Contrasting Diabetes Phenotypes Associated With Hepatocyte Nuclear Factor-1α and -1β Mutations

• Ewan R. Pearson

  Diabetes and Vascular Medicine, Peninsula Medical School, Exeter, U.K

• Michael K. Badman

  Department of Endocrinology, Hammersmith Hospital, London, U.K

• Christopher R. Lockwood

  Diabetes and Vascular Medicine, Peninsula Medical School, Exeter, U.K

• Penelope M. Clark

  Regional Endocrine Laboratories, University Hospital Birmingham NHS Trust, Birmingham, U.K

• Sian Ellard

  Diabetes and Vascular Medicine, Peninsula Medical School, Exeter, U.K

• Coralie Bingham

  Diabetes and Vascular Medicine, Peninsula Medical School, Exeter, U.K

• Andrew T. Hattersley

  Diabetes and Vascular Medicine, Peninsula Medical School, Exeter, U.K

抄録

OBJECTIVE—Mutations in the highly homologous transcription factors hepatocyte nuclear factor (HNF)-1α and -1β cause maturity-onset diabetes of the young types 3 and 5, respectively. Diabetes due to HNF-1α mutations is well characterized. However, physiological assessment of the HNF-1β phenotype is limited. We aimed to test the hypothesis that the diabetes phenotype due to HNF-1β mutations is similar to that in HNF-1α. RESEARCH DESIGN AND METHODS—Fasting biochemistry and a tolbutamide-modified intravenous glucose tolerance test (IVGTT) were compared in matched HNF-1β, HNF-1α, type 2 diabetic, and control subjects. Homeostasis model assessment indexes were determined from fasting insulin and glucose. The peak measures for the insulin increment after tolbutamide and for the insulin increment after glucose were determined from the IVGTT. RESULTS—The HNF-1β patients showed a 2.4-fold reduction in insulin sensitivity compared with the HNF-1α patients (P = 0.001) with fasting insulin concentrations 2.7-fold higher (P = 0.004). HNF-1β patients had lower HDL cholesterol (1.17 vs. 1.46 mmol/l; P = 0.009) and higher triglyceride (2.2 vs. 1.35 mmol/l; P = 0.015) levels than HNF-1α patients. The HNF-1β patients had similar β-cell responses to tolbutamide and glucose as the type 2 diabetic patients, but in the HNF-1α patients, the tolbutamide response was considerably increased relative to the response to glucose (P = 0.002). CONCLUSIONS—HNF-1β patients have a different diabetes phenotype than HNF-1α patients. Those with HNF-1β mutations have hyperinsulinemia and associated dyslipidemia consistent with insulin resistance and may have a different β-cell defect. This suggests that despite considerable homology and a shared binding site, HNF-1α and HNF-1β have a different role in maintaining normal glucose homeostasis. This result suggests a new etiological pathway for insulin resistance involving HNF-1β.

収録刊行物

• Diabetes Care

  Diabetes Care 27 (5), 1102-1107, 2004-05-01

  American Diabetes Association

キーワード

• Advanced and Specialized Nursing
• Endocrinology, Diabetes and Metabolism
• Internal Medicine

詳細情報

• CRID: 1362544419652148736
• NII論文ID: 30026280428
• DOI: 10.2337/diacare.27.5.1102
• ISSN: 19355548
• ISSN: 01495992
• Web Site: https://diabetesjournals.org/care/article-pdf/27/5/1102/565756/zdc00504001102.pdf
• データソース種別:
  • Crossref
  • CiNii Articles