title: Liver and kidney function in Japanese patients with maturity-onset diabetes of the young.
abstract: OBJECTIVE
  Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1 alpha, HNF-1 beta, and HNF-4 alpha are associated with maturity-onset diabetes of the young (MODY) and are believed to cause this form of diabetes by impairing pancreatic beta-cell function. The HNFs also play a central role in the tissue-specific regulation of gene expression in liver and kidney, suggesting that patients with MODY due to a mutation in HNF-1 alpha, HNF-1 beta, or HNF-4 alpha may exhibit abnormal liver or kidney function. Here, we have examined liver and kidney function in a series of Japanese patients with HNF-4 alpha/MODY1, HNF-1 alpha/MODY3, and HNF-1 beta/MODY5 diabetes.
  
  
  METHODS
  Clinical and biochemical data were obtained from Japanese subjects with HNF-1 alpha, HNF-1 beta, and HNF-4 alpha diabetes. The clinical data included information on BMI, age at diagnosis, current treatment, and the presence and nature of any complications. The biochemical studies examined liver and kidney function and included measures of alanine and aspartate aminotransferase, gamma-glutamyl transpeptidase, blood urea nitrogen, creatinine, uric acid, total and HDL cholesterol, triglycerides, and 17 serum proteins.
  
  
  RESULTS
  The present age and duration of diabetes were similar in patients with HNF-1 alpha, HNF-1 beta, or HNF-4 alpha diabetes, as was the age at diagnosis of diabetes in the youngest generation. All subjects were lean. Of the subjects with HNF-1 alpha and HNF-4 alpha diabetes, 50% were treated with insulin, as were all three subjects with HNF-1 beta diabetes. Retinopathy was present in patients with each form of diabetes. None of the subjects with HNF-4 alpha diabetes had evidence of nephropathy, whereas 36% of the patients with HNF-1 alpha diabetes and 100% of those with HNF-1 beta diabetes showed diminished kidney function. The three subjects with HNF-1 beta diabetes also had abnormally high serum creatinine, uric acid, and blood urea nitrogen levels, which are consistent with impaired kidney function, and one of seven subjects with HNF-1 alpha diabetes had a mild elevation in creatinine and blood urea nitrogen levels. These values were within the normal range in the three patients with HNF-4 alpha diabetes. Although the HNFs play a role in regulating the expression of the genes for most, if not all, serum proteins, there was no decrease in the levels of any of the 17 serum proteins examined, and most were within or slightly above the normal range. Lipoprotein(a) [Lp(a)] levels were elevated in the three patients with HNF-4 alpha diabetes and in one patient with HNF-1 beta diabetes, and in a second patient with HNF-1 beta diabetes, Lp(a) was at the upper limit of normal.
  
  
  CONCLUSIONS
  The results indicate that as in white patients, MODY resulting from mutations in the HNF-1 alpha, HNF-1 beta, and HNF-4 alpha genes in Japanese patients may be a severe disease similar to classic type 2 diabetes. In addition, they suggest that patients with HNF-1 beta diabetes may be characterized by diminished kidney function and perhaps abnormal liver function. Further studies are needed to determine whether tests of liver and kidney function will be useful in the diagnosis and subclassification of MODY.
authors.affiliation: Diabetes Center, Tokyo Women's Medical University, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Iwasaki
authors.forename: M
authors.initials: M
authors.lastname: Ogata
authors.forename: O
authors.initials: O
authors.lastname: Tomonaga
authors.forename: H
authors.initials: H
authors.lastname: Kuroki
authors.forename: T
authors.initials: T
authors.lastname: Kasahara
authors.forename: N
authors.initials: N
authors.lastname: Yano
authors.forename: Y
authors.initials: Y
authors.lastname: Iwamoto
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001053:Apolipoproteins / Q000097:blood; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001798:Blood Proteins / Q000032:analysis; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000503:physiopathology; D005260:Female; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007677:Kidney Function Tests; D017270:Lipoprotein(a) / Q000097:blood; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D001053:Apolipoproteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001798:Blood Proteins; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D017270:Lipoprotein(a); C403128:MLX protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D002784:Cholesterol; D003404:Creatinine