Paradoxical stimulation of glucagon secretion by high glucose concentrations.
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 alpha-cells. Studies of isolated mouse alpha-cells indicated that glucose inhibited glucagon secretion by lowering the cytoplasmic Ca(2+) concentration. However, stimulation of glucagon release by high glucose concentrations did not require elevation of Ca(2+), 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.
Salehi
Albert
A
Department of Clinical Science, Clinical Research Center, Malmö University Hospital, Malmö, Sweden.
Vieira
Elaine
E
Gylfe
Erik
E
D000818:Animals; D002118:Calcium / Q000032:analysis; D002460:Cell Line; D002478:Cells, Cultured; D002999:Clone Cells; D006224:Cricetinae; D003593:Cytoplasm / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000378:metabolism*; D005947:Glucose / Q000008:administration & dosage*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL
D007328:Insulin; D005934:Glucagon; D005947:Glucose; D002118:Calcium