Human skeletal muscle cultures (HSMCs) from type II diabetic subjects were used to determine whether metabolic abnormalities such as hyperglycemia or hyperinsulinemia contribute to the defective muscle glycogen synthase (GS) activity present in this disorder. Following ∼6 weeks of growth, diabetic cultures were fused for 4 days in normal, hyperglycemia, or hyperinsulinemia medium. Fusion of diabetic HSMCs in hyperglycemia medium (20 mmol/l vs. 5.5 mmol/l) had no effect on GS fractional velocity (FV) or mRNA levels, but impaired acute insulin-stimulation of glycogen synthesis and GS activity at 0.1 mmol/l glucoses-phosphate, and reduced GS protein content by ∼15% (P < 0.05). Fusion of diabetic muscle cultures in hyperinsulinemia medium (30 μmol/l vs. 22 pmol/l) improved basal GS activity, increasing the reduced GS FV by ∼50% (P < 0.05), and decreasing the elevated Km0.1 (half-maximal substrate concentration) by ∼47% (P < 0.05). Hyperinsulinemia also significantly increased (P < 0.05) the reduced GS mRNA and protein levels of diabetic muscle to levels similar to that in nondiabetic subjects. In contrast to the improvements in the basal state, hyperinsulinemia completely abolished acute insulin responsiveness of GS activity and glycogen synthesis in muscle of type II diabetic subjects. The combination of hyperinsulinemia and hyperglycemia produced effects on both basal and insulin-responsive GS FV and mRNA similar to hyperinsulinemia alone, but hyperinsulinemia prevented hyperglycemia's effect of lowering GS protein and glycogen synthesis. We concluded that, in diabetic muscle, hyperinsulinemia may serve to partially compensate for the impaired basal GS activity and for the adverse effects of hyperglycemia on GS protein content, activity, and glycogen formation by both pre- and posttranslational mechanisms. Despite these beneficial effects, hyperinsulinemia also induces severe impairment of insulin-stimulated GS activity and glycogen formation, which may contribute to acquired muscle insulin resistance of type II diabetes.
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Original Articles|
June 01 1997
Regulation of Glycogen Synthase Activity in Cultured Skeletal Muscle Cells From Subjects With Type II Diabetes: Role of Chronic Hyperinsulinemia and Hyperglycemia
Svetlana E Nikoulina;
Svetlana E Nikoulina
From the Department of Medicine, University of California
San Diego
; and the Veterans Affairs Medical Center
San Diego, California
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Theodore P Ciaraldi;
Theodore P Ciaraldi
From the Department of Medicine, University of California
San Diego
; and the Veterans Affairs Medical Center
San Diego, California
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Leslie Abrams-Carter;
Leslie Abrams-Carter
From the Department of Medicine, University of California
San Diego
; and the Veterans Affairs Medical Center
San Diego, California
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Sunder Mudaliar;
Sunder Mudaliar
From the Department of Medicine, University of California
San Diego
; and the Veterans Affairs Medical Center
San Diego, California
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Kyong Park Soo;
Kyong Park Soo
From the Department of Medicine, University of California
San Diego
; and the Veterans Affairs Medical Center
San Diego, California
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Henry R Robert
Henry R Robert
From the Department of Medicine, University of California
San Diego
; and the Veterans Affairs Medical Center
San Diego, California
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Address correspondence and reprint requests to Dr. Robert R. Henry, Veterans Affairs Medical Center, San Diego (V111G), 3350 La Jolla Village Dr., San Diego, CA 92161. [email protected].
1
BSA, bovine serum albumin; FBS, fetal bovine serum; FV, fractional velocity; G-6-P, glucose-6-phosphate; GS, glycogen synthase; HSMC, human skeletal muscle culture; α-MEM; α-minimum essential medium; UDP, uridine 5′-diphosphate.
Diabetes 1997;46(6):1017–1024
Article history
Received:
October 07 1996
Revision Received:
February 06 1997
Accepted:
February 06 1997
PubMed:
9166674
Citation
Svetlana E Nikoulina, Theodore P Ciaraldi, Leslie Abrams-Carter, Sunder Mudaliar, Kyong Park Soo, Henry R Robert; Regulation of Glycogen Synthase Activity in Cultured Skeletal Muscle Cells From Subjects With Type II Diabetes: Role of Chronic Hyperinsulinemia and Hyperglycemia. Diabetes 1 June 1997; 46 (6): 1017–1024. https://doi.org/10.2337/diab.46.6.1017
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