Targeting mitochondria to restore failed adaptation to exercise in diabetes

Abstract

Our translational research group focuses on addressing the problem of exercise defects in diabetes with basic research efforts in cell and rodent models and clinical research efforts in subjects with diabetes mellitus. CREB (cAMP-response-element-binding protein) regulates cellular differentiation of neurons, β-cells, adipocytes and smooth muscle cells; it is also a potent survival factor and an upstream regulator of mitochondrial biogenesis. In diabetes and cardiovascular disease, CREB protein content is decreased in the vascular media, and its regulation in aberrant in β-cells, neurons and cardiomyocytes. Loss of CREB content and function leads to decreased vascular target tissue resilience when exposed to stressors such as metabolic, oxidative or sheer stress. This basic research programme set the stage for our central hypothesis that diabetes-mediated CREB dysfunction predisposes the diabetes disease progression and cardiovascular complications. Our clinical research programme revealed that diabetes mellitus leads to defects in functional exercise capacity. Our group has determined that the defects in exercise correlate with insulin resistance, endothelial dysfunction, decreased cardiac perfusion and diastolic dysfunction, slowed muscle perfusion kinetics, decreased muscle perfusion and slowed oxidative phosphorylation. Combined basic and clinical research has defined the relationship between exercise and vascular function with particular emphasis on how the signalling to CREB and eNOS [endothelial NOS (nitric oxide synthase)] regulates tissue perfusion, mitochondrial dynamics, vascular function and exercise capacity. The present review summarizes our current working hypothesis that restoration of eNOS/NOS dysfunction will restore cellular homoeostasis and permit an optimal tissue response to an exercise training intervention.

Metabolic Effects of Exercise Training Among Fitness-Nonresponsive Patients With Type 2 Diabetes: The HART-D Study

“…Patients with diabetes have increased prevalence of chronotropic incompetence, left ventricular hypertrophy, and adverse remodeling, all of which are associated with a greater risk for fitness nonresponse ( 11 , 12 ). Also, previous studies ( 13 , 14 ) have shown that patients with diabetes have slowed muscle perfusion kinetics and slowed oxidative phosphorylation that could lead to a relatively blunted improvement in cardiorespiratory fitness with exercise training.…”

Targeting mitochondrial fitness as a strategy for healthy vascular aging

“…Importantly, robust mitochondrial stress response appears to be a feature of healthy vascular function, whereas vascular disease is characterized by impaired mitochondrial stress response [60,84,85].…”

Supplemental Oxygen Improves In Vivo Mitochondrial Oxidative Phosphorylation Flux in Sedentary Obese Adults With Type 2 Diabetes

“…Abnormalities in muscle mitochondrial content and function have been documented for over 20 years in diabetes using both muscle biopsy and 31 P-MRS measurements (10)(11)(12)39,49). Using 31 P-MRS, we have documented similar abnormalities in youth with diabetes with ,3 years of diabetes duration as compared with lean and obese youth without diabetes (14).…”