Intrahepatic glucose flux as a mechanism for defective intrahepatic islet alpha cell response to hypoglycemia

Abstract

Objective: Glucagon responses to hypoglycemia from islets transplanted in the liver are defective. To determine whether this defect is related to intrahepatic glycogen, inbred Lewis rats islets were transplanted in hepatic sinus (H), peritoneal cavity (P), omentum (O) and kidney capsule (K) of Lewis rats rendered diabetic with streptozotocin.

Research Design And Methods: Glucagon responses to hypoglycemia were obtained before and after transplantation under fed conditions and after fasting for 16h and 48h to deplete liver glycogen.

Results: Glucagon (AUC) responses to hypoglycemia in H (8839 +/− 1988 pg/ml/90min) were significantly less than in normal rats (40,777 +/− 8,192, p<0.01). Fasting significantly decreased hepatic glycogen levels. Glucagon responses in H were significantly larger after fasting (fed = 8839 +/− 1988 vs. 16h fasting = 24,715 +/−5,210, 48h fasting = 29,639 +/− 4550, p<0.01). Glucagon response in H decreased after refeeding (48h fasting = 29,639 +/− 4550, vs. refed = 10,276 +/− 2750; p<0.01). There was no difference in glucagon response to hypoglycemia between H and normal control group after fasting for 48h (H = 29,639 +/− 4550 vs. Control = 37,632 +/− 5335 p=ns). No intragroup differences were observed in the P, O, and K groups, or normal control and STZ groups, when comparing fed or fasting states.

Conclusions: These data suggest that defective glucagon responses to hypoglycemia by intrahepatic islet alpha cells is due to dominance of a suppressive signal caused by increased glucose flux and glucose levels within the liver secondary to increased glycogenolysis caused by systemic hypoglycemia.