Differential Beta-Cell Response to Intravenous Exenatide (EXEN) and Arginine (ARG) in Prediabetic Subjects with Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT)

Abstract

Beta cell dysfunction is the main determinant of progression from prediabetes to diabetes. IFG is associated to hepatic insulin resistance, while IGT primarily reflects muscle insulin resistance. The incretin effect is decreased in diabetes, but beta cell response to GLP-1-RA in prediabetic subjects with isolated defects in fasting (i.e., IFG) and postprandial (i.e., IGT) has not been fully characterized. Twenty-five individuals matched for age/BMI: 8 healthy NGT (FPG= 93 mg%±1 2h PG=102±5 mg%, A1c=5.3±0.1%), 11 IFG (FPG=108±2, 2h PG=123±4, A1c=5.7±0.1) and 6 IGT (FPG=95±1 2h PG=162±8, A1c=5.5±0.2) received a two-step hyperglycemic clamp with IV EXENatide and ARGinine infusion. First phase insulin secretion (IS) was calculated as the acute insulin response from 0-15 min; second phase IS and IS after EXEN and EXEN-ARG infusions were calculated as the area under the curve AUC for insulin secretion (IS) during the hyperglycemic clamp (AUC-EXEN and AUC-EXEN/ARG). IS was adjusted for Matsuda index to quantify beta cell function (disposition index). First and second phase insulin secretion in response to EXEN was decreased in both IFG and IGT compared to NGT to a similar extent (p<0.05). IFG individuals exhibited a marked decrease in AUC-EXEN and AUC-EXEN/ARG vs. NGT (52269 vs. 118798, p<0.for EXEN, 15096 vs. 37413 for EXEN-ARG, p<0.01). There was a modest, non-significant decrease in beta cell response in IGT for EXEN and EXEN-ARG vs. NGT (83266 vs. 118798 for EXEN and 22964 vs. 37413 EXEN-ARG, both p=ns). Conclusion: Individuals with IFG manifest a severe defect in the beta cell response to GLP-1 compared to NGT healthy control subjects. In contrast, the beta cell response to GLP-1 in IGT subject is only minimally impaired. These results suggest that a GLP-1 receptor agonist might be an effective therapy to prevent progression to overt diabetes in subjects with IFG. Disclosure T. Terasawa: None. C.L. Triplitt: Speaker0027s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Sanofi, Novo Nordisk Inc.. J.M. Adams: None. E. Cersosimo: Research Support; Self; AstraZeneca, VeroScience, LLC.. Speaker's Bureau; Self; AstraZeneca, Sanofi, Janssen Pharmaceuticals, Inc., Eli Lilly and Company. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc.. A.O. Chavez Velazquez: None.