TYPE-2 (NON-INSULIN-DEPENDENT) DIABETES-MELLITUS ASSOCIATED WITH A MUTATION OF THE GLUCOKINASE GENE IN A JAPANESE FAMILY

Mutations were screened for in the glucokinase gene of 25 Japanese pat ients with Type 2 (non-insulin-dependent) diabetes mellitus. Each exon was scanned by electrophoresis of enzymatically amplified DNA segment s under non-denaturing conditions and variants were sequenced. A varia nt pattern was detected in exon 5 of one patient. Direct sequencing of this exon revealed a single nucleotide substitution in codon 188 (GCT -->ACT) of one of two alleles resulting in the mutation of Ala188-->Th r, an invariant residue in the sequence of all mammalian glucokinases and hexokinases. This mutation was not found in 40 normal control subj ects. The proband had been diagnosed with Type 2 diabetes at the age o f 62 years. Four other members of her family have the same mutation an d all have Type 2 diabetes or impaired glucose tolerance. The youngest age at diagnosis of Type 2 diabetes in these other members was 13 yea rs, suggesting that her pedigree was maturity-onset diabetes of the yo ung (MODY). All subjects with the Thr188 mutation show a decreased ins ulin secretory response during oral glucose tolerance testing. Mutatio ns in the glucokinase gene associated with Type 2 diabetes have been p reviously identified in Caucasian (French and British) subjects. This study indicates that mutations in this gene are also implicated in the development of Type 2 diabetes in Asians. Further studies are require d to determine the frequency of mutations in glucokinase among Japanes e patients with Type 2 diabetes.