RESUMO
The signaling mechanisms that mediate the important effects of contraction to increase glucose transport in skeletal muscle are not well understood, but are known to occur through an insulin-independent mechanism. Muscle-specific knockout of LKB1, an upstream kinase for AMPK and AMPK-related protein kinases, significantly inhibited contraction-stimulated glucose transport. This finding, in conjunction with previous studies of ablated AMPKalpha2 activity showing no effect on contraction-stimulated glucose transport, suggests that one or more AMPK-related protein kinases are important for this process. Muscle contraction increased sucrose nonfermenting AMPK-related kinase (SNARK) activity, an effect blunted in the muscle-specific LKB1 knockout mice. Expression of a mutant SNARK in mouse tibialis anterior muscle impaired contraction-stimulated, but not insulin-stimulated, glucose transport. Whole-body SNARK heterozygotic knockout mice also had impaired contraction-stimulated glucose transport in skeletal muscle, and knockdown of SNARK in C2C12 muscle cells impaired sorbitol-stimulated glucose transport. SNARK is activated by muscle contraction and is a unique mediator of contraction-stimulated glucose transport in skeletal muscle.
Assuntos
Glucose/metabolismo , Contração Muscular/fisiologia , Músculo Esquelético/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases Ativadas por AMP , Adulto , Animais , Transporte Biológico/efeitos dos fármacos , Western Blotting , Linhagem Celular , Ativação Enzimática , Exercício Físico/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Técnicas In Vitro , Insulina/farmacologia , Masculino , Camundongos , Camundongos Knockout , Mioblastos/citologia , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Fosforilação , Condicionamento Físico Animal/fisiologia , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Sorbitol/farmacologiaRESUMO
The role of hyperglycemia as an independent risk factor for the development of atherosclerosis and CVD is strongly suggested by data from large epidemiologic studies as well as by numerous clinical trials. However, the specific roles of elevated fasting plasma glucose, postprandial glucose levels, and average blood glucose as measured by glycosylated hemoglobin (HbA(1c)) are less clear. Population studies and clinical trials addressing these issues have been reviewed with the conclusion that HbA(1c) is an independent risk factor for CVD in both diabetic and nondiabetic subjects. There is also strong evidence that postchallenge plasma glucose levels independently predict CVD events, whereas the evidence that fasting plasma glucose levels are predictive is much weaker. The implications for treatment are that targets for HbA(1c) and postprandial glucose levels are important to achieve, not only to reduce the risk of microvascular complications, but also to reduce the risk of CVD morbidity and mortality in people with diabetes.