Increments in insulin sensitivity during intensive treatment are closely correlated with decrements in glucocorticoid receptor mRNA in skeletal muscle from patients with Type II diabetes

To test the hypothesis that changes in the expression of the glucocorticoid receptor (GCR) and the β₂-adrenoceptor (β₂-AR) contribute significantly to the abnormal glucose metabolism in skeletal muscle from patients with Type II diabetes, we have examined (1) the levels of total GCR (α+β isoforms), the α/α2 isoform of GCR and β₂-AR mRNAs in skeletal muscle from insulin-resistant patients with Type II diabetes (n = 10) and healthy controls (n = 15), and (2) the effects of 8 weeks of intensive treatment on the whole-body glucose disposal rate and on total GCR, α/α2 GCR and β₂-AR mRNA levels in diabetic patients. The total glucose disposal rate was measured by the euglycaemic hyperinsulinaemic (2m-unitsċmin^-1ċkg^-1) clamp technique, and mRNA levels were assessed by reverse transcriptase-PCR and HPLC for separation of standard and unknown and quantification. Mean levels of total GCR and α/α2 GCR mRNAs were increased in patients with Type II diabetes when compared with control subjects [total GCR, 2.06±0.30 and 1.47±0.10 amol/μg of total RNA respectively (P = 0.09); α/α2 GCR mRNA, 1.69±0.31and 0.92±0.09amol/μg of total RNA respectively (P = 0.02)], whereas mRNA levels of the β isoform of GCR (total GCR minus α/α2 GCR) were decreased (P = 0.006). β₂-AR mRNA levels were comparable in diabetic patients and control subjects (0.53±0.05 and 0.45±0.02amol/μg of total RNA respectively; P = 0.2). Intensive treatment for 8 weeks was associated with improved glycaemic control (P = 0.019), and during the clamp a 75% (P = 0.001) increase in the whole-body insulin-stimulated glucose disposal rate was demonstrated. Total GCR (P = 0.005), α/α2 GCR (P = 0.005) and β₂-AR (P = 0.03) mRNA levels all decreased significantly after intensive insulin treatment. A close correlation was found between increments in glucose uptake during intensive treatment and decrements in skeletal muscle total GCR mRNA (r = 0.95, P<0.001; multiple regression analysis), and between glucose uptake and α/α2 GCRm RNA levels (r = 0.88, P<0.001; simple correlation). In conclusion, the abnormal regulation of GCR mRNA is likely to play a significant role in the insulin resistance observed in obese patients with Type II diabetes.