LIVER AND KIDNEY-FUNCTION IN JAPANESE PATIENTS WITH MATURITY-ONSET DIABETES OF THE YOUNG

OBJECTIVE - Heterozygous mutations in the transcription factors hepato cyte nuclear factor (HNF)-1 alpha, HNF-1 beta, and HNF-4 alpha are ass ociated with maturity-onset diabetes of the young (MODY) and are belie ved to cause this form of diabetes by impairing pancreatic beta-cell f unction. The HNFs also play a central role in the tissue-specific regu lation of gene expression in liver and kidney, suggesting that patient s with MODY due to a mutation in HNF-1 alpha, HNF-1 beta, or HNF-4 alp ha may exhibit abnormal liver or kidney function. Here, we have examin ed 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. RESE ARCH DESIGN AND METHODS - Clinical and biochemical data were obtained from Japanese subjects with HNF-1 alpha, HNF-1 beta, and HNF-4 alpha d iabetes. The clinical data included information on BMI, age at diagnos is, current treatment, and the presence and nature of any complication s. The biochemical studies examined liver and kidney function and incl uded measures of alanine and aspartate aminotransferase, gamma-glutamy l transpeptidase, blood urea nitrogen, creatinine, uric acid, total an d HDL cholesterol, triglycerides, and 17 serum proteins. RESULTS - The present age and duration of diabetes were similar in patients with HN F-1 alpha, HNF-1 beta, or HNF-4 alpha diabetes, as was the age at diag nosis of diabetes in the youngest generation. All subjects were lean. Of the subjects with HNF-1 alpha and HNF-4 alpha diabetes, 50% were tr eated with insulin, as were all three subjects with HNF-1 beta diabete s. Retinopathy was present in patients with each form of diabetes. Non e of the subjects with HNF-4 alpha diabetes had evidence of nephropath y, whereas 36% of the patients with HNF-1 alpha diabetes and 100% of t hose with HNF-1 beta diabetes showed diminished kidney function. The t hree subjects with HNF-1 beta diabetes also had abnormally high serum creatinine, uric acid, and blood urea nitrogen levels, which are consi stent with impaired kidney function, and one of seven subjects with HN F-1 alpha diabetes had a mild elevation in creatinine and blood urea n itrogen 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 pro teins, there was no decrease in the levels of any of the 17 serum prot eins examined, and most were within or slightly above the normal range . Lipoprotein(a) [Lp(a)] levels were elevated in the three patients wi th HNF-4 alpha diabetes and in one patient with HNF-1 beta diabetes, a nd in a second patient with HNF-1 beta diabetes, Lp(a) was at the uppe r limit of normal. CONCLUSIONS - The results indicate that as in white patients, MODY resulting from mutations in the HNF-1 alpha, HNF-1 bet a, and HNF-4 alpha genes in Japanese patients may be a severe disease similar to classic type 2 diabetes. In addition, they suggest that pat ients with HNF-1 beta diabetes may be characterized by diminished kidn ey function and perhaps abnormal liver function. Further studies are n eeded to determine whether tests of liver and kidney function will be useful in the diagnosis and subclassification of MODY.