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      Novos mecanismos pelos quais o exercício físico melhora a resistência à insulina no músculo esquelético Translated title: New mechanisms by which physical exercise improves insulin resistance in the skeletal muscle

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          Abstract

          O prejuízo no transporte de glicose estimulada por insulina no músculo constitui um defeito crucial para o estabelecimento da intolerância à glicose e do diabetes tipo 2. Por outro lado, é notório o conhecimento de que tanto o exercício aeróbio agudo quanto o crônico podem ter efeitos benéficos na ação da insulina em estados de resistência à insulina. No entanto, pouco se sabe sobre os efeitos moleculares pós-exercício sobre a sinalização da insulina no músculo esquelético. Assim, esta revisãoapresenta novos entendimentos sobre os mecanismos por meio dos quais o exercício agudo restaura a sensibilidade à insulina, com destaque ao importante papel que proteínas inflamatórias e a S-nitrosação possuem sobre a regulação de proteínas da via de sinalização da insulina no músculo esquelético.

          Translated abstract

          Insulin resistance of skeletal muscle glucose transport is a key-defect for the development of impaired glucose tolerance and type 2 diabetes. However, it is known that both an acute bout of exercise and chronic endurance exercise training can bring beneficial effects on insulin action in insulin-resistant states. However, little is currently known about the molecular effects of acute exercise on muscle insulin signaling in the post-exercise state in insulin-resistant organisms. This review provides new insight into the mechanism through which acute exercise restores insulin sensitivity, highlighting an important role for inflammatory proteins and S-nitrosation in the regulation of insulin signaling proteins in skeletal muscle.

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          Most cited references62

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          Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.

          Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors--elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle--are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups. The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.
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            Inflammatory pathways and insulin action.

            Obesity and type 2 diabetes are associated with a state of abnormal inflammatory response. While this correlation has also been recognized in the clinical setting, its molecular basis and physiological significance are not yet fully understood. Studies in recent years have provided important insights into this curious phenomenon. The state of chronic inflammation typical of obesity and type 2 diabetes occurs at metabolically relevant sites, such as the liver, muscle, and most interestingly, adipose tissues. The biological relevance of the activation of inflammatory pathways became evident upon the demonstration that interference with these pathways improve or alleviate insulin resistance. The abnormal production of tumor necrosis factor alpha (TNF-alpha) in obesity is a paradigm for the metabolic significance of this inflammatory response. When TNF-alpha activity is blocked in obesity, either biochemically or genetically, the result is improved insulin sensitivity. Studies have since focused on the identification of additional inflammatory mediators critical in metabolic control and on understanding the molecular mechanisms by which inflammatory pathways are coupled to metabolic control. Recent years have seen a critical progress in this respect by the identification of several downstream mediators and signaling pathways, which provide the crosstalk between inflammatory and metabolic signaling. These include the discovery of c-Jun N-terminal kinase (JNK) and I kappa beta kinase (I kappa K) as critical regulators of insulin action activated by TNF-alpha and other inflammatory and stress signals, and the identification of potential targets. Here, the role of the JNK pathway in insulin receptor signaling, the impact of blocking this pathway in obesity and the mechanisms underlying JNK-induced insulin resistance will be discussed.
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              Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes: a time-course and dose-response study.

              Activation of AMP-activated protein kinase (AMPK) by exercise induces several cellular processes in muscle. Exercise activation of AMPK is unaffected in lean (BMI approximately 25 kg/m(2)) subjects with type 2 diabetes. However, most type 2 diabetic subjects are obese (BMI >30 kg/m(2)), and exercise stimulation of AMPK is blunted in obese rodents. We examined whether obese type 2 diabetic subjects have impaired exercise stimulation of AMPK, at different signaling levels, spanning from the upstream kinase, LKB1, to the putative AMPK targets, AS160 and peroxisome proliferator-activated receptor coactivator (PGC)-1alpha, involved in glucose transport regulation and mitochondrial biogenesis, respectively. Twelve type 2 diabetic, eight obese, and eight lean subjects exercised on a cycle ergometer for 40 min. Muscle biopsies were done before, during, and after exercise. Subjects underwent this protocol on two occasions, at low (50% Vo(2max)) and moderate (70% Vo(2max)) intensities, with a 4-6 week interval. Exercise had no effect on LKB1 activity. Exercise had a time- and intensity-dependent effect to increase AMPK activity and AS160 phosphorylation. Obese and type 2 diabetic subjects had attenuated exercise-stimulated AMPK activity and AS160 phosphorylation. Type 2 diabetic subjects had reduced basal PGC-1 gene expression but normal exercise-induced increases in PGC-1 expression. Our findings suggest that obese type 2 diabetic subjects may need to exercise at higher intensity to stimulate the AMPK-AS160 axis to the same level as lean subjects.
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                Author and article information

                Contributors
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Journal
                abem
                Arquivos Brasileiros de Endocrinologia & Metabologia
                Arq Bras Endocrinol Metab
                Sociedade Brasileira de Endocrinologia e Metabologia (São Paulo )
                1677-9487
                June 2009
                : 53
                : 4
                : 399-408
                Affiliations
                [1 ] Universidade Federal de São Paulo Brazil
                [2 ] Universidade do Extremo Sul Catarinense Brazil
                [3 ] Universidade Estadual de Campinas Brazil
                Article
                S0004-27302009000400003
                10.1590/S0004-27302009000400003
                0df1222d-1eaa-4133-bac9-fe14c50bc860

                http://creativecommons.org/licenses/by/4.0/

                History
                Product

                SciELO Brazil

                Self URI (journal page): http://www.scielo.br/scielo.php?script=sci_serial&pid=0004-2730&lng=en
                Categories
                ENDOCRINOLOGY & METABOLISM

                Endocrinology & Diabetes
                Exercise,insulin resistance,inflammation,skeletal muscle,Exercício,resistência à insulina,inflamação,músculo esquelético

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