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Two phases of palmitate-induced insulin resistance in skeletal muscle: impaired GLUT4 translocation is followed by a reduced GLUT4 intrinsic activity

¹Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada; ²Department of Physiology, Medical University of Bialystok, Bialystok, Poland; and ³Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands

Submitted 15 December 2006 ; accepted in final form 4 June 2007

We examined, in soleus muscle, the effects of prolonged palmitate exposure (0, 6, 12, 18 h) on insulin-stimulated glucose transport, intramuscular lipid accumulation and oxidation, activation of selected insulin-signaling proteins, and the insulin-stimulated translocation of GLUT4. Insulin-stimulated glucose transport was progressively reduced after 6 h (–33%), 12 h (–66%), and 18 h (–89%) of palmitate exposure. These decrements were closely associated with concurrent reductions in palmitate oxidation at 6 h (–40%), 12 h (–60%), and 18 h (–67%). In contrast, intramuscular ceramide (+24%) and diacylglycerol (+32%) concentrations, insulin-stimulated AS160 (–36%) and PRAS40 (–33%) phosphorylations, and Akt (–40%), PKC (–50%), and GLUT4 translocation (–40%) to the plasma membrane were all maximally altered within the first 6 h of palmitate treatment. No further changes were observed in any of these parameters after 12 and 18 h of palmitate exposure. Thus, the intrinsic activity of GLUT4 was markedly reduced after 12 and 18 h of palmitate treatment. During this reduced GLUT4 intrinsic activity phase at 12 and 18 h, the reduction in glucose transport was twofold greater compared with the early phase (6 h), when only GLUT4 translocation was impaired. Our study indicates that palmitate-induced insulin resistance is provoked by two distinct mechanisms: 1) an early phase (6 h), during which lipid-mediated impairments in insulin signaling and GLUT4 translocation reduce insulin-stimulated glucose transport, followed by 2) a later phase (12 and 18 h), during which the intrinsic activity of GLUT4 is markedly reduced independently of any further alterations in intramuscular lipid accumulation, insulin signaling and GLUT4 translocation.

glucose transport; glucose transporter 4; ceramide; diacylglycerol; Akt; AS160; protein kinase C/; protein kinase C; palmitate oxidation

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