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

Abstract

It has previously been shown that Wortmannin, a phosphatidylinositol 3-kinase inhibitor, inhibits glucose transport activated by insulin but not by ischemia, suggesting the importance of an activating mechanism that bypasses the insulin signal. To evaluate the relevance of this insulin-independent pathway 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, respectively; 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 interstitial 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 interstitial 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. The 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 each 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 concentration difference was abolished immediately postischemia and regained after ~15 min, whereas high interstitial lactate levels remained elevated throughout the study. Subcutaneous interstitial glucose concentrations remained unchanged during ischemia and postischemia in both groups, whereas the interstitial lactate concentration in adipose tissue increased during 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 control subjects, respectively. Plasma glucose and lactate levels were unchanged in both groups during the study period. The results show that in muscle, but not in adipose tissue, glucose uptake is efficiently activated by ischemia in insulin-resistant type 2 diabetic subjects, suggesting the activation of a putative alternative pathway to the insulin signal in muscle cells. Diabetes 49:1178-1185, 2000 I n skeletal muscle, insulin activates glucose transport through the translocation of GLUT4 from intracellular compartments to the plasma membrane (1). At least 2 distinct signaling pathways for the activation of glucose transport have been detected. In addition to the pathway used by the insulin signal, another pathway activated by contraction or ischemia has been described (2,3). One argument for multiple independent pathways for activation of glucose transport has been based on the observation that a maximal stimulation of glucos...

Implications for burn shock resuscitation of a new in vivo human vascular microdosing technique (microdialysis) for dermal administration of noradrenaline

“…Glucose concentrations in skin changed inversely to those of lactate during exposure to the drugThe parallel changes seen in glucose and lactate are consistent with previous investigations in non-insulin-dependent diabetic patients, which shows that cellular glucose uptake during acute ischaemia is initially dependent on the delivery of insulin and integrity of the insulin receptor, which is energy-dependent [22].…”

“…As ischaemia leads to local depletion of energy and insulin, it mediates activation of other pathways of glucose turnover that are different from that induced by insulin [22]. Our finding is interesting, because the mechanism of stress-induced peripheral insulin resistance is not completely understood and the present model may be useful in future investigations.…”

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“…Such an explanation would also be relevant for burns given that microvascular disturbances during early resuscitation for shock are to be expected. What then becomes puzzling is that experimental studies either on induced vasoconstriction or ischaemia all show decreased glucose levels interstitially [26]. …”

“…Other authors [26,29] have proposed the hypothesis that comparing the recovery (that is, the fraction of the absolute tissue concentration recovered in the perfusate) values of urea in vivo and the substance of interest would assess the relative in vivo recovery of the given substance. We found median recovery values of 80% and 74% for glucose in uninjured and burned skin, respectively, and 96% to 100% for urea for all categories (controls and injured and uninjured skin), and this strongly supports the view that our microdialysis results accurately reflect events in tissues.…”

“…It has been used to study burns in animals in which histamine turnover in the skin was examined successfully [25]. More recently, it has been used in studies of skeletal muscle and brain metabolism for the prediction of ischaemia and changes in the metabolism of glucose [20,26]. It has also been used to assess the metabolism, permeability, and local inflammation of skin in dermatology [27].…”