Nondiabetic subjects with the Q268X mutation in the hepatocyte nuclear factor (HNF)-4α/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 ∼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-4α 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-4α may lead to α-cell as well as β-cell secretory defects or a reduction in pancreatic islet mass.
Diminished Insulin and Glucagon Secretory Responses to Arginine in Nondiabetic Subjects With a Mutation in the Hepatocyte Nuclear Factor–4α/MODY1 Gene
William H Herman, Stefan S Fajans, Maria J Smith, Kenneth S Polonsky, Graeme I Bell, Jeffrey B Halter; Diminished Insulin and Glucagon Secretory Responses to Arginine in Nondiabetic Subjects With a Mutation in the Hepatocyte Nuclear Factor–4α/MODY1 Gene. Diabetes 1 November 1997; 46 (11): 1749–1754. https://doi.org/10.2337/diab.46.11.1749
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