Sandbox-insulin-bat7

Insulin is a hormone that controls carbohydrate metabolism and storage in the human body. The body is able to sense the concentration of glucose in the blood and respond by secreting insulin, which is produced by beta cells in the pancreas. Synthesis of human insulin in E. coli is important to producing insulin for the treatment of type 1 diabetes. Proinsulin (Pins) is processed by several proteases in the Golgi apparatus to form insulin which is shorter by 35 amino acids. DPI is a monomeric despentapeptide (B26-B30) Ins analogue. DTRI is a monomeric destripeptide (B28-B30) Ins analogue. DHPI is for desheptapeptide (B24-B30) Ins. LIns is a legume Ins.

       Insulin is made up of two pieces called the A- and B-chain, shown above in blue and green respectively. These two chains are joined by disulfide bonds, which are shown in yellow. This single piece made up of the A- and B-chains is the active form of the insulin hormone. This is the form that binds the insulin receptor on fat or muscle cells in the body, singling them to take up glucose, or sugar, from the blood and save it for later.

       Insulin is able to pair-up with itself and form a dimer by forming hydrogen bonds between the ends of two B-chains. These are shown above in white. Then, 3 dimers can come together in the presence of zinc ions and form a hexamer. Insulin is stored in the in the body. This the hydrophobic (gray) and polar (purple) parts of an insulin monomer at a pH of 7. It is believed that the hydrophobic sections on the B-chain cause insulin aggregation which initially caused problems in the manufacture and storage of insulin for pharmaceutical use.

Synthesis

Insulin is produced in the pancreas and released when any of several stimuli are detected. These stimuli include ingested protein and glucose in the blood produced from digested food.[17] Carbohydrates can be polymers of simple sugars or the simple sugars themselves. If the carbohydrates include glucose, then that glucose will be absorbed into the bloodstream and blood glucose level will begin to rise. In target cells, insulin initiates a signal transduction, which has the effect of increasing glucose uptake and storage. Finally, insulin is degraded, terminating the response. For additional details see Insulin Structure & Function.

Insulin undergoes extensive posttranslational modification along the production pathway. Production and secretion are largely independent; prepared insulin is stored awaiting secretion. Both C-peptide and mature insulin are biologically active. Cell components and proteins in this image are not to scale.

In mammals, insulin is synthesized in the pancreas within the β-cells of the islets of Langerhans. One million to three million islets of Langerhans (pancreatic islets) form the endocrine part of the pancreas, which is primarily an exocrine gland. The endocrine portion accounts for only 2% of the total mass of the pancreas. Within the islets of Langerhans, beta cells constitute 65–80% of all the cells.

Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1), which starts many protein activation cascades (2). These include translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and triglyceride (6).

University of Massachusetts Amherst Chemistry-Biology Interface Program

Structural highlights

Disease

[INS_HUMAN] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:176730].^{[1] [2] [3] [4]} Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:125852]. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.^[5] Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:606176]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.^{[6] [7]} Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:613370]. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.^{[8] [9] [10]}

Function

[INS_HUMAN] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.