Hyperuricemia and young-onset gout are consistent features of the phenotype associated with HNF-1beta mutations, but the mechanism is uncertain. Families with HNF-1beta mutations may fit diagnostic criteria for FJHN. Identification of HNF-1beta patients by recognizing the features of diabetes and disorders of renal development is important in resolving the genetic heterogeneity in FJHN.

OBJECTIVE -Mutations in the highly homologous transcription factors hepatocyte nuclear factor (HNF)-1␣ and -1␤ cause maturity-onset diabetes of the young types 3 and 5, respectively. Diabetes due to HNF-1␣ mutations is well characterized. However, physiological assessment of the HNF-1␤ phenotype is limited. We aimed to test the hypothesis that the diabetes phenotype due to HNF-1␤ mutations is similar to that in HNF-1␣. RESEARCH DESIGN AND METHODS-Fasting biochemistry and a tolbutamidemodified intravenous glucose tolerance test (IVGTT) were compared in matched HNF-1␤, HNF-1␣, 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-1␤ patients showed a 2.4-fold reduction in insulin sensitivity compared with the HNF-1␣ patients (P ϭ 0.001) with fasting insulin concentrations 2.7-fold higher (P ϭ 0.004). HNF-1␤ patients had lower HDL cholesterol (1.17 vs. 1.46 mmol/l; P ϭ 0.009) and higher triglyceride (2.2 vs. 1.35 mmol/l; P ϭ 0.015) levels than HNF-1␣ patients. The HNF-1␤ patients had similar ␤-cell responses to tolbutamide and glucose as the type 2 diabetic patients, but in the HNF-1␣ patients, the tolbutamide response was considerably increased relative to the response to glucose (P ϭ 0.002).CONCLUSIONS -HNF-1␤ patients have a different diabetes phenotype than HNF-1␣ patients. Those with HNF-1␤ mutations have hyperinsulinemia and associated dyslipidemia consistent with insulin resistance and may have a different ␤-cell defect. This suggests that despite considerable homology and a shared binding site, HNF-1␣ and HNF-1␤ have a different role in maintaining normal glucose homeostasis. This result suggests a new etiological pathway for insulin resistance involving HNF-1␤. Diabetes Care 27:1102-1107, 2004H eterozygous mutations in the transcription factor genes hepatocyte nuclear factor (HNF)-1␣ (TCF1) and HNF-1␤ (TCF2) cause maturity-onset diabetes of the young (MODY) types 3 and 5, respectively. The phenotype of HNF-1␣ mutations is primarily characterized by diabetes (1). In contrast, mutations in HNF-1␤ are associated with a syndrome characterized predominantly by nondiabetic renal dysfunction, particularly renal cystic disease, diabetes, genital tract malformation, abnormal liver function, and hyperuricemia (2-13).HNF-1␤ is a homeodomain transcription factor, structurally related to HNF-1␣. They share Ͼ90% sequence homology in their DNA binding domains and recognize the same DNA binding site. HNF-1␣ and HNF-1␤ function as homodimers or heterodimers (14). They are expressed in a number of tissues including liver, kidney, intestine, and pancreatic islets where they play a role in embryonic development of these organs and tissuespecific gene expression. It is not clear how the role of these transcription factors differs in the complex transcription factor network. However, they do differ both in...

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