Role of mitochondrial dynamics in regulating skeletal muscle insulin sensitivity in obesity and type 2 diabetes.
Obesity is a global epidemic and contribute to a significantly increased risk for the development of insulin resistance, type 2 diabetes (T2D) and cardiovascular diseases. One of the characteristic features of obesity and a forerunner of T2D is the impaired insulin action in skeletal muscle to regulate glucose metabolism.
The orchestrated balance between mitochondrial fission and fusion is crucial for maintaining mitochondrial morphology and function. Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission. While Drp1-mediated mitochondrial fission plays an essential role in maintaining mitochondrial function and overall skeletal muscle health, excessive activation/upregulation of Drp1 leads to aberrant mitochondrial fission causing imbalanced mitochondrial dynamics and mitochondrial fragmentation. Our lab recently reported that Drp1 is hyperactivated in skeletal muscle from obese insulin resistant humans and this hyperactivation is strongly correlated to impaired insulin signaling and glucose metabolism in skeletal muscle. We subsequently demonstrated that pharmacological inhibition enhances skeletal muscle insulin action under obese insulin resistant condition both in vitro and in vivo.
Funded by NIH, our current research is focused on
A. Establishing the direct causal relationship between Drp1-mediated mitochondrial fission and obesity-induced skeletal muscle insulin resistance. underlying mechanism has not been fully understood.
B. Identifying the molecular mechanism by which reduced Drp1-mediated mitochondrial fission contributes to the improvements in skeletal muscle insulin sensitivity and whole-body glucose homeostasis.