Insulin resistance in type I diabetes mellitus: a major role for reduced glucose extraction.

Abstract

We determined whether insulin resistance in Type I diabetes is caused by a defect in glucose extraction or blood flow and whether it is the rate of glucose metabolism rather than insulin that increases blood flow in these patients. To make this determination, 9 Type I diabetic patients (age 33 +/- 3 yr, body mass index 24 +/- 1 kg/m2, HbA1c 8.3 +/- 0.1%) and 10 matched normal subjects were first studied under normoglycemic hyperinsulinemic conditions. The diabetic patients were then restudied under similar conditions, but now whole body glucose uptake was normalized by glucose mass-action (glucose 8.7 +/- 0.6 mmol/L). During normoglycemia, rates of whole body (46 +/- 2 vs. 66 +/- 3 mumol/kg.min, P < 0.001) and forearm (47 +/- 9 vs. 78 +/- 7 mumol/kg forearm.min, P < 0.05) glucose uptake were decreased in the diabetic patients, because of a 32% decrease in the glucose AV-difference (1.5 +/- 0.2 vs. 2.2 +/- 0.2 mmol/L, P < 0.05). Forearm blood flow was similar in the diabetic patients (3.6 +/- 0.7 mL/dl.min) and normal subjects (3.7 +/- 0.3 mL/dL.min). During matched rates of whole body glucose uptake (68 +/- 1 vs. 66 +/- 3 mumol/kg.min, normoglycemic study in controls vs. hyperglycemic study in the diabetic patients), the glucose AV-difference across the forearm was 64% higher than during normoglycemia (2.4 +/- 0.3 vs. 1.5 +/- 0.2 mmol/L, P < 0.05). Forearm blood flow (3.6 +/- 0.4 mL/dL.min) under conditions of matched glucose flux was similar to that during the normoglycemic study. We conclude that a defect in glucose extraction rather than blood flow characterizes insulin resistance in uncomplicated Type I diabetes. The signal for the flow increase is insulin and not the rate of glucose metabolism.

The effects of insulin and short-term hyperglycaemia on myocardial blood flow in young men with uncomplicated Type I diabetes

“…In skeletal muscle in the two studies available insulin induced vasodilation was reduced in one study [48] but was normal in another study [49] in Type I diabetic patients.…”

“…2 days) is not feasible in non-diabetic subjects. In peripheral vasculature the effects of acute hyperglycaemia on blood flow are controversial because in one study hyperglycaemia blunted insulin induced vasodilation [48] while in another more recent study hyperglycaemia did not alter blood flow or its response to insulin [49].…”

Intact insulin stimulation of skeletal muscle blood flow, its heterogeneity and redistribution, but not of glucose uptake in non-insulin-dependent diabetes mellitus.

“…The latter studies have been performed under intravenously maintained normoglycemic hyperinsulinemic (clamp) conditions, where the insulin concentrations have been either in the high physiological (2,4,5) or supraphysiological (6) range. Under physiological hyperglycemic hyperinsulinemic conditions after an oral glucose load or a meal (7,8), as well as in the basal state (7,9), the absolute rates of glucose uptake (7)(8)(9) and blood flow are normal (9,10), possibly because hyperglycemia compensates for defects in blood flow (11,12) or glucose extraction (13,14). The reason for the discrepant results regarding insulin stimulation of blood flow is unclear.…”

Mechanism of impaired nitric oxide synthase activity in skeletal muscle of streptozotocin-induced diabetic rats

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Type I (insulin-dependent) diabetes mellitus is characterised by pronounced insulin resistance for glucose disposal in skeletal muscle [1,2]. This metabolic impairment is at least in part related to a post-insulin signalling defect in the expression and translocation of GLUT4 glucose transporters to the muscle cell surface [3±5].

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“…This metabolic impairment is at least in part related to a post-insulin signalling defect in the expression and translocation of GLUT4 glucose transporters to the muscle cell surface [3±5]. The lack of insulin action on glucose metabolism in muscle of people with Type I diabetes could also be explained by an impaired vasodilatory effect of insulin on the muscle vasculature [2], although this impairment has not been confirmed in a more recent study [1]. Several studies have shown that endothelium-dependent relaxation is altered in Abstract Aims/hypothesis.…”