DIMINISHED INSULIN AND GLUCAGON SECRETORY RESPONSES TO ARGININE IN NONDIABETIC SUBJECTS WITH A MUTATION IN THE HEPATOCYTE NUCLEAR FACTOR 4-ALPHA MODY1 GENE/

Nondiabetic subjects with the Q268X mutation in the hepatocyte nuclear factor (HNF)-4 alpha/MODY1 gene have impaired glucose-induced insulin secretion. To ascertain the effects of the nonglucose secretagogue ar ginine 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 po sitive (D[+]), We gave arginine as a 5-g bolus, followed by a 25-min i nfusion at basal glucose concentrations, and after glucose infusion to clamp plasma glucose at similar to 200 mg/dl, The acute insulin respo nse (AIR), the 10-60 min insulin area under the curve (AUG), and the i nsulin secretion rate (ISR) were compared, as were the acute glucagon response (AGR) and glucagon AUC. The ND[+] and D[+] groups had decreas ed insulin AUC and ISR and decreased glucose potentiation of AIR, insu lin AUG, and ISR to arginine administration when compared with the ND[ -] group, At basal glucose concentrations, glucagon AUC was greatest f or the ND[-] group, intermediate for the ND[+] group, and lowest for t he D[+] group, During the hyperglycemic clamp, there was decreased sup pression of glucagon AUC for both ND[+] and D[+] groups compared with the ND[-] group, The decreased ISR to arginine in the ND[+] group comp ared with the ND[-] group, magnified by glucose potentiation, indicate d that HNF-4 alpha affects the signaling pathway for arginine-induced insulin secretion, The decrease in glucagon AUC and decreased suppress ion of glucagon AUC with hyperglycemia suggest that mutations in HNF-4 alpha may lead to alpha-cell as well as beta-cell secretory defects o r a reduction in pancreatic islet mass.