Insulin enhances glucose-stimulated insulin secretion in healthy humans

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-03, Vol.107 (10), p.4770-4775
• Main Authors: Bouche, Clara, Lopez, Ximena, Fleischman, Amy, Cypess, Aaron M, O'Shea, Sheila, Stefanovski, Darko, Bergman, Richard N, Rogatsky, Eduard, Stein, Daniel T, Kahn, C. Ronald, Kulkarni, Rohit N, Goldfine, Allison B
• Format: Article
• Language: English
• Subjects: Adult; Beta cells; Biological Sciences; Blood Glucose - metabolism; C-Peptide - metabolism; C-Peptide - pharmacokinetics; Cells; Diabetes mellitus; Enzyme-Linked Immunosorbent Assay; Female; Glucose; Glucose - pharmacology; Hormones - metabolism; Humans; Hyperinsulinism; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Insulin; Insulin - metabolism; Insulin - pharmacokinetics; Insulin - pharmacology; Insulin resistance; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Isotopes; Male; Metabolic Clearance Rate; Peptides; Proteins; Receptors; Rodents; Single-Blind Method; Type 1 diabetes mellitus; Type 2 diabetes mellitus; Young Adult
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1000002107

Islet β-cells express both insulin receptors and insulin-signaling proteins. Recent evidence from rodents in vivo and from islets isolated from rodents or humans suggests that the insulin signaling pathway is physiologically important for glucose sensing. We evaluated whether insulin regulates β-cell function in healthy humans in vivo. Glucose-induced insulin secretion was assessed in healthy humans following 4-h saline (low insulin/sham clamp) or isoglycemic-hyperinsulinemic (high insulin) clamps using B28-Asp insulin that could be immunologically distinguished from endogenous insulin. Insulin and C-peptide clearance were evaluated to understand the impact of hyperinsulinemia on estimates of β-cell function. Preexposure to exogenous insulin increased the endogenous insulin secretory response to glucose by [almost equal to]40%. C-peptide response also increased, although not to the level predicted by insulin. Insulin clearance was not saturated at hyperinsulinemia, but metabolic clearance of C-peptide, assessed by infusion of stable isotope-labeled C-peptide, increased modestly during hyperinsulinemic clamp. These studies demonstrate that insulin potentiates glucose-stimulated insulin secretion in vivo in healthy humans. In addition, hyperinsulinemia increases C-peptide clearance, which may lead to modest underestimation of β-cell secretory response when using these methods during prolonged dynamic testing.