"Type 2 diabetes (T2D) is a growing health concern with nearly 400 million affected worldwide as of 2014 (418). T2D presents with hyperglycemia and insulin resistance resulting in increased risk for blindness, renal failure, nerve damage and premature death (10). Skeletal muscle is a major site for insulin resistance and is responsible for up to 80% of glucose uptake during euglycemic hyperinsulinemic clamps (89). Glucose uptake in skeletal muscle is driven by mitochondrial oxidative phosphorylation (MOP) and for this reason mitochondrial dysfunction has been implicated in T2D (225). Mitochondrial function in this sense is defined as the capacity for skeletal muscle mitochondria to produce ATP. In the present document, skeletal muscle mitochondrial function and its limitations were studied utilizing the Goto-Kakizaki (GK) rat model of type 2 diabetes. Mitochondrial function was defined computationally demonstrating the relationship between the drivers of ATP production (ADP, Pi) and ATP production itself. Computational depiction of MOP allowed for a functional understanding of any changes in mitochondrial function. Quantification of mitochondrial function demonstrated deficits during high metabolic workloads in the GK rat. However, upon closer analysis utilizing both computational and in vitro techniques results suggested that metabolic deficits were due to limitations separate from mitochondrial dysfunction. Since MOP ATP production requires oxygen utilization by the mitochondria and oxygen supply to the mitochondria, oxygen deficits may present in the same fashion as dysfunctional mitochondria and thus the most logical explanation to target for dysregulation was a limitation in oxygen supply. For this reason, cardiovascular function was measured in the conscious GK rat utilizing an array of challenges. Results showed no deficits in skeletal muscle performance at low workloads consistent with measures of normal mitochondrial function. However, measures indicated a harder working heart along with cardiovascular disease risk factors that may cause blood flow limitations during high intensity workloads. Quantification of blood flow using the identical setup that measured mitochondrial function during hindlimb contraction showed reductions in blood flow that could limit MOP during high intensity workloads in the diabetic GK rat. Taken together this culmination of works suggests that mitochondrial dysfunction is not inherent to type 2 diabetes, but rather muscle metabolic deficits manifest from blunted oxygen supply. This result is crucial to advance therapeutic interventions in type 2 diabetes and similar experiments in humans may direct drug therapies away from targeting skeletal muscle mitochondria and towards improving skeletal muscle blood flow."--Pages ii-iii.
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