Journal
DIABETES
Volume 49, Issue 12, Pages 1978-1985Publisher
AMER DIABETES ASSOC
DOI: 10.2337/diabetes.49.12.1978
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Glucose transport in skeletal muscle is stimulated by two distinct stimuli, insulin and exercise, The mechanism by which exercise stimulates glucose transport is not known, although it is distinct from the insulin-mediated pathway Recently, it has been shown that AMP-activated protein kinase (AMPK) is activated by exercise in skeletal muscle, whereas pharmacological activation of AMPK by 5-amino-4-imidazolecarboxamide riboside (AICAR) leads to increased glucose transport. It has been postulated, therefore, that AMPK may be the link between exercise and glucose transport. To address this, we have examined the signaling pathway involved in the stimulation of glucose uptake after activation of AMPK. Here we show that activation of AMPK: by AICAR in rat muscle and mouse H-2K(b) muscle cells activates glucose transport approximately twofold. AMPK in H-2H(b) cells is also activated by hyperosmotic stress and the mitochondrial uncoupling agent, dinitrophenol, both of which lead to increased glucose transport. In contrast, insulin, which activates glucose transport two- to- threefold in both rat muscle and H-2K(b) cells, has no effect on AMPK activity. A previous study has shown that AMPK phosphorylates and activates endothelial nitric oxide synthase (NOS). me show here that NOS activity in H-2Kb cells is activated after stimulation of AMPK by AICAR. Treatment of H-2Hb cells or rat muscle with NOS inhibitors completely blocks the increase in glucose transport after activation of AMPK. In addition, an inhibitor of guanylate cyclase also blocks activation of glucose transport by AICAR in 8-2K(b) cells. These results indicate that activation of AMPK in muscle cells stimulates glucose transport by activation of NOS coupled to downstream signaling components, including cyclic GMP.
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