Diminished insulin and glucagon secretory responses to arginine in nondiabetic subjects with a mutation in the hepatocyte nuclear factor-4alpha/MODY1 gene.
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.
Herman
W H
WH
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0354, USA. wherman@umich.edu
Fajans
S S
SS
Smith
M J
MJ
Polonsky
K S
KS
Bell
G I
GI
Halter
J B
JB
D000328:Adult; D001120:Arginine / Q000494:pharmacology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics*; D005260:Female; D005934:Glucagon / Q000097:blood / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics*; D017354:Point Mutation; D012016:Reference Values; D014157:Transcription Factors / Q000235:genetics*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose; D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin; C403128:MLX protein, human; D010750:Phosphoproteins; D014157:Transcription Factors; D005934:Glucagon; D001120:Arginine; D005947:Glucose