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Cultured Muscle Cells from Insulin-Resistant Type 2 Diabetes Patients Have Impaired Insulin, but Normal 5-Amino-4-Imidazolecarboxamide Riboside-Stimulated, Glucose Uptake

School of Clinical Medical Sciences (E.A.M., M.W.) and School of Cell and Molecular Biosciences (R.H., S.J.Y.), University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom NE2 4HH

Address all correspondence and requests for reprints to: Prof. Mark Walker, School of Clinical Medical Sciences, The Medical School, Framlington Place, University of Newcastle, Newcastle upon Tyne, United Kingdom NE2 4HH. E-mail: mark.walker{at}ncl.ac.uk.

Impaired insulin action is a characteristic feature of type 2 diabetes. The study aims were to investigate whether after prolonged culture skeletal muscle cultures from insulin-resistant, type 2 diabetic patients (taking >100 U insulin/d) displayed impaired insulin signaling effects compared with cultures from nondiabetic controls and to determine whether retained abnormalities were limited to insulin action by studying an alternative pathway of stimulated glucose uptake. Studies were performed on myotubes differentiated for 7 d between passages 4 and 6. Insulin-stimulated glucose uptake (100 nM; P < 0.05) and insulin-stimulated glycogen synthesis (1 nM; P < 0.01) were significantly impaired in the diabetic vs. control cultures. Protein kinase B (PKB) expression and phosphorylated PKB levels in response to insulin stimulation (20 nM) were comparable in the diabetic and control cultures. 5-Amino-4-imidazolecarboxamide riboside (AICAR) mimics the effect of exercise on glucose uptake by activating AMP-activated protein kinase. There was no difference in AICAR (2 mM)-stimulated glucose uptake between diabetic vs. control myotube cultures (P = not significant). In conclusion, diabetic muscle cultures retain signaling defects after prolonged culture that appear specific to the insulin signaling pathway, but not involving PKB. This supports an intrinsic abnormality of the diabetic muscle cells that is most likely to have a genetic basis.

E.A.M. was supported by Diabetes UK.

Abbreviations: AICAR, 5-Amino-4-imidazolecarboxamide; AMPK, AMP-activated protein kinase; BMI, body mass index; FBS, fetal bovine serum; GLUT4, glucose transporter molecule 4; GS, glycogen synthase; GSK-3, glycogen synthase kinase 3; PKB, protein kinase B.

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