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.
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Original Articles|
November 01 1997
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;
William H Herman
Department of Internal Medicine, University of Michigan Medical Center
Ann Arbor, Michigan
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Stefan S Fajans;
Stefan S Fajans
Department of Internal Medicine, University of Michigan Medical Center
Ann Arbor, Michigan
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Maria J Smith;
Maria J Smith
Department of Internal Medicine, University of Michigan Medical Center
Ann Arbor, Michigan
Department of Veterans Affairs Medical Center
Ann Arbor, Michigan
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Kenneth S Polonsky;
Kenneth S Polonsky
Departments of Medicine, University of Chicago
Chicago, Illinois
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Graeme I Bell;
Graeme I Bell
Biochemistry and Molecular Biology, and Howard Hughes Medical Institute, University of Chicago
Chicago, Illinois
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Jeffrey B Halter
Jeffrey B Halter
Department of Internal Medicine, University of Michigan Medical Center
Ann Arbor, Michigan
Department of Veterans Affairs Medical Center
Ann Arbor, Michigan
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Address correspondence and reprint requests to Dr. William H. Herman, Division of Endocrinology and Metabolism, 3920 Taubman Center, Box 0354, University of Michigan Medical Center, Ann Arbor, MI 48109-0354. E-mail: [email protected].
Diabetes 1997;46(11):1749–1754
Article history
Received:
May 27 1997
Revision Received:
July 16 1997
Accepted:
July 16 1997
PubMed:
9356021
Citation
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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