Postprandial Suppression of Glucagon Secretion Depends on Intact Pulsatile Insulin Secretion

Abstract

Type 2 diabetes is characterized by an ϳ60% loss of ␤-cell mass, a marked defect in postprandial insulin secretion, and a failure to suppress postprandial glucagon concentrations. It is possible that postprandial hyperglucagonemia in type 2 diabetes is due to impaired postprandial insulin secretion. To address this, we studied eight adult Goettingen minipigs before and after an ϳ60% reduction in ␤-cell mass induced by alloxan. Pigs were studied fasting and after ingestion of a mixed meal. Insulin and glucagon secretion were determined by deconvolution of blood hormone concentrations measured at 1-min intervals. The relationship between insulin and glucagon release was analyzed using cross-correlation and forward versus reverse cross-approximate entropy. We report that glucagon and insulin were secreted in ϳ4-min pulses. Prealloxan, postprandial insulin secretion drove an ϳ20% suppression of glucagon concentrations (P < 0.01), through inhibition of glucagon pulse mass. The alloxan-induced ϳ60% deficit in ␤-cell mass lead to an ϳ70% deficit in postprandial insulin secretion and loss of the postprandial insulindriven suppression of glucagon secretion. We conclude that postprandial hyperglucagonemia in type 2 diabetes is likely due to loss of intraislet postprandial suppression of glucagon secretion by insulin. Diabetes 55: [1051][1052][1053][1054][1055][1056] 2006 H yperglucagonemia is a characteristic of both type 1 and type 2 diabetes (1-3). In the overnight-fasted state, plasma glucagon concentrations in patients with diabetes are often comparable to those of nondiabetic individuals but are inappropriately high in the setting of hyperglycemia (1). After glucose ingestion, there is impaired glucagon suppression in both type 1 and type 2 diabetes (4,5). Postprandial hyperglucagonemia is an important contributor to failed suppression of hepatic glucose release after meal ingestion (3,6). Several hypotheses have been expounded to account for hyperglucagonemia in people with diabetes. Type 1 and type 2 diabetes are both characterized by a deficit in ␤-cell mass (7-11) and impaired postprandial insulin secretion (6,12,13). This is consistent with the role of the deficient intraislet insulin on postprandial suppression of glucagon secretion (14 -16).To address this, we studied a porcine model of type 2 diabetes with an alloxan-induced ϳ60% deficit in ␤-cell mass (17). We measured, in 1-min intervals, circulating insulin and glucagon concentrations in the fasting state and then after ingestion of a mixed meal in the same pigs before and after the alloxan-induced reduction of ␤-cell mass. We analyzed these data to address the following questions: 1) Is glucagon secreted in pulses, and if so, are these pulses modulated to regulate glucagon secretion? 2) After ingestion of a mixed meal, does insulin secretion contribute to suppression of glucagon secretion? 3) Does an ϳ60% decrease in ␤-cell mass lead to impaired insulinmediated suppression of glucagon secretion? RESEARCH DESIGN AND METHODSInsulin secretion in relation ...

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