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.

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