AMINO-ACID SUBSTITUTIONS IN HEXOKINASE-II AMONG PATIENTS WITH NIDDM

Hexokinase (HX) II plays an important role in intracellular glucose metabolism by catalyzing the conversion of glucose to glucose-6-phosphate. HKII is considered to be a promising candidate gene for non-insulin-dependent diabetes mellitus (NIDDM) and insulin resistance. Therefore, we investigated the frequency of variants in the coding region of the HKII gene in patients with NIDDM. Initial screening included a population-based sample of 40 Finnish patients with typical NIDDM, and subsequent screening included an additional 72 patients with NIDDM. By applying single-strand conformation polymorphism analysis and direct sequencing, the following amino acid substitutions were found among the 112 NIDDM patients: Ala(314)Val in one patient (0.9%), Arg(353)Cys in three patients (2.7%), and Arg Gin substitution in three patients (2.7%), We also screened 97 subjects with completely normal glucose tolerance and a negative family history of diabetes for these mutations. The Ala(314)Val and the Arg(353)Cys substitutions were not found in control subjects, but the Arg(775)Gln substitution was found in two (2.1%) control subjects, None of these mutations were located close to the glucose- and ATP-binding sites of HKII. We conclude that mutations of the HKII gene are not a major etiological factor for NIDDM in the Finnish population.