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- Title
Diminished insulin and glucagon secretory responses to arginine in nondiabetic subjects with a mutation in the hepatocyte nuclear factor-4alpha/MODY1 gene.
- Authors
Herman, William H.; Fajans, Stefan S.; Smith, Maria J.; Polonsky, Kenneth S.; Bell, Graeme I.; Halter, Jeffrey B.; Herman, W H; Fajans, S S; Smith, M J; Polonsky, K S; Bell, G I; Halter, J B
- Abstract
Nondiabetic subjects with the Q268X mutation in the hepatocyte nuclear factor (HNF)-4alpha/MODY1 gene have impaired glucose-induced insulin secretion. To ascertain the effects of the nonglucose secretagogue arginine on insulin and glucagon secretion in these subjects, we studied 18 members of the RW pedigree: 7 nondiabetic mutation negative (ND[-]), 7 nondiabetic mutation positive (ND[+]), and 4 diabetic mutation positive (D[+]). We gave arginine as a 5-g bolus, followed by a 25-min infusion at basal glucose concentrations, and after glucose infusion to clamp plasma glucose at approximately 200 mg/dl. The acute insulin response (AIR), the 10-60 min insulin area under the curve (AUC), and the insulin secretion rate (ISR) were compared, as were the acute glucagon response (AGR) and glucagon AUC. The ND[+] and D[+] groups had decreased insulin AUC and ISR and decreased glucose potentiation of AIR, insulin AUC, and ISR to arginine administration when compared with the ND[-] group. At basal glucose concentrations, glucagon AUC was greatest for the ND[-] group, intermediate for the ND[+] group, and lowest for the D[+] group. During the hyperglycemic clamp, there was decreased suppression of glucagon AUC for both ND[+] and D[+] groups compared with the ND[-] group. The decreased ISR to arginine in the ND[+] group compared with the ND[-] group, magnified by glucose potentiation, indicated that HNF-4alpha affects the signaling pathway for arginine-induced insulin secretion. The decrease in glucagon AUC and decreased suppression of glucagon AUC with hyperglycemia suggest that mutations in HNF-4alpha may lead to alpha-cell as well as beta-cell secretory defects or a reduction in pancreatic islet mass.
- Publication
Diabetes, 1997, Vol 46, Issue 11, p1749
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.46.11.1749