期刊
DIABETES CARE
卷 27, 期 5, 页码 1102-1107出版社
AMER DIABETES ASSOC
DOI: 10.2337/diacare.27.5.1102
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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 Lest the hypothesis that the diabetes phenotype due to HNF-1beta mutations is similar to that in HNF-1alpha. RESEARCH DESIGN AND METHODS- Fasting biochernistry and a tolbutarmide-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 HFL cholesterol (1. 17 vs. 1.46mmol/l; P = 0.009)ancl 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-lalpha and HNF-1beta have a different rote in maintaining normal glucose homeostasis. This result suggests a new etiological pathway for insulin resistance involving HNF-1beta.
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