Objective: To investigate the prevalence of the unique HNF-1alpha G319S mutation in a population of aboriginal youth with type 2 diabetes and to describe the relationship between clinical and historical characteristics and the presence or absence of the HNF-1alpha G319S mutation.
Research design and methods: Participating youth were genotyped for the G319S mutation of the HNF-1alpha gene. Clinical, laboratory, and historical data were collected via chart review (blinded to genotype results). Comparison data were derived from another study involving young nondiabetic pregnant aboriginal women.
Results: A total of 51 youth seen sequentially in a type 2 diabetes clinic participated in this study. Of these, 21 (41.2%) had at least one copy of the mutant allele. The allele frequency in the study population was 0.29 (95% CI 0.20-0.38), which was significantly different from the allele frequency of 0.13 in the comparison population (chi(2) = 6.78, P = 0.009). The frequency of the homozygous mutation (S319/S319) was 0.18. Mean BMI was significantly lower (P = 0.002), mean HbA(1c) was significantly higher (P = 0.02), and acanthosis nigricans was significantly less frequent (P = 0.004) in those with the mutation compared with the wild type. Mean insulin levels were lower and insulin sensitivity (assessed by homeostasis model assessment [HOMA]) was greater in the homozygote group compared with the wild-type group (P = 0.002 and P = 0.0007, respectively). A dose-dependent gradient was observed for these characteristics.
Conclusions: These data support the association between the HNF-1alpha G319S mutation and early-onset type 2 diabetes in this population. Those with the mutation lacked clinical characteristics of insulin resistance (e.g., obesity and acanthosis nigricans) and had lower insulin levels, suggesting that an insulin-secretory and/or -production defect plays an important role in the development of diabetes in this group. Further investigation of the pathophysiology of the S319 homo- and heterozygote is needed because it may impact treatment and/or prevention of this disease.