Insulin secretion and action and the response of endogenous glucose production to a lack of glucagon suppression in non-diabetic subjects

Type 2 diabetes is a disease characterized by impaired insulin secretion and defective glucagon suppression in the postprandial period. We examined the effect of impaired glucagon suppression on glucose concentrations and Endogenous Glucose Production (EGP) at different degrees of insulin secretory impairment. The contribution of anthropometric characteristics, peripheral, and hepatic insulin action to this variability was also examined. To do so, we studied 54 non-diabetic subjects on two occasions in which endogenous hormone secretion was inhibited by somatostatin, with glucagon infused at a rate of 0.65 ng/kg/min, at 0 min to prevent a fall in glucagon (non-suppressed day) or at 120 min to create a transient fall in glucagon (suppressed day). Subjects received glucose (labeled with [3-3H]-glucose) infused to mimic the systemic appearance of 50g oral glucose. Insulin was infused to mimic a prandial insulin response in 18 subjects, another 18 received 80% of the dose and the remaining 18 received 60%. EGP was measured using the tracer-dilution technique. Decreased prandial insulin resulted in greater % increase in peak glucose but not in integrated glucose concentrations attributable to non-suppressed glucagon. The % change in integrated EGP was unaffected by insulin dose. Multivariate regression analysis, adjusted for age, sex, weight and insulin dose, did not show a relationship between the EGP response to impaired suppression of glucagon and insulin action as measured at the time of screening by oral glucose tolerance. A similar analysis for hepatic insulin action also did not show a relationship with the EGP response. These data indicate that the effect of impaired glucagon suppression on EGP is independent of anthropometric characteristics and insulin action.

Effect of Medical and Surgical Interventions on α-Cell Function in Dysglycemic Youth and Adults in the RISE Study

<b>Objective</b>: To compare effects of medications and laparoscopic gastric band surgery (LB) on α-cell function in dysglycemic youth and adults in the Restoring Insulin Secretion (RISE) Study protocols. <p><b>Research Design and Methods</b>: Glucagon was measured in three randomized, parallel, clinical studies: (1) 91 youth studied at baseline, after 12 months on metformin alone (MET) or glargine followed by metformin (G/M), and 3 months after treatment withdrawal; (2) 267 adults studied at the same timepoints and treated with MET, G/M, liraglutide plus metformin (L+M) or placebo (PLAC); and (3) 88 adults studied at baseline, and after 12 and 24 months of LB or MET. Fasting glucagon, glucagon suppression by glucose and acute glucagon response (AGR) to arginine were assessed during hyperglycemic clamps. Glucagon suppression was also measured during oral glucose tolerance tests (OGTTs).</p> <p><b>Results</b>: No change in fasting glucagon, steady-state glucagon or AGR was seen at 12 months following treatment with MET or G/M (in youth and adults) or PLAC (in adults). In contrast, L+M reduced these measures at 12 months (all p≤0.005), which was maintained three months after treatment withdrawal (all p<0.01). LB in adults also reduced fasting glucagon, steady-state glucagon and AGR at 12 and 24 months (p<0.05 for all, except AGR at 12 months [p=0.098]). Similarly, glucagon suppression during OGTTs was greater with L+M and LB. Linear models demonstrated that treatment effects on glucagon with L+M and LB were largely associated with weight loss. </p> <p><b>Conclusions</b>: Glucagon concentrations were reduced by L+M and LB in adults with dysglycemia, an effect principally attributed to weight loss in both interventions.</p>

Effect of Medical and Surgical Interventions on α-Cell Function in Dysglycemic Youth and Adults in the RISE Study

<b>Objective</b>: To compare effects of medications and laparoscopic gastric band surgery (LB) on α-cell function in dysglycemic youth and adults in the Restoring Insulin Secretion (RISE) Study protocols. <p><b>Research Design and Methods</b>: Glucagon was measured in three randomized, parallel, clinical studies: (1) 91 youth studied at baseline, after 12 months on metformin alone (MET) or glargine followed by metformin (G/M), and 3 months after treatment withdrawal; (2) 267 adults studied at the same timepoints and treated with MET, G/M, liraglutide plus metformin (L+M) or placebo (PLAC); and (3) 88 adults studied at baseline, and after 12 and 24 months of LB or MET. Fasting glucagon, glucagon suppression by glucose and acute glucagon response (AGR) to arginine were assessed during hyperglycemic clamps. Glucagon suppression was also measured during oral glucose tolerance tests (OGTTs).</p> <p><b>Results</b>: No change in fasting glucagon, steady-state glucagon or AGR was seen at 12 months following treatment with MET or G/M (in youth and adults) or PLAC (in adults). In contrast, L+M reduced these measures at 12 months (all p≤0.005), which was maintained three months after treatment withdrawal (all p<0.01). LB in adults also reduced fasting glucagon, steady-state glucagon and AGR at 12 and 24 months (p<0.05 for all, except AGR at 12 months [p=0.098]). Similarly, glucagon suppression during OGTTs was greater with L+M and LB. Linear models demonstrated that treatment effects on glucagon with L+M and LB were largely associated with weight loss. </p> <p><b>Conclusions</b>: Glucagon concentrations were reduced by L+M and LB in adults with dysglycemia, an effect principally attributed to weight loss in both interventions.</p>

Randomized, Controlled Trial Of Sitagliptin And Islet Function In Cystic Fibrosis With Abnormal Glucose Tolerance

Purpose Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) concentrations augment insulin secretion and glucagon suppression and lower post-prandial glycemia in PI-CF with AGT. Methods Twenty-six adults from Children’s Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT (defined by oral glucose tolerance test glucose [mg/dL]: early glucose intolerance [1-hour ≥155 & 2-hour &lt;140], impaired glucose tolerance [2-hour ≥140 and &lt;200 mg/dl], or diabetes [2-hour ≥200]) were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched-placebo; 24 completed the trial (n=12 sitagliptin; n=12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISR), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of β- and α-cell function. Results Following 6-months of sitagliptin vs. placebo, MMTT intact GLP-1 and GIP responses increased (P &lt;0.001), ISR dynamics improved (P &lt;0.05), and glucagon suppression was modestly enhanced (P &lt;0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or β-cell sensitivity to glucose, including for second-phase insulin response were found. Conclusions In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting post-prandial glycemia.

Genome-wide association study of circulating levels of glucagon during an oral glucose tolerance test

Background In order to explore the pathophysiology underlying type 2 diabetes we examined the impact of gene variants associated with type 2 diabetes on circulating levels of glucagon during an oral glucose tolerance test (OGTT). Furthermore, we performed a genome-wide association study (GWAS) aiming to identify novel genomic loci affecting plasma glucagon levels. Methods Plasma levels of glucagon were examined in samples obtained at three time points during an OGTT; 0, 30 and 120 min, in two separate cohorts with a total of up to 1899 individuals. Cross-sectional analyses were performed separately in the two cohorts and the results were combined in a meta-analysis. Results A known type 2 diabetes variant in EYA2 was significantly associated with higher plasma glucagon level at 30 min during the OGTT (Beta 0.145, SE 0.038, P = 1.2 × 10–4) corresponding to a 7.4% increase in plasma glucagon level per effect allele. In the GWAS, we identified a marker in the MARCH1 locus, which was genome-wide significantly associated with reduced suppression of glucagon during the first 30 min of the OGTT (Beta − 0.210, SE 0.037, P = 1.9 × 10–8), equivalent to 8.2% less suppression per effect allele. Nine additional independent markers, not previously associated with type 2 diabetes, showed suggestive associations with reduced glucagon suppression during the first 30 min of the OGTT (P < 1.0 × 10–5). Conclusions A type 2 diabetes risk variant in the EYA2 locus was associated with higher plasma glucagon levels at 30 min. Ten additional variants were suggestively associated with reduced glucagon suppression without conferring increased type 2 diabetes risk.

Pharmacokinetic and Pharmacodynamic Head-to-Head Comparison of Clinical, Equivalent Doses of Insulin Glargine 300 units/mL and Insulin Degludec 100 units/mL in Type 1 Diabetes

<b>OBJECTIVE</b> <p><b> </b></p> <p>To prove equivalence of individual, clinically-titrated basal insulin doses of Gla-300 and Deg-100 under steady-state conditions in a single-blind, randomized, crossover study, on the glucodynamics (PD) in people with type 1 diabetes (T1DM).</p> <p><b>RESEARCH DESIGN AND METHODS</b></p> <p>T1DM subjects [N=22, 11 males M, age 44.3±12.4 years, disease duration 25.5±11.7 years, A1C 7.07±0.63% (53.7±6.9 mmol/mol), BMI 22.5±2.7 kg/m²], naïve to Gla-300 and Deg-100, underwent 24-h euglycemic clamps with individual clinical doses of Gla-300 (0.34±0.08 U.Kg^-1) and <a>Deg-100 </a>(0.26±0.06 U.Kg^-1), (dosing at 20.00h), after 3 months of optimal titration of basal (and bolus) insulin.</p> <p><b>RESULTS</b></p> <p>At the end of 3 months, Gla-300 and Deg-100 reduced slightly and similarly A1C vs baseline. Clamp average plasma glucose (0-24h) was euglycemic with both insulins. The area under curve of glucose infused [AUC-GIR_(0-24h)] was equivalent for the two insulins (ratio 1.04, 90% CIs 0.91, 1.18). Suppression of endogenous glucose production, free fatty acids (FFA), glycerol and b-hydroxybutyrate was 9%, 14%, 14% and 18% greater respectively, with Gla-300 as compared with Deg-100, during the first 12 h, while glucagon suppression was no different. Relative within-day PD variability was 23% lower with Gla-300 vs Deg-100 (ratio 0.77, 90% CI 0.63, 0.92).</p> <p><b>CONCLUSIONS</b></p> <p>In T1DM, individualized, clinically titrated doses of Gla-300 and Deg-100 at steady-state result in similar glycemic control and PD equivalence during euglycemic clamps. Clinical doses of Gla-300 as compared with Deg-100 are higher, and associated with quite similar even 24h distribution of PD and anti-lipolytic effects.</p>

Pharmacokinetic and Pharmacodynamic Head-to-Head Comparison of Clinical, Equivalent Doses of Insulin Glargine 300 units/mL and Insulin Degludec 100 units/mL in Type 1 Diabetes

<b>OBJECTIVE</b> <p><b> </b></p> <p>To prove equivalence of individual, clinically-titrated basal insulin doses of Gla-300 and Deg-100 under steady-state conditions in a single-blind, randomized, crossover study, on the glucodynamics (PD) in people with type 1 diabetes (T1DM).</p> <p><b>RESEARCH DESIGN AND METHODS</b></p> <p>T1DM subjects [N=22, 11 males M, age 44.3±12.4 years, disease duration 25.5±11.7 years, A1C 7.07±0.63% (53.7±6.9 mmol/mol), BMI 22.5±2.7 kg/m²], naïve to Gla-300 and Deg-100, underwent 24-h euglycemic clamps with individual clinical doses of Gla-300 (0.34±0.08 U.Kg^-1) and <a>Deg-100 </a>(0.26±0.06 U.Kg^-1), (dosing at 20.00h), after 3 months of optimal titration of basal (and bolus) insulin.</p> <p><b>RESULTS</b></p> <p>At the end of 3 months, Gla-300 and Deg-100 reduced slightly and similarly A1C vs baseline. Clamp average plasma glucose (0-24h) was euglycemic with both insulins. The area under curve of glucose infused [AUC-GIR_(0-24h)] was equivalent for the two insulins (ratio 1.04, 90% CIs 0.91, 1.18). Suppression of endogenous glucose production, free fatty acids (FFA), glycerol and b-hydroxybutyrate was 9%, 14%, 14% and 18% greater respectively, with Gla-300 as compared with Deg-100, during the first 12 h, while glucagon suppression was no different. Relative within-day PD variability was 23% lower with Gla-300 vs Deg-100 (ratio 0.77, 90% CI 0.63, 0.92).</p> <p><b>CONCLUSIONS</b></p> <p>In T1DM, individualized, clinically titrated doses of Gla-300 and Deg-100 at steady-state result in similar glycemic control and PD equivalence during euglycemic clamps. Clinical doses of Gla-300 as compared with Deg-100 are higher, and associated with quite similar even 24h distribution of PD and anti-lipolytic effects.</p>