title: Contrasting diabetes phenotypes associated with hepatocyte nuclear factor-1alpha and -1beta mutations.
abstract: 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.
  
  
  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.
authors.affiliation: Diabetes and Vascular Medicine, Peninsula Medical School, Exeter, UK.
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Pearson
authors.forename: Michael K
authors.initials: MK
authors.lastname: Badman
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Lockwood
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Clark
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Coralie
authors.initials: C
authors.lastname: Bingham
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000328:Adult; D017668:Age of Onset; D001786:Blood Glucose / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005951:Glucose Tolerance Test; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D012016:Reference Values; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta