Abstract
Type 2 diabetes (T2D) is a growing health concern with nearly 400 million affected worldwide as of 2014. T2D presents with hyperglycemia and insulin resistance resulting in increased risk for blindness, renal failure, nerve damage, and premature death. Skeletal muscle is a major site for insulin resistance and is responsible for up to 80% of glucose uptake during euglycemic hyperglycemic clamps. Glucose uptake in skeletal muscle is driven by mitochondrial oxidative phosphorylation and for this reason mitochondrial dysfunction has been implicated in T2D. In this review we integrate mitochondrial function with physiologic function to present a broader understanding of mitochondrial functional status in T2D utilizing studies from both human and rodent models. Quantification of mitochondrial function is explained both in vitro and in vivo highlighting the use of proper controls and the complications imposed by obesity and sedentary lifestyle. This review suggests that skeletal muscle mitochondria are not necessarily dysfunctional but limited oxygen supply to working muscle creates this misperception. Finally, we propose changes in experimental design to address this question unequivocally. If mitochondrial function is not impaired it suggests that therapeutic interventions and drug development must move away from the organelle and toward the cardiovascular system.
Highlights
DefinitionsA brief list of specific definitions is provided for clarity in conceptual aspects of this document
Zucker Diabetic Fatty (ZDF) rats were developed through selective breeding of obese Zucker rats (OZR) showing the greatest increase in the severity of insulin resistance and poor glycemic control with time [145]
Because of insulin overproduction, most OZR do not present with severe fasting hyperglycemia until they become significantly older than matched ZDF [146]
Summary
A brief list of specific definitions is provided for clarity in conceptual aspects of this document. Muscle mitochondrial oxidative phosphorylation capacity (MOP Capacity)—Absolute capacity for muscle to produce ATP aerobically. Type 2 diabetes is characterized by increased blood glucose, resistance to insulin action, and beta cell failure [7] This results in reduced net glucose disposal and increased risk for cardiovascular disease, blindness, renal failure, nerve damage, loss of limb, and other co-morbidities [8,9]. Skeletal muscle mitochondria oxidize carbohydrates to support ATP production and fuel contracting muscle and as a consequence glucose uptake is largely driven by mitochondrial ATP production [1,3,29]. Acetyl-CoA is introduced from carbohydrate or fatty acid oxidation from pyruvate dehydrogenase (PDH) or 3-ketoacyl-CoA thiolase reactions respectively Within the cycle these biochemical reactions produce reducing equivalents including. The relationship between ATP demand and glucose oxidation perhaps explains at least a portion of the improved glucose handling in type 2 diabetes following exercise intervention
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