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

Hexokinase (HX) II plays an important role in intracellular glucose me tabolism by catalyzing the conversion of glucose to glucose-6-phosphat e. 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 th e HKII gene in patients with NIDDM. Initial screening included a popul ation-based sample of 40 Finnish patients with typical NIDDM, and subs equent screening included an additional 72 patients with NIDDM. By app lying single-strand conformation polymorphism analysis and direct sequ encing, the following amino acid substitutions were found among the 11 2 NIDDM patients: Ala(314)Val in one patient (0.9%), Arg(353)Cys in th ree patients (2.7%), and Arg Gin substitution in three patients (2.7%) , We also screened 97 subjects with completely normal glucose toleranc e and a negative family history of diabetes for these mutations. The A la(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%) co ntrol subjects, None of these mutations were located close to the gluc ose- 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.