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Secretion of insulin from pancreas b cells: A Case Study of Exocytosis and Cell Signaling Cultured Mouse Pancreatic Islets (10x magnification). Provided by David Zhiyong Gao, Ph.D. Designed by Leonardo Da Vinci in 1501, this figure is an exact representation of clathrin as it appears in coated pits. Exocytosis Case Study: Secretion of insulin from pancreas b cells Cultured Mouse Pancreatic Islets (10x magnification). Insulin is a peptide hormone that regulates glucose uptake and metabolism. Provided by David Zhiyong Gao, Ph.D. In diabetes mellitus (sweet urine), insulin secretion by ß-cells of islets of Langerhans is deficient or absent. Insulin Monomer Structure 51 amino acid residues a and ß chain disulfide bonds connect the two chains The amino acid sequence of bovine insulin. Insulin is stored in crystalline structures made up of insulin hexamers containing two Zn2+ ions. This figure was created using RasMol by Roger Sayle. Cultured Mouse Pancreatic Islets (10x magnification). Pancreatic islets are scattered throughout the pancreas. There are about 1 million islets, Provided by David Zhiyong Gao, Ph.D. comprising 1 to 2% of the total volume of the pancreas. Islets have a central core of insulin producing ß-cells surrounded by cells that produce other pancreatic hormones such as glucagon (alphacells), somatostatin (D or delta-cells), and pancreatic polypeptide (F or PP cells). In type 2 diabetes, beta cells fail to secrete insulin normally in response to glucose. About 16 million people or 6% of the US population has diabetes. Of those, type 2 diabetes is by far the most common. The number of people with type 2 diabetes is predicted to increase as the population grows older. Exocytotic membrane fusion occurs by a highly conserved mechanism that involves membrane vesicles and membrane proteins. TEM Showing Exocytosis of the Contents of a Secretory Vesicle Figure source: http://tidepool.st.usm.edu/crs wr/exocytosis.html Members of the SNARE, Sec1p, and Rab families are involved in the docking and fusion of transport vesicles to target membranes. Time Out 2 Botulinum toxin: Types A and E cleave SNAP 25 (synaptosomal associated protein) a highly conserved protein known to be involved in exocytosis. Type C cleaves syntaxin, a synaptic membrane protein also involved in exocytosis. Role of NSF in membrane fusion NSF is a molecular chaperone that induces conformation al change into its targets syntaxin and, to a lesser extent, SNAP-25. Model for membrane fusion Figure source: http://www.mpibpc.gwdg.de/abteilungen/190/fusmodel.html How does this happen with insulin secretion? Preproinsulin is synthesized and inserted across the rough endoplasmic reticulum membrane membrane. (A proprotein, is one that is made in an inactive form and later activated by the cell.) http://www.accessexcel lence.org/AB/GG/exocy tosis.html The prepeptide is cleaved to form the active hormone and packaged in the Golgi apparatus into secretory vesicles. There are about 15,000 secretory vesicles (in this case, they are called secretory granules) per cell. This is about a 5-day supply in a normal human. Figure from “Access Excellence” http://www.accessexcellence.org/AB/GG/exocytosis.html Time Out Mistletoe extract (Viscum album) has a long history as a traditional treatment for diabetes. Mistletoe exerts its antidiabetic effect by stimulating insulin secretion. Cell Signaling Case Study: Secretion of insulin from pancreas b cells In general, signaling by cell-surface receptors initiates a cascade of biochemical events that result changes in the metabolism of the cell. Insulin is secreted in response to elevated blood concentrations of glucose. How does glucose stimulate insulin secretion from b cells of the pancreas? Glucose metabolism produces cellular ATP, which closes the ATP-sensitive potassium channel; then the voltage-dependent L-type Ca2+ channels open. Ca2+ from the extracellular space (and intercelluar stores) leads to the exocytosis of insulin. Overwhelming evidence supports the idea that glucokinase is the major regulator of glucose metabolism, allowing it to function as the glucose sensor of the ß-cell. Figure source: http://mcb1.ims.abdn.ac. uk/teaching/courses/mo dules/Ercs.html Signaling is about communication between different groups of cells and tissues…how one group of cells informs another group of cells what to do. Signal transduction refers to how the presence of an extracellular signal can produce a change in the intracellular state of the cell without the initial signal crossing the membrane. Signal transduction systems Ca2+/calmodulin adenylate cyclase/cAMP NO PLC/PKC PI/IP3/DAG membrane receptors G proteins steroid hormones How does insulin work? INSULIN ACTS TO STORE NUTRIENTS. (carbohydrates, fats and protein) It is the only hormone that does this. A lack of insulin is fatal. Insulin acts on three major organs, the liver, muscle and adipose tissue.. Insulin is not needed for glucose transport into the brain, red blood cells, liver, renal medulla or active muscle. Review 1.Compare the structures, locations and functions of preproinsulin and insulin. 2. Outline the events from translation of the preproinsulin gene to exocytosis of insulin. 3. Describe the mechanisms by which glucose promotes insulin secretion. 4. Identify the components of insulin secretion that are defective in type II diabetes mellitus.