Since the mitochondrial
pyruvate dehydrogenase complex (PDC) controls the rate of
carbohydrate oxidation, impairment of PDC activity mediated by high-fat intake has been advocated as a causative factor for the skeletal muscle
insulin resistance,
metabolic syndrome, and the onset of
type 2 diabetes (T2D). There are also situations where muscle
insulin resistance can occur independently from high-
fat dietary intake such as
sepsis,
inflammation, or
drug administration though they all may share the same underlying mechanism, i.e., via activation of forkhead box family of
transcription factors, and to a lower extent via
peroxisome proliferator-activated receptors. The main feature of T2D is a chronic elevation in
blood glucose levels. Chronic systemic hyperglycaemia is toxic and can lead to cellular dysfunction that may become irreversible over time due to deterioration of the pericyte cell's ability to provide vascular stability and control to endothelial proliferation. Therefore, it may not be surprising that T2D's complications are mainly macrovascular and microvascular related, i.e., neuropathy, retinopathy, nephropathy, coronary artery, and
peripheral vascular diseases. However, life style intervention such as exercise, which is the most potent physiological activator of muscle PDC, along with pharmacological intervention such as administration of dichloroacetate or
L-carnitine can prove to be viable strategies for treating muscle
insulin resistance in
obesity and T2D as they can potentially restore whole body
glucose disposal.