Mechanisms of impaired fasting glucose and glucose intolerance induced by an approximate 50% pancreatectomy.
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. beta-Cell mass is approximately 50% deficient in IFG and approximately 65% deficient in type 2 diabetes. To establish the effect of a approximately 50% deficit in beta-cell mass on carbohydrate metabolism, we performed a approximately 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 approximately 50 and approximately 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 approximately 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 approximately 50% deficit in beta-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 beta-cell mass in the evolution of IFG/IGT and subsequently type 2 diabetes.
Matveyenko
Aleksey V
AV
Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, 900A Weyburn Place, Los Angeles, CA 90095, USA.
Veldhuis
Johannes D
JD
Butler
Peter C
PC
D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology; D004195:Disease Models, Animal; D004285:Dogs; D005215:Fasting; D005947:Glucose / Q000494:pharmacology; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000209:etiology*; D006400:Hematocrit; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism; D010180:Pancreatectomy
D001786:Blood Glucose; D007328:Insulin; D005947:Glucose