Regular physical activity improves glucose tolerance and decreases adiposity. Our aim was to investigate the effects of exercise training on subcutaneous (inguinal) and visceral (parametrial) adipose tissue in rats that were fed a chow diet (13% fat) or made insulin resistant by a high-fat diet (60% fat). Sprague-Dawley rats performed 4 wk of voluntary wheel running or were kept as sedentary controls. The training groups fed chow and the high-fat diet achieved similar running distances (8.8 +/- 1.8 and 9.3 +/- 1.9 km/day, respectively). Training improved oral glucose tolerance in chow-fed rats and prevented the glucose intolerance that occurred in sedentary rats fed the high-fat diet. In both subcutaneous and visceral adipose tissue, the high-fat diet-induced increases in fat pad weight (67% and 133%, respectively), adipocyte size (20% and 43%), and cell number (36% and 65%) were completely prevented by exercise training. Cytokine mRNA expression in visceral fat did not change with exercise training. However, in subcutaneous fat, training actually increased mRNA expression of several cytokines [IL-6: 80% (P < 0.05); TNF-alpha: 100% (P < 0.05); IL-1 receptor antagonist (IL-1Ra): 57% (P = 0.08)] with no detectable increases in serum cytokine concentrations. In summary, exercise training can overcome high-fat diet-induced impairments in glucose tolerance and increases in adipocyte size, cell number, and fat pad mass. Improved glucose tolerance was accompanied by an increase in cytokine gene expression in subcutaneous fat. This finding raises the possibility of a specific role of subcutaneous adipose tissue in adaptive responses to exercise training.
Chronic exercise training results in numerous skeletal muscle adaptations, including increases in insulin sensitivity and glycogen content. To understand the mechanism for increased muscle glycogen, we studied the effects of exercise training on glycogen regulatory proteins in rat skeletal muscle. Female Sprague Dawley rats performed voluntary wheel running for 1, 4, or 7 weeks. After 7 weeks of training, insulin-stimulated glucose uptake was increased in epitrochlearis muscle. Compared to sedentary control rats, muscle glycogen did not change after 1 week of training, but increased significantly after 4 and 7 weeks. The increases in muscle glycogen were accompanied by elevated glycogen synthase activity and protein expression. To assess the regulation of glycogen synthase, we examined its major activator, protein phosphatase 1 (PP1), and its major deactivator, glycogen synthase kinase 3 (GSK3). Consistent with glycogen synthase activity, PP1 activity was unchanged after 1 week of training but significantly increased after 4 and 7 weeks of training. Protein expression of RGL(GM), another regulatory PP1 subunit, significantly decreased after 4 and 7 weeks of training. Unlike PP1, GSK3 phosphorylation did not follow the pattern of glycogen synthase activity. The ~40% decrease in GSK-3α phosphorylation after 1 week of exercise training persisted until 7 weeks and may function as a negative feedback to elevated glycogen. Our findings suggest that exercise training-induced increases in muscle glycogen content could be regulated by multiple mechanisms including enhanced insulin sensitivity, glycogen synthase expression, allosteric activation of glycogen synthase and PP1activity.
Many obese people with type 2 diabetes develop non-alcoholic fatty liver disease, which may progress to liver fibrosis. EndoBarrier gastrointestinal liner is an innovative interventional treatment option for type 2 diabetic patients, which could affect diabetes associated liver disease. The aim of this retrospective study was to analyze the effect of 1-year EndoBarrier therapy on liver fibrosis and steatosis. As an indicator of fibrosis, liver stiffness was assessed by liver elastography at baseline, 2 weeks after EndoBarrier implantation and then every 3 months until explantation. 13/19 patients had elevated liver stiffness at baseline, corresponding to liver fibrosis grade 2 to 4. In these patients, liver stiffness reduced significantly during EndoBarrier therapy from 10.4 kPa (IQR 6.0-14.3) at baseline to 5.3 kPa (IQR 4.3-7.7, p<0.01) by the time of EndoBarrier explantation, corresponding to a normalization of the initially pathologic findings in most patients. Liver steatosis was also assessed by elastographic measurements in terms of the controlled attenuation parameter. In all patients, baseline measurements showed high grade steatosis. Improvements were seen from initially 343 dB/m (IQR 326-384) to 317 dB/m (IQR 269-375, p<0.05) by the time of explantation. However, most patients were still classified high grade steatosis after completion of EndoBarrier treatment. In this observational study, we show that liver fibrosis is a common condition in obese patients suffering from type 2 diabetes, and that EndoBarrier gastrointestinal liner substantially improves liver fibrosis in these patients.
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