Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 10, Pages 4770-4775Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1000002107
Keywords
beta cell; type 2 diabetes mellitus; insulin resistance; insulin clearance; C-peptide
Categories
Funding
- National Institutes of Health [K23-DK02795, R01 DK070648, DK67536, DK061644, DK33201, P30-DK36836, M01-RR001032, RR12248]
- American Diabetes Association [06-CD-07]
- Harvard 50th Anniversary Scholars in Medicine
- Priscilla White Fellowship
- Lilly Fellowship
- Harvard Massachusetts Institute of Technology Health Sciences and Technology-Beth Israel Deaconess Medical Center
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Islet beta-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 beta-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 beta-cell function. Preexposure to exogenous insulin increased the endogenous insulin secretory response to glucose by approximate 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 beta-cell secretory response when using these methods during prolonged dynamic testing.
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