Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1α, HNF-1β, and HNF-4α are associated with maturity-onset diabetes of the young (MODY) and are believed to cause this form of diabetes by impairing pancreatic β-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-1α, HNF-1β, or HNF-4α may exhibit abnormal liver or kidney function. Here, we have examined liver and kidney function in a series of Japanese patients with HNF-4α/MODY1, HNF-1α/MODY3, and HNF-1β/MODY5 diabetes.


Clinical and biochemical data were obtained from Japanese subjects with HNF-1α, HNF-1β, and HNF-4α 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, γ-glutamyl transpeptidase, blood urea nitrogen, creatinine, uric acid, total and HDL cholesterol, triglycerides, and 17 serum proteins.


The present age and duration of diabetes were similar in patients with HNF-1α, HNF-1β, or HNF-4α diabetes, as was the age at diagnosis of diabetes in the youngest generation. All subjects were lean. Of the subjects with HNF-1α and HNF-4α diabetes, 50% were treated with insulin, as were all three subjects with HNF-1β diabetes. Retinopathy was present in patients with each form of diabetes. None of the subjects with HNF-4α diabetes had evidence of nephropathy, whereas 36% of the patients with HNF-1α diabetes and 100% of those with HNF-1α diabetes showed diminished kidney function. The three subjects with HNF-1β 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-1α 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-4α 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-4α diabetes and in one patient with HNF-1β diabetes, and in a second patient with HNF-1β diabetes, Lp(a) was at the upper limit of normal.


The results indicate that as in white patients, MODY resulting from mutations in the HNF-1α, HNF-1β, and HNF-4α genes in Japanese patients may be a severe disease similar to classic type 2 diabetes. In addition, they suggest that patients with HNF-1β 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.

This content is only available via PDF.