Different ß-cell secretory phenotype in non-obese compared to obese early type 2 diabetes.

BACKGROUND: Type 2 diabetes (T2D) is characterized by impaired tissue sensitivity to insulin action (ie, insulin resistance) and impaired ß-cell insulin secretion. Because obesity contributes importantly to the development of insulin resistance, we sought to determine whether insulin secretory defects would predominate in non-obese compared to obese T2D. METHODS: We measured ß-cell function and secretory capacity using the glucose-potentiated arginine test in T2D subjects early in the disease course classified as non-obese (BMI <30; n = 12) or obese (BMI ≥30 kg/m2 ; n = 28) and additionally compared responses from non-obese T2D with a non-diabetic control group (n = 12). RESULTS: The acute insulin response to glucose potentiation of arginine-induced insulin release was less in non-obese T2D than in controls and associated with impaired ß-cell sensitivity to glucose (PG50 ). Proinsulin secretory ratios were increased in non-obese T2D when compared to obese T2D. Obese T2D subjects had reduced insulin sensitivity (M/I) while non-obese T2D subjects had insulin sensitivity that was comparable to controls. CONCLUSIONS: In non-obese T2D, insulin secretory defects predominate with impaired ß-cell sensitivity to glucose and proinsulin processing in the absence of insulin resistance. Future studies should consider whether different ß-cell secretory phenotypes and tissue sensitivity to insulin explain the varying responsiveness to T2D interventions.

Reduced ß-Cell Secretory Capacity in Pancreatic-Insufficient, but Not Pancreatic-Sufficient, Cystic Fibrosis Despite Normal Glucose Tolerance.

Patients with pancreatic-insufficient cystic fibrosis (PI-CF) are at increased risk for developing diabetes. We determined ß-cell secretory capacity and insulin secretory rates from glucose-potentiated arginine and mixed-meal tolerance tests (MMTTs), respectively, in pancreatic-sufficient cystic fibrosis (PS-CF), PI-CF, and normal control subjects, all with normal glucose tolerance, in order to identify early pathophysiologic defects. Acute islet cell secretory responses were determined under fasting, 230 mg/dL, and 340 mg/dL hyperglycemia clamp conditions. PI-CF subjects had lower acute insulin, C-peptide, and glucagon responses compared with PS-CF and normal control subjects, indicating reduced ß-cell secretory capacity and α-cell function. Fasting proinsulin-to-C-peptide and proinsulin secretory ratios during glucose potentiation were higher in PI-CF, suggesting impaired proinsulin processing. In the first 30 min of the MMTT, insulin secretion was lower in PI-CF compared with PS-CF and normal control subjects, and glucagon-like peptide 1 and gastric inhibitory polypeptide were lower compared with PS-CF, and after 180 min, glucose was higher in PI-CF compared with normal control subjects. These findings indicate that despite "normal" glucose tolerance, adolescents and adults with PI-CF have impairments in functional islet mass and associated early-phase insulin secretion, which with decreased incretin responses likely leads to the early development of postprandial hyperglycemia in CF.

Effect of exenatide, sitagliptin, or glimepiride on ß-cell secretory capacity in early type 2 diabetes.

OBJECTIVE: Agents that augment GLP-1 effects enhance glucose-dependent ß-cell insulin production and secretion and thus are hoped to prevent progressive impairment in insulin secretion characteristic of type 2 diabetes (T2D). The purpose of this study was to evaluate GLP-1 effects on ß-cell secretory capacity, an in vivo measure of functional ß-cell mass, early in the course of T2D. RESEARCH DESIGN AND METHODS: We conducted a randomized controlled trial in 40 subjects with early T2D who received the GLP-1 analog exenatide (n = 14), the dipeptidyl peptidase IV inhibitor sitagliptin (n = 12), or the sulfonylurea glimepiride (n = 14) as an active comparator insulin secretagogue for 6 months. Acute insulin responses to arginine (AIRarg) were measured at baseline and after 6 months of treatment with 5 days of drug washout under fasting, 230 mg/dL (glucose potentiation of arginine-induced insulin release [AIRpot]), and 340 mg/dL (maximum arginine-induced insulin release [AIRmax]) hyperglycemic clamp conditions, in which AIRmax provides the ß-cell secretory capacity. RESULTS: The change in AIRpot was significantly greater with glimepiride versus exenatide treatment (P < 0.05), and a similar trend was notable for the change in AIRmax (P = 0.1). Within each group, the primary outcome measure, AIRmax, was unchanged after 6 months of treatment with exenatide or sitagliptin compared with baseline but was increased with glimepiride (P < 0.05). α-Cell glucagon secretion (AGRmin) was also increased with glimepiride treatment (P < 0.05), and the change in AGRmin trended higher with glimepiride than with exenatide (P = 0.06). CONCLUSIONS: After 6 months of treatment, exenatide or sitagliptin had no significant effect on functional ß-cell mass as measured by ß-cell secretory capacity, whereas glimepiride appeared to enhance ß- and α-cell secretion.