Insulin

insulin, hormone that regulates the level of sugar (glucose) in the blood and that is produced by the beta cells of the islets of Langerhans in the pancreas. Insulin is secreted when the level of blood glucose rises—as after a meal. When the level of blood glucose falls, secretion of insulin stops, and the liver releases glucose into the blood. Insulin was first reported in pancreatic extracts in 1921, having been identified by Canadian scientists Frederick G. Banting and Charles H. Best and by Romanian physiologist Nicolas C. Paulescu, who was working independently and called the substance “pancrein.” After Banting and Best isolated insulin, they began work to obtain a purified extract, which they accomplished with the help of Scottish physiologist J.J.R. Macleod and Canadian chemist James B. Collip. Banting and Macleod shared the 1923 Nobel Prize for Physiology or Medicine for their work.

Insulin is a protein composed of two chains, an A chain (with 21 amino acids) and a B chain (with 30 amino acids), which are linked together by sulfur atoms. Insulin is derived from a 74-amino-acid prohormone molecule called proinsulin. Proinsulin is relatively inactive, and under normal conditions only a small amount of it is secreted. In the endoplasmic reticulum of beta cells the proinsulin molecule is cleaved in two places, yielding the A and B chains of insulin and an intervening, biologically inactive C peptide. The A and B chains become linked together by two sulfur-sulfur (disulfide) bonds. Proinsulin, insulin, and C peptide are stored in granules in the beta cells, from which they are released into the capillaries of the islets in response to appropriate stimuli. These capillaries empty into the portal vein, which carries blood from the stomach, intestines, and pancreas to the liver. The pancreas of a normal adult contains approximately 200 units of insulin, and the average daily secretion of insulin into the circulation in healthy individuals ranges from 30 to 50 units.

Several factors stimulate insulin secretion, but by far the most important is the concentration of glucose in the arterial (oxygenated) blood that perfuses the islets. When blood glucose concentrations increase (i.e., following a meal), large amounts of glucose are taken up and metabolized by the beta cells, and the secretion of insulin increases. Conversely, as blood glucose concentrations decrease, the secretion of insulin decreases; however, even during fasting, small amounts of insulin are secreted. The secretion of insulin may also be stimulated by certain amino acids, fatty acids, keto acids (products of fatty acid oxidation), and several hormones secreted by the gastrointestinal tract. The secretion of insulin is inhibited by somatostatin and by activation of the sympathetic nervous system (the branch of the autonomic nervous system responsible for the fight-or-flight response).

Insulin acts primarily to stimulate glucose uptake by three tissues—adipose (fat), muscle, and liver—that are important in the metabolism and storage of nutrients. Like other protein hormones, insulin binds to specific receptors on the outer membrane of its target cells, thereby activating metabolic processes within the cells. A key action of insulin in these cells is to stimulate the translocation of glucose transporters (molecules that mediate cell uptake of glucose) from within the cell to the cell membrane.

In adipose tissue, insulin stimulates glucose uptake and utilization. The presence of glucose in adipose cells in turn leads to increased uptake of fatty acids from the circulation, increased synthesis of fatty acids in the cells, and increased esterification (when an acid molecule binds to an alcohol) of fatty acids with glycerol to form triglycerides, the storage form of fat. In addition, insulin is a potent inhibitor of the breakdown of triglycerides (lipolysis). This prevents the release of fatty acids and glycerol from fat cells, saving them for when they are needed by the body (e.g., when exercising or fasting). As serum insulin concentrations decrease, lipolysis and fatty acid release increase.

In muscle tissue, insulin stimulates the transport of glucose and amino acids into muscle cells. The glucose is stored as glycogen, a storage molecule that can be broken down to supply energy for muscle contraction during exercise and to supply energy during fasting. The amino acids transported into muscle cells in response to insulin stimulation are utilized for the synthesis of protein. In contrast, in the absence of insulin the protein of muscle cells is broken down to supply amino acids to the liver for transformation into glucose.

Insulin is not required for the transport of glucose into liver cells, but it has profound effects on glucose metabolism in these cells. It stimulates the formation of glycogen, and it inhibits the breakdown of glycogen (glycogenolysis) and the synthesis of glucose from amino acids and glycerol (gluconeogenesis). Therefore, the overall effect of insulin is to increase glucose storage and to decrease glucose production and release by the liver. These actions of insulin are opposed by glucagon, another pancreatic hormone produced by cells in the islets of Langerhans.

Inadequate production of insulin is responsible for the condition called diabetes mellitus. Severe diabetics require periodic injections of insulin. The first insulin injections utilized hormone extracts from pigs, sheep, and cattle, but by the early 1980s certain strains of bacteria had been genetically modified to produce human insulin. Today the treatment of diabetes mellitus relies primarily on a form of human insulin that is made using recombinant DNA technology.