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Mechanisms of Impaired Fasting Glucose and Glucose Intolerance Induced by a 50% Pancreatectomy

¹ Larry L. Hillblom Islet Research Center, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California
² Endocrine Division, Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota

Address correspondence and reprint requests to Dr. Peter C. Butler, Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, 900A Weyburn Place, Los Angeles, CA 90095. E-mail: pbutler{at}mednet.ucla.edu

Abbreviations: IFG, impaired fasting glucose; IGT, impaired glucose tolerance

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) often coexist and as such represent a potent risk factor for subsequent development of type 2 diabetes. ß-Cell mass is 50% deficient in IFG and 65% deficient in type 2 diabetes. To establish the effect of a 50% deficit in ß-cell mass on carbohydrate metabolism, we performed a 50% partial pancreatectomy versus sham surgery in 14 dogs. Insulin secretion was quantified from insulin concentrations measured in the portal vein at 1-min sampling intervals under basal conditions, after a 30-g oral glucose, and during a hyperglycemic clamp. Insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp combined with isotope dilution. Partial pancreatectomy resulted in IFG and IGT. After partial pancreatectomy both basal and glucose-stimulated insulin secretion were decreased through the mechanism of a selective 50 and 80% deficit in insulin pulse mass, respectively (P < 0.05). These defects in insulin secretion were partially offset by decreased hepatic insulin clearance (P < 0.05). Partial pancreatectomy also caused a 40% decrease in insulin-stimulated glucose disposal (P < 0.05), insulin sensitivity after partial pancreatectomy being related to insulin pulse amplitude (r = 0.9, P < 0.01). We conclude that a 50% deficit in ß-cell mass can recapitulate the alterations in glucose-mediated insulin secretion and insulin action in humans with IFG and IGT. These data support a mechanistic role of a deficit in ß-cell mass in the evolution of IFG/IGT and subsequently type 2 diabetes.

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