title: Insulin augmentation of glucose-stimulated insulin secretion is impaired in insulin-resistant humans.
abstract: Type 2 diabetes (T2D) is characterized by insulin resistance and pancreatic β-cell dysfunction, the latter possibly caused by a defect in insulin signaling in β-cells. We hypothesized that insulin's effect to potentiate glucose-stimulated insulin secretion (GSIS) would be diminished in insulin-resistant persons. To evaluate the effect of insulin to modulate GSIS in insulin-resistant compared with insulin-sensitive subjects, 10 participants with impaired glucose tolerance (IGT), 11 with T2D, and 8 healthy control subjects were studied on two occasions. The insulin secretory response was assessed by the administration of dextrose for 80 min following a 4-h clamp with either saline infusion (sham) or an isoglycemic-hyperinsulinemic clamp using B28-Asp-insulin (which can be distinguished immunologically from endogenous insulin) that raised insulin concentrations to high physiologic concentrations. Pre-exposure to insulin augmented GSIS in healthy persons. This effect was attenuated in insulin-resistant cohorts, both those with IGT and those with T2D. Insulin potentiates glucose-stimulated insulin secretion in insulin-resistant subjects to a lesser degree than in normal subjects. This is consistent with an effect of insulin to regulate β-cell function in humans in vivo with therapeutic implications.
authors.affiliation: 1Joslin Diabetes Center, Boston, Massachusetts, USA.
authors.forename: Florencia
authors.initials: F
authors.lastname: Halperin
authors.forename: Ximena
authors.initials: X
authors.lastname: Lopez
authors.forename: Raquel
authors.initials: R
authors.lastname: Manning
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.forename: Allison B
authors.initials: AB
authors.lastname: Goldfine
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology; D008297:Male; D008875:Middle Aged
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D005947:Glucose; D002118:Calcium