OBJECTIVE: Mutations in the highly homologous transcription factors hepatocyte nuclear factor (HNF)-1alpha and -1beta cause maturity-onset diabetes of the young types 3 and 5, respectively. Diabetes due to HNF-1alpha mutations is well characterized. However, physiological assessment of the HNF-1beta phenotype is limited. We aimed to test the hypothesis that the diabetes phenotype due to HNF-1beta mutations is similar to that in HNF-1alpha. RESEARCH DESIGN AND METHODS: Fasting biochemistry and a tolbutamide-modified intravenous glucose tolerance test (IVGTT) were compared in matched HNF-1beta, HNF-1alpha, 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-1beta patients showed a 2.4-fold reduction in insulin sensitivity compared with the HNF-1alpha patients (P = 0.001) with fasting insulin concentrations 2.7-fold higher (P = 0.004). HNF-1beta 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-1alpha patients. The HNF-1beta patients had similar beta-cell responses to tolbutamide and glucose as the type 2 diabetic patients, but in the HNF-1alpha patients, the tolbutamide response was considerably increased relative to the response to glucose (P = 0.002). CONCLUSIONS: HNF-1beta patients have a different diabetes phenotype than HNF-1alpha patients. Those with HNF-1beta mutations have hyperinsulinemia and associated dyslipidemia consistent with insulin resistance and may have a different beta-cell defect. This suggests that despite considerable homology and a shared binding site, HNF-1alpha and HNF-1beta have a different role in maintaining normal glucose homeostasis. This result suggests a new etiological pathway for insulin resistance involving HNF-1beta.
OBJECTIVE: Mutations in the highly homologous transcription factors hepatocyte nuclear factor (HNF)-1alpha and -1beta cause maturity-onset diabetes of the young types 3 and 5, respectively. Diabetes due to HNF-1alpha mutations is well characterized. However, physiological assessment of the HNF-1beta phenotype is limited. We aimed to test the hypothesis that the diabetes phenotype due to HNF-1beta mutations is similar to that in HNF-1alpha. RESEARCH DESIGN AND METHODS: Fasting biochemistry and a tolbutamide-modified intravenous glucose tolerance test (IVGTT) were compared in matched HNF-1beta, HNF-1alpha, 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-1betapatients showed a 2.4-fold reduction in insulin sensitivity compared with the HNF-1alphapatients (P = 0.001) with fasting insulin concentrations 2.7-fold higher (P = 0.004). HNF-1betapatients 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-1alphapatients. The HNF-1betapatients had similar beta-cell responses to tolbutamide and glucose as the type 2 diabeticpatients, but in the HNF-1alphapatients, the tolbutamide response was considerably increased relative to the response to glucose (P = 0.002). CONCLUSIONS:HNF-1betapatients have a different diabetes phenotype than HNF-1alphapatients. Those with HNF-1beta mutations have hyperinsulinemia and associated dyslipidemia consistent with insulin resistance and may have a different beta-cell defect. This suggests that despite considerable homology and a shared binding site, HNF-1alpha and HNF-1beta have a different role in maintaining normal glucose homeostasis. This result suggests a new etiological pathway for insulin resistance involving HNF-1beta.
Authors: L W Harries; Coralie Bingham; Christine Bellanne-Chantelot; A T Hattersley; Sian Ellard Journal: Hum Genet Date: 2005-11-15 Impact factor: 4.132