Muscle glucose uptake is effectively activated by ischemia in type 2 diabetic subjects

It has previously been shown that Wortmannin, a phosphatidylinositol 3-kina se inhibitor, inhibits glucose transport activated by insulin but not by is chemia, suggesting the importance of an activating mechanism that bypasses the insulin signal. To evaluate the relevance of this insulin-independent p athway in insulin-resistant subjects, the ability of ischemia to stimulate glucose uptake was investigated in 9 patients with type 2 diabetes and in 9 healthy control subjects (fasting glucose level 9.4 +/- 0.8 vs. 5.1 +/- 0. 1 mmol/l, P < 0.001, in type 2 diabetic patients and control subjects, resp ectively; fasting insulin level insulin 8.1 +/- 2.6 vs. 4.5 +/- 0.7 mU/l, P < 0.05, respectively) matched for sex, age, and BMI. Arterial plasma and i nterstitial concentrations of glucose and lactate (measured by subcutaneous and muscle microdialysis) were recorded in the forearm before, during, and after ischemia induced locally for 20 min. During ischemia, the muscle int erstitial glucose concentration decreased significantly from 7.7 +/- 0.6 to 5.4 +/- 0.4 mmol/l (P < 0.01) and from 4.4 +/- 0.3 to 3.6 +/- 0.3 mmol/l ( P < 0.05) in type 2 diabetic patients and control subjects, respectively. T he arterial-interstitial (A-I) glucose concentration difference was 1.7 +/- 0.6 and 0.7 +/- 0.3 mmol/l at basal, and it increased significantly to 3.5 +/- 0.7 (P < 0.01) and 1.4 +/- 0.3 mmol/l (P < 0.05) during ischemia in ea ch group, respectively. Interstitial lactate increased significantly during ischemia from 0.8 +/- 0.1 to 1.1 +/- 0.1 mmol/l (P < 0.05) and from 0.5 +/ - 0.1 to 0.9 +/- 0.2 mmol/l (P < 0.05), respectively. The A-I glucose conce ntration difference was abolished immediately postischemia and regained aft er similar to 15 min, whereas high interstitial lactate levels remained ele vated throughout the study. Subcutaneous interstitial glucose concentration s remained unchanged during ischemia and postischemia in both groups, where as the interstitial lactate concentration in adipose tissue increased durin g ischemia from 1.4 +/- 0.2 to 2.0 +/- 0.2 mmol/l (P < 0.05) and from 1.1 /- 0.1 to 1.8 +/- 0.3 mmol/l (P < 0.05) in type 2 diabetic patients and con trol subjects, respectively. Plasma glucose and lactate levels were unchang ed in both groups during the study period. The results show that in muscle, but not in adipose tissue, glucose uptake is efficiently activated by isch emia in insulin-resistant type 2 diabetic subjects, suggesting the activati on of a putative alternative pathway to the insulin signal in muscle cells.