Contractile activity during physical exercise induces an increase in GLUT4 expression in skeletal muscle, helping to improve glucose transport capacity and insulin sensitivity. An important mechanism by which exercise upregulates GLUT4 is through the activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in response to elevated levels of cytosolic Ca2+ during muscle contraction. This review discusses the mechanism by which Ca2+ activates CaMKII, explains research techniques currently used to alter CaMK activity in cells, and highlights various exercise models and pharmacological agents that have been used to provide evidence that CaMKII plays an important role in regulating GLUT4 expression. With regard to transcriptional mechanisms, the key research studies that identified myocyte enhancer factor 2 (MEF2) and GLUT4 enhancer factor as the major transcription factors regulating glut4 gene expression, together with their binding domains, are underlined. Experimental evidence showing that CaMK activation induces hyperacetylation of histones in the vicinity of the MEF2 domain and increases MEF2 binding to its cis element to influence MEF2-dependent Glut4 gene expression are also given along with data suggesting that p300 might be involved in acetylating histones on the Glut4 gene. Finally, an appraisal of the roles of other calcium- and non-calcium-dependent mechanisms, including the major HDAC kinases in GLUT4 expression, is also given.

In the last 50 years, sub-Saharan Africa has witnessed a significant increase in the prevalence of type 2 diabetes mellitus (T2DM), from <1% recorded in some countries in the 1960s to a regional prevalence of 4.3% in 2012 (compared with a current global prevalence of 6.4%). There is great variability in prevalence of T2DM among the African communities with some countries, such as Réunion, recording an average of 16% and others, such as Uganda registering <1% in rural communities. The greatest increase in prevalence has been registered among urban dwellers. The cause of the rapid increase in T2DM prevalence is not clear. However, studies in both rural and urban areas have found that physical activity is not an independent risk factor for the disease in the region. Physical activity level was found to be adequate in Africa, with 83.8% of men and 75.7% of women meeting the WHO recommendation of at least 150 min of moderate- to vigorous-intensity physical activity per week. The paper argues that the rapidly growing number of people >40 years old, increasing urbanization, adaptation of lifestyle behaviors that accompany urbanization and the interaction of these with a genetic predisposition to T2DM, are plausible reasons for the increasing prevalence of T2DM.

This chapter reviews current knowledge of the various signaling pathways that cause the glucose transporter isoform 4 (GLUT4)-containing vesicles to translocate from intracellular compartments of skeletal muscle cells to the plasma membrane in response to exercise. Specifically, the signaling cascades that arise from increases in AMP (adenosine monophosphate), nitric oxide (NO) and calcium (Ca2+) are described. Evidence is provided that these signaling pathways converge with the insulin signaling cascade at: (a) aPKC (atypical protein kinase C), which signals via GTPases to remodel microtubules along which GLUT4-containing vesicles translocate, and (b) AS160 (a 160-kDa Akt substrate that has Rab-GTPase activity) to activate microtubule motor kinesin proteins that power vesicle translocation. Experimental evidence showing that joint activation of AS160 and aPKC pathways are necessary for GLUT4 mobilization to the cell surface is given along with evidence of overlap between Ca2+, NO and AMP-dependent protein kinase-signaling pathways. The chapter also describes the molecular mechanisms by which exercise increases GLUT4 expression to boost glucose disposal capacity of skeletal muscle.

Goyaram V, Kohn TA, Ojuka EO. Suppression of the GLUT4 adaptive response to exercise in fructose-fed rats. Am J Physiol Endocrinol Metab 306: E275-E283, 2014. First published December 19, 2013 doi:10.1152/ajpendo.00342.2013.-Exercise-induced increase in skeletal muscle GLUT4 expression is associated with hyperacetylation of histone H3 within a 350-bp DNA region surrounding the myocyte enhancer factor 2 (MEF2) element on the Glut4 promoter and increased binding of MEF2A. Previous studies have hypothesized that the increase in MEF2A binding is a result of improved accessibility of this DNA segment. Here, we investigated the impact of fructose consumption on exercise-induced GLUT4 adaptive response and directly measured the accessibility of the above segment to nucleases. Male Wistar rats (n ϭ 30) were fed standard chow or chow ϩ 10% fructose or maltodextrin drinks ad libitum for 13 days. In the last 6 days five animals per group performed 3 ϫ 17-min bouts of intermittent swimming daily and five remained untrained. Triceps muscles were harvested and used to measure 1) GLUT4, pAMPK, and HDAC5 contents by Western blot, 2) accessibility of the DNA segment from intact nuclei using nuclease accessibility assays, 3) acetylation level of histone H3 and bound MEF2A by ChIP assays, and 4) glycogen content. Swim training increased GLUT4 content by ϳ66% (P Ͻ 0.05) but fructose and maltodextrin feeding suppressed the adaptation. Accessibility of the DNA region to MNase and DNase I was significantly increased by swimming (ϳ2.75-and 5.75-fold, respectively) but was also suppressed in trained rats that consumed fructose or maltodextrin. Histone H3 acetylation and MEF2A binding paralleled the accessibility pattern. These findings indicate that both fructose and maltodextrin modulate the GLUT4 adaptive response to exercise by mechanisms involving chromatin remodeling at the Glut4 promoter.