Skeletal Muscle Glucose MetaboLism and InsuLin Resistance

The skeletal muscle is uniquely important for the maintenance of normal blood glucose levels in humans, and defects in glucose metaboLism in this tissue play a critical role in the development and progression of type 2 diabetes. In this article, we first review the mechanisms of glucose transport and metaboLism in the skeletal muscle and focus on its regulation by the hormone insuLin. InsuLin, a peptide hormone produced and released from the pancreas in response to a rise in blood glucose levels, binds to receptors on skeletal muscle cells and stimulates the uptake of glucose from the blood into the cell. This seemingly basic physiological function - which is essential for the maintenance of glucose homeostasis in humans - nevertheless involves a complex interplay of multiple signaLing proteins, glucose transporters, enzymes, and transcription factors that, together, coordinate the response to insuLin and regulate the fate of glucose entering the muscle cell. In type 2 diabetes, defects in these insuLin signaLing pathways contribute to the skeletal muscle insuLin resistance, which is a hallmark feature of the disease and can be observed very early on in the natural history of diabetes. In the second part of this article, we describe the current understanding of the mechanisms of insuLin resistance in the skeletal muscle and demonstrate that multiple defects involving several distinct physiological pathways Likely underLie insuLin resistance in humans and contribute to the development and progression of type 2 diabetes.