Rationale: Insulin acts by acutely modulating rate-controlling enzymes of metabolism and by inducing longer-term changes through its effects upon gene expression. The three main targets of insulin in the body are skeletal muscle and liver, which help maintain plasma glucose homeostasis, and adipose tissue, which is regulated hormonally to ensure delivery of plasma free fatty acids (FFAs) to and removal of triglycerides from the circulation, as appropriate to condition. Insulin binding to a single receptor is able to differentially control energy metabolism in these three tissues in part through the unique, tissue-specific expression of protein isoforms.
In response to an elevation of circulating glucose levels after a meal and other stimuli associated with eating, pancreatic beta cells increase insulin secretion until plasma glucose levels return to the pre-meal physiological set point. Insulin binds to a cell surface receptor on target cells, which causes a conformation change that is transduced across the cell membrane and disinhibits an intrinsic tyrosine kinase activity present in the intracellular portion of the receptor. The activation of the insulin receptor tyrosine kinase results in the autophosphorylation of the receptor on tyrosine residues and the recruitment of several signaling molecules, which are then phosphorylated by the insulin receptor. The most important of these substrates is a family of insulin receptor substrate (IRS) proteins. The tyrosine phosphorylation of IRS proteins activates numerous signaling cascades that mediate the plethora of responses in target cells. Insulin's effects can be broadly divided into two categories: mitogenic, those promoting cell growth and division, and metabolic, those promoting glucose and triglyceride uptake, utilization, and storage.
The principal physiological effect of insulin secretion is to reduce plasma glucose levels. Enhanced glucose uptake in skeletal muscle accounts for up to 90% of insulin-mediated glucose disposal in peripheral tissues, making it a critical step in the maintenance of blood glucose levels. Skeletal muscle is also a key site for the development of insulin resistance preceding diabetes. Insulin promotes glucose uptake in muscle by stimulating the translocation of specialized vesicles containing the facilitative glucose transporter isoform GLUT4 from the perinuclear region to the cell surface.
The liver is the principal organ responsible for maintaining plasma glucose levels during times of fasting or increased demand, such as during exercise. When blood glucose levels start to fall, counter-regulatory hormones such as glucagon elevate cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) activity, which stimulate glycogen breakdown and gluconeogenesis (de novo production of glucose), increasing hepatic glucose output. In contrast, insulin suppresses hepatic glucose production and promotes glucose storage as glycogen in hepatocytes. The ratio of insulin to glucagon levels dictates whether the liver will store glucose (high insulin) or produce glucose for use by the rest of the body (low insulin). Hepatocytes express an insulin-insensitive glucose transporter isoform termed GLUT2 that is always present at the cell surface, enabling glucose uptake during hyperglycemia and glucose release into the bloodstream during episodes of hypoglycemia. Thus, insulin does not directly stimulate glucose uptake by liver cells. However, insulin does increase rate-limiting enzymes controlling glycogen metabolism and promotes glucose storage as glycogen. Additionally, if hepatic glycogen stores are full, excess glucose can be converted to fatty acids and shipped within triglycerides on very low density lipoproteins (VLDLs) via the circulation to adipose tissue for long-term storage. Thus, the liver is the second most important peripheral tissue after skeletal muscle for clearance of plasma glucose following a meal.
The adipocyte is the third major site of insulin action. Insulin promotes glucose uptake in the fat cell through the translocation of GLUT4 storage vesicles similar to that found in muscle cells. However, the glucose that adipocytes take up is not stored as glycogen, but rather partially metabolized down the glycolytic pathway to form glycerol-3-phosphate, which is the backbone for triglycerides.