RT Journal Article
SR Electronic
T1 Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 2318
OP 2323
DO 10.2337/db06-0080
VO 55
IS 8
A1 Salehi, Albert
A1 Vieira, Elaine
A1 Gylfe, Erik
YR 2006
UL http://diabetes.diabetesjournals.org/content/55/8/2318.abstract
AB Hypersecretion of glucagon contributes to the dysregulation of glucose homeostasis in diabetes. To clarify the underlying mechanism, glucose-regulated glucagon secretion was studied in mouse pancreatic islets and clonal hamster In-R1-G9 glucagon-releasing cells. Apart from the well-known inhibition of secretion with maximal effect around 7 mmol/l glucose, we discovered that mouse islets showed paradoxical stimulation of glucagon release at 25–30 mmol/l and In-R1-G9 cells at 12–20 mmol/l sugar. Whereas glucagon secretion in the absence of glucose was inhibited by hyperpolarization with diazoxide, this agent tended to further enhance secretion stimulated by high concentrations of the sugar. Because U-shaped dose-response relationships for glucose-regulated glucagon secretion were observed in normal islets and in clonal glucagon-releasing cells, both the inhibitory and stimulatory components probably reflect direct effects on the α-cells. Studies of isolated mouse α-cells indicated that glucose inhibited glucagon secretion by lowering the cytoplasmic Ca2+ concentration. However, stimulation of glucagon release by high glucose concentrations did not require elevation of Ca2+, indicating involvement of novel mechanisms in glucose regulation of glucagon secretion. A U-shaped dose-response relationship for glucose-regulated glucagon secretion may explain why diabetic patients with pronounced hyperglycemia display paradoxical hyperglucagonemia.