Rithwik Terala

Introduction. Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by persistent hyperglycemia due to impaired insulin secretion, resistance to peripheral actions of insulin, or both¹. Insulin resistance corresponds with a failure of pancreatic islets to compensate for the decline in insulin sensitivity (β-cell failure) associated with impaired mitochondrial respiration and augmented oxidative stress^1,2. Recent studies have found that exercise induces mitochondrial dynamics and glucose tolerance/utilization in tissue-specific and systemic settings, suggesting potential prevention and treatment mechanisms for T2DM^3-5. Methods. Mice were randomly assigned to the sedentary or exercise group without or with a running wheel, respectively. Western blotting evaluated mitochondrial protein levels in mice skeletal muscle and subcutaneous white adipose tissue (scWAT). scWAT from donor trained mice was transplanted to sedentary recipient mice. Fiber-type-specific proteomics analysis probed human skeletal muscle biopsies before and after 12 weeks of endurance training. Single fibers were typified using MHC antibodies. A 75-g oral glucose tolerance test (OGTT) measured levels of incretin hormones, including glucagon-like polypeptide-1 (GLP-1). Results. The levels of various mitochondrial proteins involved in glucose utilization, including glycolysis, glycogen metabolism, pyruvate dehydrogenase complex, tricarboxylic acid cycle, and oxidative phosphorylation, increased after exercise in skeletal muscle in human whole-muscle samples⁴. These mitochondrial proteins also elevated in skeletal muscle and white adipose tissue in comparison to sedentary mice⁵. Iron sulfur domain-containing (CISD) proteins, mitochondrial matrix proteins that upregulate mitochondrial biogenesis, had amplified expression after exercise in mice skeletal muscle and scWAT⁵. Furthermore, the association between CISD and mitochondrial protein expression in the plantaris muscle and WAT in mice was positively correlated⁵. Transient decreases in blood glucose were observed in mice transplanted with scWAT from trained mice 9 days after transplantation⁶. Additionally, GLP-1, a metabolic hormone that diminishes blood glucose levels by augmenting insulin secretion, increased in the blood coupled with the decline in blood glucose levels after exercise training. Conclusions. The positive association between CISD proteins and mitochondrial dynamics proposes exercise directly maintains mitochondrial integrity to prevent the progression of T2DM-mediated oxidative stress and failure of oxidative phosphorylation. The elevation of mitochondrial proteins indicates a potential mechanism for bolstered mitochondrial involvement in glucose uptake/utilization after exercise, associated with potential preventions and treatments for T2DM. The short-term improvements in glucose tolerance evince significant endocrine effects on systemic metabolism after exercise. The exercise-induced change in the blood suggests GLP-1 and other incretins may be some of the signals involved with exercise and its effects to reduce blood glucose levels, critical for evaluation of risk and treatments for T2DM.

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