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The incidence of Type 2 diabetes is now increasing at alarming rates. For example, in the United States alone, ~7% of the total population is affected. Even more alarming is the recent warning from the U.S. government that as many as 16 million Americans over the age of 40 are prediabetic and are at high risk for developing Type 2 diabetes. The prediabetic condition is associated with obesity and a resistance to the action of insulin. Today's sedentary lifestyles are largely responsible for this epidemic; more and more of us are trading in soccer shoes for computer games. However, Type 2 diabetes may be a preventable disease with proper diet and exercise. Molecular and cellular research into the actions of muscle insulin signaling is crucial for combating Type 2 diabetes, and, with the featured articles in this Highlighted Topics series, we hope to shed some light on the underlying mechanisms of this condition. We also hope to promote further research into this important area of investigation.

In the first mini-review of this Highlighted Topics series, entitled "Intracellular signaling in contracting skeletal muscle," Drs. Laurie J. Goodyear and Kei Sakamoto explore a central issue in exercise biology: the elucidation of underlying molecular signaling mechanisms that regulate the multiple metabolic and transcriptional events that occur in skeletal muscle in response to exercise. In this mini-review, the authors summarize research from the past several years that has demonstrated that physical exercise can regulate multiple intracellular signaling cascades in skeletal muscle, including three of the mitogen-activated protein (MAP) kinase signaling pathways, AMP-activated protein kinase (AMP kinase), glycogen synthase kinase 3, Akt, and p70 S6 kinase. A fundamental goal of such research is to determine the biological consequences of exercise-induced signaling cascades, and Goodyear and Sakamoto provide an update of recent progress in this area.

Also in this issue, in a mini-review entitled "Effect of acute exercise on insulin signaling and action in humans," Drs. Jørgen F. P. Wojtaszewski, Jacob N. Nielsen, and Erik A. Richter examine the increase in insulin sensitivity observed in skeletal muscle after a single bout of exercise. This phenomenon does not seem to be related to increased signaling through the insulin receptor-phosphatidylinositol 3-kinase pathway but is strongly related to the exercise-induced decrease of muscle glycogen stores. In addition, exercise-induced activation of 5'-AMP kinase seems to be involved in the increase in insulin sensitivity following exercise.

In the August issue, in a mini-review entitled "Exercise training-induced changes in insulin signaling in skeletal muscle," Dr. Juleen R. Zierath will provide insight into intracellular signaling mechanisms that cause increases in glucose metabolism and gene expression in skeletal muscle during exercise training. The molecular mechanism for enhanced insulin-stimulated glucose uptake after exercise training may be partly related to increased expression and activity of key proteins known to regulate glucose metabolism in skeletal muscle. Changes in protein expression may be related to increased signal transduction through MAP kinase signaling cascades, pathways known to regulate transcriptional activity. Dr. Zierath will explore current studies that are directed toward unraveling the mysteries of these signaling pathways.

In the second mini-review in the August issue, entitled "Regulation of skeletal muscle GLUT-4 expression by exercise," Dr. G. Lynis Dohm will focus on the GLUT-4 protein and its effects on skeletal muscle. The amount of GLUT-4 protein is a primary factor in determining the maximal rate of glucose transport into skeletal muscle. Therefore, it is important that we understand how exercise regulates GLUT-4 expression so that therapeutic strategies can be designed to increase muscle glucose disposal as a treatment for diabetes. Muscle contraction increases the rates of GLUT-4 transcription and translation. Transcriptional control likely requires at least two DNA binding proteins, myocyte enhancer factor 2 (MEF2) and GLUT-4 enhancer factor (GEF), which bind to the promoter. Increased GLUT-4 expression may be mediated by AMP kinase, which is activated during exercise and has been demonstrated to increase GLUT-4 transcription. Further research is needed to investigate whether AMP kinase activates MEF2 and GEF to increase transcription of the GLUT-4 gene.

Also in the August issue, in a mini-review entitled "Effects of acute exercise and exercise training on insulin resistance," Dr. Erik J. Henriksen will explore the effect of a single bout of exercise and the cumulative effects of repeated bouts of exercise (exercise training) on whole body and skeletal muscle glucose disposal in insulin-resistant states, such as impaired glucose tolerance and Type 2 diabetes. This mini-review will focus on findings from the obese Zucker rat, a widely used rodent model of obesity-associated insulin resistance as well as from insulin-resistant humans with impaired glucose tolerance or Type 2 diabetes. Dr. Henriksen will pay particular attention to the effects of exercise interventions on the insulin signaling pathway in skeletal muscle, which is defective in conditions of insulin resistance.

In the September issue, in a mini-review entitled "Autocrine/paracrine IGF-I and skeletal muscle adaptation," Dr. Gregory R. Adams will revisit the hypothesis that insulin-like growth factor I (IGF-I), functioning in an autocrine/paracrine mode, is an important mediator of skeletal muscle adaptation. Dr. Adams will explore a number of recent findings, which highlight the potential for interactions between IGF-I-related signaling pathways and other intracellular signaling mechanisms.

Also in the September issue, in a mini-review entitled "Role of insulin in translational control of protein synthesis in skeletal muscle by amino acids or exercise," Drs. Scot R. Kimball, Peter A. Farrell, and Leonard S. Jefferson describe how insulin acts in concert with either increased amino acid availability or exercise to stimulate protein synthesis in skeletal muscle. Specifically, these authors focus on the translational control of protein synthesis and the signal transduction pathways that mediate the effects of insulin, amino acids, and exercise. This mini-review also provides a comparison of the different protein synthetic responses associated with endurance compared with resistance exercise. Circulating concentrations of insulin, which cause a loss of glucoregulation, are still sufficient to allow increases in rates of protein synthesis in response to increased amino acid availability and during recovery from resistance exercise; however, below a minimal concentration of insulin, these responses are precluded. Selected translation initiation factors are stimulated in response to increased amino acid availability and after acute resistance exercise only when a minimal amount of insulin is available. In contrast, glucose uptake during and immediately after low-intensity endurance-type exercise can occur in the absence of insulin. These observations are testament to the complex nature of insulin-stimulated intracellular pathways and the fact that branch points for regulation can occur.

Finally, another feature of this Highlighted Topics series will be a Historical Perspectives article by Drs. Neil Ruderman, Eva Tomás, and Antonio Zorzano, which will offer insight into the current thinking in the area of exercise and insulin signaling, how it has evolved over time, and the individuals who are most responsible for shaping the field as it is today.

The importance of ongoing research in this field of investigation is readily apparent. Every one of us literally needs to take an active role in ensuring our own well being. Current data suggest that simply walking 30 minutes a day along with maintaining a healthy weight can prevent the occurrence of Type 2 diabetes. As with each of the Highlighted Topics series, the Associate Editors and I hope to draw attention to this vitally important field of research and to stimulate further investigation. We will continue to welcome manuscript submissions that further this cause.