Intrahepatic Glucose Flux as a Mechanism for Defective Intrahepatic Islet α-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, islets from inbred Lewis rats were transplanted into the hepatic sinus (H group), peritoneal cavity (P group), omentum (O group), and kidney capsule (K group) of recipient Lewis rats previously rendered diabetic with streptozotocin (STZ). RESEARCH DESIGN AND METHODS— Glucagon responses to hypoglycemia were obtained before and after transplantation under fed conditions and after fasting for 16 h and 48 h to deplete liver glycogen. RESULTS— Glucagon (area under the curve) responses to hypoglycemia in the H group (8,839 ± 1,988 pg/ml per 90 min) were significantly less than in normal rats (40,777 ± 8,192; P < 0.01). Fasting significantly decreased hepatic glycogen levels. Glucagon responses in the H group were significantly larger after fasting (fed 8,839 ± 1,988 vs. 16-h fasting 24,715 ± 5,210 and 48-h fasting 29,639 ± 4,550; P < 0.01). Glucagon response in the H group decreased after refeeding (48-h fasting 29,639 ± 4,550 vs. refed 10,276 ± 2,750; P < 0.01). There was no difference in glucagon response to hypoglycemia between the H and the normal control group after fasting for 48 h (H 29,639 ± 4,550 vs. control 37,632 ± 5,335; 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 α-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.

Defective Glucagon Secretion During Hypoglycemia After Intrahepatic But Not Nonhepatic Islet Autotransplantation

“…The probability that this is a transplantation site-specific defect is strengthened by our finding that TP/IAT subjects who received not only intrahepatic, but also non-hepatic islets had virtually normal glucagon and symptom responses to hypoglycemia. These observations are consistent with previously reported animal studies that demonstrated intrahepatic islets failed to secrete glucagon normally during hypoglycemia, although they secreted glucagon in response to intravenous arginine (9, 10). As with the current work, islets transplanted into non-hepatic sites in animals had intact glucagon responses to hypoglycemia (9, 10).…”

Total Pancreatectomy With Islet Autotransplantation

“…Unfortunately, however, glucagon responses from islets transplanted intrahepatically are greatly suppressed, whereas their responses to intravenous arginine are less impaired (51), indicating the defect in secreting glucagon is specific to hypoglycemia, and cannot be explained by reduced surviving islet mass. The mechanism for the glucose sensing defect may be increased glucose flux within the liver during glycogenolysis and hypoglycemia, which masks intrahepatic alpha cells to the stimulatory effects of low blood glucose in the general circulation (52). Glucagon secretion induced by hypoglycemia was normalized and hypoglycemic awareness improved by transplantation of a portion of the islets into the peritoneal cavity in younger recipients of a larger number is autoislets, supporting a site specific defect in alpha cell function (51).…”

Rapid Adaptation of Rat Brain and Liver Metabolism to a Ketogenic Diet: An Integrated Study Using 1H- and 13C-NMR Spectroscopy

“…13 The KD group was fasted for 48 hours before starting the KD to deplete hepatic glycogen stores and favor ketogenesis, as recommended during clinical use of the KD. 7,14 Body weight and food intake were monitored every day at 09:00 am. Tail vein whole blood β-HB was measured every other day using test strips and a hand-held device (Precision Xtra, Abbott Laboratories, Alameda, CA, USA).…”