A MISSENSE MUTATION OF THE MUSCLE GLYCOGEN-SYNTHASE GENE (M416V) IS ASSOCIATED WITH INSULIN-RESISTANCE IN THE JAPANESE POPULATION

Muscle glycogen synthase (GYS1) is a key enzyme of non-oxidative pathw ay of glucose metabolism that has been reported to be related to insul in resistance in non-insulin-dependent diabetic (NIDDM) patients. We s canned the GYS1 gene for mutation by single strand conformational poly morphism in 244 non-obese Japanese NIDDM patients and 181 non-diabetic control subjects, and found two missense mutations; Met to Val at pos ition 416 in the exon 10 (M416V) and Pro to Ala at position 442 in the exon 11 (P442A). The P442A mutation was found in only one NIDDM patie nt treated with sulfonylureas. On the other hand, the M416V mutation w as widely found in the Japanese population. The mutant allele frequenc y in the NIDDM patients (13.7%) was slightly higher but not statistica lly significant compared with that in non-diabetic subjects (9.7%). Ho wever, the insulin sensitivity index [SI: x 10(-4) x min(-1) x (mu U/m l)(-1)] estimated by Minimal Model analysis in the NIDDM patients carr ying the M416V mutation was significantly lower than that in those wit hout the mutation (1.18 +/- 0.27, n = 21 vs 2.20 +/- 0.20, n = 60, mea n +/- SEM, p < 0.01). Glucose effectiveness, age, body mass index, and levels of glycated haemoglobin and serum lipids were not significantl y different between the two groups. The same trend could be seen in no n-diabetic subjects (SI: 3.70 +/- 0.46, 9 subjects with the mutation v s 5.94 +/- 0.66, 19 subjects without the mutation, p < 0.05). These fi ndings indicate that the M416V mutation of the GYS1 gene is one of the factors contributing to the insulin resistance in the Japanese popula tion and may play some role in the pathogenesis of NIDDM.