Mechanisms of Hyperglycemia-Induced Insulin Resistance in Whole Body and Skeletal Muscle of Type I Diabetic Patients

Abstract

To examine the mechanisms of hyperglycemia-induced insulin resistance, eight insulin-dependent (type I) diabetic men were studied twice, after 24 h of hyperglycemia (mean blood glucose 20.0 +/- 0.3 mM, i.v. glucose) and after 24 h of normoglycemia (7.1 +/- 0.4 mM, saline) while receiving identical diets and insulin doses. Whole-body and forearm glucose uptake were determined during a 300-min insulin infusion (serum free insulin 359 +/- 22 and 373 +/- 29 pM, after hyper- and normoglycemia, respectively). Muscle biopsies were taken before and at the end of the 300-min insulin infusion. Plasma glucose levels were maintained constant during the 300-min period by keeping glucose for 150 min at 16.7 +/- 0.1 mM after 24-h hyperglycemia and increasing it to 16.5 +/- 0.1 mM after normoglycemia and by allowing it thereafter to decrease in both studies to normoglycemia. During the normoglycemic period (240-300 min), total glucose uptake (25.0 +/- 2.8 vs. 33.8 +/- 3.9 mumol.kg-1 body wt.min-1, P less than 0.05) was 26% lower, forearm glucose uptake (11 +/- 4 vs. 18 +/- 3 mumol.kg-1 forearm.min-1, P less than 0.05) was 35% lower, and nonoxidative glucose disposal (8.9 +/- 2.2 vs. 19.4 +/- 3.3 mumol.kg-1 body wt-1min-1, P less than 0.01) was 54% lower after 24 h of hyper- and normoglycemia, respectively. Glucose oxidation rates were similar. Basal muscle glycogen content was similar after 24 h of hyperglycemia (234 +/- 23 mmol/kg dry muscle) and normoglycemia (238 +/- 22 mmol/kg dry muscle). Insulin increased muscle glycogen to 273 +/- 22 mmol/kg dry muscle after 24 h of hyperglycemia and to 296 +/- 33 mmol/kg dry muscle after normoglycemia (P less than 0.05 vs. 0 min for both). Muscle ATP, free glucose, glucose-6-phosphate, and fructose-6-phosphate concentrations were similar after both 24-h treatment periods and did not change in response to insulin. We conclude that a marked decrease in whole-body, muscle, and nonoxidative glucose disposal can be induced by hyperglycemia alone.

Expression of glycogen synthase and phosphofructokinase in muscle from Type 1 (insulin-dependent) diabetic patients before and after intensive insulin treatment

“…Hence, the present data suggest that the impaired glycogen synthesis of skeletal muscle from Type 1 diabetic patients in poor metabolic control [1][2][3] is caused by post-translational modifications of the GS enzyme which may be secondary to metabolic derangements [3,7]. This interpretation of results is compatible with the study of Vuorinen-Markkola et al [28] demonstrating that 24 h of hyperglycaemia induces a severe impairment of whole-body non-oxidative glucose metabolism in Type I diabetic patients.…”

Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance

“…Studies in both man [1,41,42] and animals [43,44] have shown that sustained hyperglycaemia for as little as 6-24 h induces insulin resistance through a down regulation of the glucose transport system [6,45] both at the level of insulin-independent and insulin-dependent tissues [46,47].…”

Role of insulin resistance in the pathogenesis of NIDDM

“…9), forearm glucose uptake was determined under similar conditions of glycaemia and insulinaemia. Reproduced with permission from reference [116] Glucose toxicity -the common acquired cause of insulin resistance in IDDM and NIDDM…”

“…The degree of insulin resistance is inversely correlated with average glycaemic control in both patients with NIDDM [2,112,113] and IDDM [105,114]. Direct proof of the ability of hyperglycaemia per se to induce insulin resistance has been obtained in studies in patients with IDDM [115,116] as well as in studies performed in diabetic …”

“…Exposure to hyperglycaemia decreased forearm glucose uptake significantly due to a decrease in glucose extraction (*p < 0.05 for hyper-vs normoglycaemia) rats [117,118]. In IDDM, simply increasing the glucose concentration for 24 h is sufficient to induce insulin resistance in skeletal muscle [115,116] (Figs. 8 and 9).…”