insulin

insulin. Insulin is a peptide hormone produced by the beta cells of the pancreatic islets within the pancreas. It is central to the regulation of glucose metabolism, facilitating the cellular uptake of glucose from the bloodstream into tissues such as liver, muscle, and adipose tissue. Its discovery and therapeutic use revolutionized the treatment of diabetes mellitus, a group of metabolic disorders characterized by chronic hyperglycemia.

Structure and biosynthesis

Insulin is synthesized as a single-chain precursor molecule called proinsulin within the endoplasmic reticulum of pancreatic beta cells. This process involves the translation of messenger RNA transcribed from the INS gene located on chromosome 11 in humans. The maturation of proinsulin occurs in the Golgi apparatus, where protease enzymes cleave it to yield the active hormone, consisting of two polypeptide chains (A chain and B chain) linked by disulfide bonds, and the excised C-peptide. The hormone is then stored in secretory granules awaiting release. The structure of insulin was first determined through the pioneering X-ray crystallography work of Dorothy Hodgkin, and its amino acid sequence varies somewhat among species like bovine and porcine insulin.

Regulation of secretion

The primary stimulus for insulin secretion is an elevation in blood glucose concentration, such as after a meal. Glucose enters the beta cell via GLUT2 transporters, leading to increased glycolysis and a rise in the ATP/ADP ratio. This change causes the closure of ATP-sensitive potassium channels, depolarizing the cell membrane and opening voltage-gated calcium channels. The influx of calcium ions triggers the exocytosis of insulin-containing granules. Secretion is potentiated by other nutrients like amino acids and free fatty acids, as well as by incretin hormones such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) released from the gut in response to food. Neural inputs from the autonomic nervous system and other hormones like growth hormone also modulate secretion.

Mechanism of action

Insulin exerts its effects by binding to the insulin receptor, a tyrosine kinase receptor embedded in the plasma membrane of target cells like those in the liver, skeletal muscle, and adipose tissue. This binding triggers autophosphorylation of the receptor and the recruitment and phosphorylation of intracellular signaling proteins such as insulin receptor substrate (IRS) proteins. This activates major pathways including the PI3K/Akt pathway and the MAPK/ERK pathway. The primary metabolic actions include promoting GLUT4 translocation to the cell surface to increase glucose uptake, stimulating glycogen synthesis in the liver and muscle, enhancing lipogenesis in adipose tissue, and inhibiting processes like gluconeogenesis, glycogenolysis, and lipolysis.

Medical uses

The primary medical use of insulin is the treatment of diabetes mellitus. It is essential for all individuals with type 1 diabetes, where autoimmunity destroys pancreatic beta cells, and for many with advanced type 2 diabetes or gestational diabetes. Therapeutic insulins are classified by their duration of action, including rapid-acting insulin (e.g., insulin lispro, insulin aspart), short-acting insulin (regular insulin), intermediate-acting insulin (NPH insulin), and long-acting insulin analogs (e.g., insulin glargine, insulin detemir). Administration is typically via subcutaneous injection using syringes, insulin pens, or insulin pumps. It is also used in hyperkalemia to drive potassium into cells and is a component of intravenous dextrose solutions for total parenteral nutrition.

Adverse effects and complications

The most common and serious adverse effect is hypoglycemia, which can lead to symptoms like tachycardia, sweating, confusion, seizures, and loss of consciousness. Local reactions at injection sites can include lipodystrophy (lipoatrophy or lipohypertrophy) and allergic reactions. Weight gain is a common side effect due to insulin's anabolic properties. Prolonged use, especially with suboptimal glycemic control, is associated with complications of diabetes such as diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. Improper dosing or missed doses can lead to diabetic ketoacidosis or hyperosmolar hyperglycemic state.

History and etymology

The history of insulin begins with the work of Oskar Minkowski and Joseph von Mering, who demonstrated the pancreas's role in diabetes in 1889. The hormone was isolated in 1921 by Frederick Banting and Charles Best at the University of Toronto, with crucial contributions from John Macleod and the biochemist James Collip. The first successful treatment of a human patient, Leonard Thompson, occurred in 1922. Banting and Macleod were awarded the Nobel Prize in Physiology or Medicine in 1923. The term "insulin" is derived from the Latin insula, meaning "island," referring to the pancreatic islets (islets of Langerhans) where it is produced. Subsequent milestones include the determination of its amino acid sequence by Frederick Sanger (for which he received the Nobel Prize in Chemistry), the synthesis of human insulin using recombinant DNA technology by Genentech and Eli Lilly and Company, and the development of modern insulin analogs. Category:Peptide hormones Category:Diabetes Category:Hormones of the pancreas