Glucose transport and cell surface GLUT-4 protein in skeletal muscle of the obese Zucker rat

Abstract

The relationship between 3-O-methyl-D-glucose transport and 2-N-4-(1-azi-2,2,2-trifluoroethyl)-benzoyl-1, 3-bis-(D-mannos-4-yloxy)-2-propylamine (ATB-BMPA)-labeled cell surface GLUT-4 protein was assessed in fast-twitch (epitrochlearis) and slow-twitch (soleus) muscles of lean and obese (fa/fa) Zucker rats. In the absence of insulin, glucose transport as well as cell surface GLUT-4 protein was similar in both epitrochlearis and soleus muscles of lean and obese rats. In contrast, insulin-stimulated glucose transport rates were significantly higher for lean than obese rats in both soleus (0.74 +/- 0.05 vs. 0.40 +/- 0.02 mumol.g-1.10 min-1) and epitrochlearis (0.51 +/- 0.05 vs. 0.17 +/- 0.02 mumol.g-1.10 min-1) muscles. The ability of insulin to enhance glucose transport in fast- and slow-twitch muscles from both lean and obese rats corresponded directly with changes in cell surface GLUT-4 protein. Muscle contraction elicited similar increases in glucose transport in lean and obese rats, with the effect being more pronounced in fast-twitch (0.70 +/- 0.07 and 0.77 +/- 0.04 mumol.g-1.10 min-1 for obese and lean, respectively) than in slow-twitch muscle (0.36 +/- 0.03 and 0.40 +/- 0.02 mumol.g-1.10 min-1 for obese and lean, respectively). The contraction-induced changes in glucose transport directly corresponded with the observed changes in cell surface GLUT-4 protein. Thus the reduced glucose transport response to insulin in skeletal muscle of the obese Zucker rat appears to result directly from an inability to effectively enhance cell surface GLUT-4 protein.

Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats

“…The obese Zucker rats studied exhibited the expected characteristics, including: (1) increased circulating concentrations of fatty acids and insulin, with comparable levels of glucose; (2) impairment of insulin-stimulated glucose transport in muscle [25,26]; (3) g Fig. 1 Relationship of PGCα protein with muscle fibre composition and with selected metabolic proteins in metabolically heterogenous skeletal muscles in lean and obese Zucker rats.…”

“…FAT (r=0.96), and (g) FABPpm (r=0.89) White circles, lean; black circles, obese. Data are shown as mean ± SEM and are based on muscles from four to six animals phosphorylation [27,28]; and (4) increased concentration of intramuscular triacylglycerol [14,25,26]. The latter presumably reflects an attempt to limit intramuscular muscle lipotoxicity, as this lipid depot is increased in insulinsensitive athletes (the athlete paradox) [2] and triacylglycerol provides a cytoprotective role in lipid overload states [29].…”

Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin-resistant skeletal muscle

“…One of the underlying features of non-insulin-dependent diabetes mellitus is an inability to respond to physiological concentrations of insulin, so-called insulin resistance [3,4]. Although the response of glucose metabolism to insulin is poor in insulin-resistant skeletal muscle, it will respond normally to contraction [5]. Perhaps this is a partial explanation of why exercise is believed to be beneficial for people with noninsulin-dependent diabetes mellitus [6].…”

“…Perhaps this is a partial explanation of why exercise is believed to be beneficial for people with noninsulin-dependent diabetes mellitus [6]. Indeed there is growing interest in the utility of activation of the contraction apparatus as a means for stimulation of glucose utilization in insulin-resistant skeletal muscle [5,7]. Thus, once the mechanism by which contraction stimulates glucose utilization in skeletal muscle has been fully elucidated, specific targets for future pharmaceutical compounds as anti-diabetic agents could be developed.…”

“…Indeed, concentrationdependent elevations in intracellular cGMP levels in response to zaprinast incubation in isolated Wistar rat soleus muscle have been observed (M. E. Young and B. Leighton, unpublished work). Consequently we have determined the effects of zaprinast on cGMP levels in soleus muscles isolated from both insulinsensitive and insulin-resistant Zucker rats (see [5] and [14] for insulin resistance in Zucker rat skeletal muscle).…”