TRANSMEMBRANE GLUCOSE-TRANSPORT IN SKELETAL-MUSCLE OF PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES

Insulin resistance for glucose metabolism in skeletal muscle is a key feature in non-insulin-dependent diabetes mellitus (NIDDM). Which cell ular effectors of glucose metabolism are involved is still unknown. We investigated whether transmembrane glucose transport in vivo is impai red in skeletal muscle in nonobese NIDDM patients. We performed euglyc emic insulin clamp studies in combination with the forearm balance tec hnique (brachial artery and deep forearm vein catheterization) in six nonobese NIDDM patients and five age- and weight-matched controls. Unl abeled D-mannitol (a nontransportable molecule) and radioactive 3-0-me thyl-D-glucose (the reference molecular probe to assess glucose transp ort activity) were simultaneously injected into the brachial artery, a nd the washout curves were measured in the deep venous effluent blood. In vivo transmembrane transport of 3-0-methyl-D-glucose in forearm mu scle was determined by computerized analysis of the washout curves. At similar steady-state plasma concentrations of insulin (approximately 500 pmol/liter) and glucose (approximately 5.15 mmol/liter), transmemb rane inward transport of 3-0-methyl-D-glucose in skeletal muscle was m arkedly reduced in the NIDDM patients (6.5 x 10(-2) +/- 0.56 x 10(-2) . min-1) compared with controls (12.5 x 10(-2) +/- 1.5 x 10(-2) - min- 1, P < 0.005). Mean glucose uptake was also reduced in the diabetics b oth at the whole body level (9.25 +/- 1.84 vs. 28.3 +/- 2.44 mumol/min per kg, P < 0.02) and in the forearm tissues (5.84 +/- 1.51 vs. 37.5 +/- 7.95 mumol/min per kg, P < 0.02). When the latter rates were extra polated to the whole body level, skeletal muscle accounted for - 80% o f the defect in insulin action seen in NIDDM patients. We conclude tha t transmembrane glucose transport, when assessed in vivo in skeletal m uscle, is insensitive to insulin in nonobese NIDDM patients, and plays a major role in determining whole body insulin resistance.