Beta cells (Insulin Production)

Beta cells (beta-cells, β-cells) are a type of cell in the pancreas in areas called the islets of Langerhans. They make up 65-80% of the cells in the islets.
In mammals, insulin is synthesized in the pancreas within the beta cells (β-cells) of the islets of Langerhans. One to three million islets of Langerhans (pancreatic islets) form the endocrine part of the pancreas, which is primarily an exocrine gland. The endocrine portion only accounts for 2% of the total mass of the pancreas. Within the islets of Langerhans, beta cells constitute 60–80% of all the cells.

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In beta cells, insulin is synthesized from the proinsulin precursor molecule by the action of proteolytic enzymes, known as prohormone convertases (PC1 and PC2), as well as the exoprotease carboxypeptidase E. These modifications of proinsulin remove the center portion of the molecule, or C-peptide, from the C- and N- terminal ends of the proinsulin. The remaining polypeptides (51 amino acids in total), the B- and A- chains, are bound together by disulfide bonds/disulphide bonds. Confusingly, the primary sequence of proinsulin goes in the order "B-C-A", since B and A chains were identified on the basis of mass, and the C peptide was discovered after the others.
Glucose enters the beta cells through the glucose transporter GLUT2
Glucose goes into the glycolysis and the respiratory cycle where multiple high-energy ATP molecules are produced by oxidation Dependent on ATP levels, and hence blood glucose levels, the ATP-controlled potassium channels (K+) close and the cell membrane depolarizes On depolarization, voltage controlled calcium channels (Ca2+) open and calcium flows into the cells An increased calcium level causes activation of phospholipase C, which cleaves the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate into inositol 1,4,5-triphosphate and diacylglycerol. Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the membrane of endoplasmic reticulum (ER). This allows the release of Ca2+ from the ER via IP3 gated channels, and further raises the cell concentration of calcium. Significantly increased amounts of calcium in the cells causes release of previously synthesised insulin, which has been stored in secretory vesicles

This is the main mechanism for release of insulin and regulation of insulin synthesis. In addition some insulin synthesis and release takes place generally at food intake, not just glucose or carbohydrate intake, and the beta cells are also somewhat influenced by the autonomic nervous system. The signalling mechanisms controlling this are not fully understood.
Other substances known to stimulate insulin release include amino acids from ingested proteins, acetylcholine, released from vagus nerve endings (parasympathetic nervous system), cholecystokinin[citation needed], released by enteroendocrine cells of intestinal mucosa and glucose-dependent insulinotropic peptide (GIP). Three amino acids (alanine, glycine and arginine) act similarly to glucose by altering the beta cell's membrane potential. Acetylcholine triggers insulin release through phospholipase C, while the last acts through the mechanism of adenylate cyclase.
The sympathetic nervous system (via Alpha2-adrenergic stimulation as demonstrated by the agonists clonidine or methyldopa) inhibit the release of insulin. However, it is worth noting that circulating Epinephrine will activate Beta2-Receptors on the Beta cells in the pancreatic islets to promote insulin release. This is important since muscle cannot benefit from the the raised blood sugar resultant from adrenergic stimulation (increased gluconeogenisis and glycogenolysis from the low blood insulin:glucogon state) unless insulin in present to allow for GLUT-4 translocation in the tissue. So in summary, first through direct innervation, NE inhibits insulin release via alpha2-receptors, then later, circulating Epi from the adrenal medulla will stimulate beta2-receptors thereby promoting insulin release.
When the glucose level comes down to the usual physiologic value, insulin release from the beta cells slows or stops. If blood glucose levels drop lower than this, especially to dangerously low levels, release of hyperglycemic hormones (most prominently glucagon from Islet of Langerhans' alpha cells) forces release of glucose into the blood from cellular stores, primarily liver cell stores of glycogen. By increasing blood glucose, the hyperglycemic hormones correct life-threatening hypoglycemia. Release of insulin is strongly inhibited by the stress hormone norepinephrine (noradrenaline), which leads to increased blood glucose levels during stress.

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