kg/min over 121–180 min, 1.5 pmol/kg/min over 181–240 min). β-Cell responsivity (ΦTotal) was measured using a C-peptide minimal model. The effect of 21 tag single nucleotide polymorphisms (SNPs) in GLP1R on ΦTotal was examined.RESULTSTwo SNPs (rs6923761 and rs3765467) were nominally associated with altered β-cell responsivity in response to GLP-1 infusion.CONCLUSIONSVariation in GLP1R may alter insulin secretion in response to exogenous GLP-1. Future studies will determine whether such variation accounts for interindividual differences in response to GLP-1–based therapy.

Objective Low Glucagon-like Peptide-1 (GLP-1) concentrations have been observed in impaired fasting glucose (IFG). It is uncertain if these abnormalities contribute directly to the pathogenesis of IFG and impaired glucose tolerance. Dipeptidyl peptidase-4 (DPP-4) inhibitors raise incretin hormone concentrations enabling an examination of their effects on glucose turnover in IFG. Research Design and Methods We studied 22 subjects with IFG using a double blind, placebo-controlled parallel group design. At the time of enrollment, subjects ate a standardized meal labeled with [1-13C]-glucose. Infused [6-3H] glucose enabled measurement of systemic meal appearance (MRa). Infused [6,6-2H2] glucose enabled measurement of endogenous glucose production (EGP) and glucose disappearance (Rd). Subsequently, subjects were randomized to100mg of sitagliptin daily or placebo. After an 8-week treatment period, the mixed meal was repeated. Results As expected, subjects with IFG who received placebo did not experience any change in glucose concentrations. Despite raising intact GLP-1 concentrations, treatment with sitagliptin did not alter either fasting or postprandial glucose, insulin or C-peptide concentrations. Postprandial EGP (18.1±0.7 vs. 17.6±0.8 µmol/kg/min, p = 0.53), Rd (55.6±4.3 vs. 58.9±3.3 µmol/kg/min, p = 0.47) and MRa (6639±377 vs. 6581±316 µmol/kg per 6h, p = 0.85) were unchanged. Sitagliptin was associated with decreased total GLP-1 implying decreased incretin secretion. Conclusions DPP-4 inhibition did not alter fasting or postprandial glucose turnover in people with IFG. Low incretin concentrations are unlikely to be involved in the pathogenesis of IFG.

Six weeks of caloric restriction lowers fasting glucose and EGP with accompanying improvements in β cell function in people with type 2 diabetes. An additional 6 wk of caloric restriction maintained the improvement in glucose metabolism. This trial was registered at clinicaltrials.gov as NCT01094054.

2 ) by use of a hyperglycemic clamp. A variable infusion maintained glucose concentrations at 150 mg/dl for 240 min. At 120 min, an intravenous infusion of GLP-1 was started (0.75 pmol · kg Ϫ1 · min Ϫ1 from 120 -180 min, 1.5 pmol · kg Ϫ1 · min Ϫ1 from 181-240 min). Consequently, plasma C-peptide concentration rose from 1,852.0 Ϯ 62.8 pmol/l at 120 min to 4,272.2 Ϯ 176.4 pmol/l at 180 min and to 6,995.8 Ϯ 323.5 pmol/l at 240 min. Four models of GLP-1 action on insulin secretion were considered. All models share the common assumption that insulin secretion is made up of two components, one proportional to glucose rate of change through dynamic responsivity, ⌽ d, and one proportional to glucose through static responsivity, ⌽ s, but differing by modality of GLP-1 control. The model that best fit C-peptide data assumes that above-basal insulin secretion depends linearly on GLP-1 concentration and its rate of change. An index (⌸) measuring the percentage increase of secretion due to GLP-1 is derived. Before GLP-1 infusion, ⌽d ϭ 245.7 Ϯ 15.6 10 Ϫ9 and ⌽s ϭ 25.2 Ϯ 1.4 10 Ϫ9 min Ϫ1 . Under GLP-1 stimulus, ⌸ ϭ 12.6 Ϯ 0.71% per pmol/l, meaning that an increase of 5 pmol/l in peripheral GLP-1 concentrations induces an ϳ60% increase in over-basal insulin secretion.glucagon-like peptide-1; incretins; C-peptide; hyperglycemic clamp; ␤-cell responsivity; parameter estimation GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is produced by the enteroendocrine L cells of the intestinal mucosa and is released into the portal circulation in response to meal ingestion (2). It arises from the posttranslational processing of proglucagon by prohormone convertase-1 (PC-1) in the enteroendocrine L cells of the intestinal mucosa (16). GLP-1 enhances insulin secretion and inhibits glucagon release in a glucose-dependent manner (17), prompting the development of GLP-1-based therapies for the treatment of diabetes (11). However, infused GLP-1 is rapidly inactivated by the widely distributed enzyme dipeptidyl peptidase-4 (DPP-4), which removes the two NH 2 -terminal amino acids, consequently requiring constant infusion to maintain its effects on insulin secretion. GLP-1-based therapy for type 2 diabetes has required the development of GLP-1 receptor agonists that resist the action of DPP-4 (21) or compounds that inhibit DPP-4, thereby raising endogenous concentrations of active GLP-1 (10). It has previously been suggested that genetic differences may explain some of the variation to GLP-1 response in prior studies (25).Several studies are available on GLP-1 action on insulin secretion both at the cellular (13,14,18) and at the whole body levels (1, 2, 10, 15, 17, 19); however, none of them has ever aimed to mechanistically model GLP-1 action on insulin secretion. In fact, quantitating the effect of GLP-1 on insulin secretion is not straightforward, given that GLP-1 delays gastric emptying (26) and is a glucose-dependent secretagogue. Consequently, measuring the response to an oral meal challenge has required the use of modeling techniques to account for change...

The mechanisms by which common genetic variation predisposes to type 2 diabetes remain unclear. The disease-associated variants in TCF7L2 (rs7903146) and WFS1 (rs10010131) have been shown to affect response to exogenous glucagon-like peptide 1 (GLP-1), while variants in KCNQ1 (rs151290, rs2237892, and rs2237895) alter endogenous GLP-1 secretion. We set out to validate these observations using a model of GLP-1–induced insulin secretion. We studied healthy individuals using a hyperglycemic clamp and GLP-1 infusion. In addition, we measured active and total GLP-1 in response to an oral challenge in nondiabetic subjects. After genotyping the relevant single nucleotide polymorphisms, generalized linear regression models and repeated-measures ANCOVA models incorporating potential confounders, such as age and BMI, were used to assess the associations, if any, of response with genotype. These variants did not alter GLP-1 concentrations in response to oral intake. No effects on β-cell responsiveness to hyperglycemia and GLP-1 infusion were apparent. Diabetes-associated variation (T allele at rs7903146) in TCF7L2 may impair the ability of hyperglycemia to suppress glucagon (45 ± 2 vs. 47 ± 2 vs. 60 ± 5 ng/L for CC, CT, and TT, respectively, P = 0.02). In nondiabetic subjects, diabetes-associated genetic variation does not alter GLP-1 concentrations after an oral challenge or its effect on insulin secretion.

We describe a model that can quantitate the GLP-1-based contribution to insulin secretion in response to meal ingestion. This methodology will allow a better understanding of β-cell function at various stages of glucose tolerance.