Mechanisms of hyperglycemia-induced insulin resistance in whole body and skeletal muscle of type I diabetic patients.
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.
Vuorinen-Markkola
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H
Second Department of Medicine, University of Helsinki, Finland.
Koivisto
V A
VA
Yki-Jarvinen
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H
D000255:Adenosine Triphosphate / Q000032:analysis; D000328:Adult; D001706:Biopsy; D001786:Blood Glucose / Q000032:analysis; D002940:Circadian Rhythm; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D004734:Energy Metabolism / Q000502:physiology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005636:Fructosephosphates / Q000032:analysis; D019298:Glucose-6-Phosphate; D005958:Glucosephosphates / Q000032:analysis; D006003:Glycogen / Q000032:analysis; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006943:Hyperglycemia / Q000503:physiopathology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D007773:Lactates / Q000097:blood; D008297:Male; D009132:Muscles / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology*; D009994:Osmolar Concentration; D010084:Oxidation-Reduction; D011188:Potassium / Q000097:blood; D012709:Serum Albumin / Q000032:analysis
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D005636:Fructosephosphates; D005958:Glucosephosphates; D007328:Insulin; D007773:Lactates; D012709:Serum Albumin; D019298:Glucose-6-Phosphate; C027618:fructose-6-phosphate; D000255:Adenosine Triphosphate; D013006:Growth Hormone; D006003:Glycogen; D011188:Potassium; D006854:Hydrocortisone