SummaryWe have previously shown that the mRNA expression of muscle glycogen synthase is decreased in non-insulin-dependent diabetic (NIDDM) patients; the objective of the present protocol was to examine whether the gene expression of muscle glycogen synthase in NIDDM is affected by chronic sulphonylurea treatment. Ten obese patients with NIDDM were studied before and after 8 weeks of treatment with a weight-maintaining diet in combination with the sulphonylurea gliclazide. Gliclazide treatment was associated with significant reductions in HbAlc (p = 0.01) and fasting plasma glucose (p = 0.005) as well as enhanced beta-cell responses to an oral glucose load. During euglycaemic, hyperinsulinaemic clamp (2 mU. kg -1. rain -1) in combination with indirect calorimetry, a 35 % (p = 0.005) increase in whole-body insulin-stimulated glucose disposal rate, predominantly due to an increased nonoxidative glucose metabolism (p = 0.02) was demonstrated in the gliclazide-treated patients when cornpared to pre-treatment values. In biopsies obtained from vastus lateralis muscle during insulin infusion, the half-maximal activation of glycogen synthase was achieved at a significantly lower concentration of the allosteric activator glucose 6-phosphate (p = 0.01). However, despite significant increases in both insulin-stimulated non-oxidative glucose metabolism and muscle glycogen synthase activation in gliclazide-treated patients no changes were found in levels of glycogen synthase mRNA or immunoreactive protein in muscle. In conclusion, improved blood glucose control in gliclazide-treated obese N1DDM patients has no impact on the gene expression of muscle glycogen synthase. [Diabetologia (1995[Diabetologia ( ) 38: 1230[Diabetologia ( -1238 Key words Non-insulin-dependent diabetes mellitus, skeletal muscle, glycogen synthase, gene expression, sulphonylurea treatment.Under clamp conditions of euglycaemia and hyperinsulinaemia glucose clearance in most patients with non-insulin-dependent diabetes mellitus (NIDDM) is characteristically decreased by 30-50 % with glucose storage as glycogen in skeletal muscle being the quantitatively most affected path-