Biosynthesis and Secretion

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The insulin molecule is initially translated in pancreatic p-cells as a large single-chain polypeptide called pre-proinsulin, then further processed to proinsulin by specific endopeptidases and packaged into storage granules prior to release. Proinsulin has little inherent biological activity and must be converted to insulin by the action of specific proteases in the Golgi apparatus; this enzyme action results in the formation of insulin and C (connecting) peptide. C-peptide facilitates the correct folding of the a- and p-chains of insulin and maintains the alignment of the disulfide bridges in insulin before cleavage of the C-peptide from insulin. Both insulin and C-peptide are stored in the pancreatic p-cell granules, and both are liberated during insulin secretion. Though it is unclear whether C-peptide has any function after it enters the circulation, it is sometimes measured as an indicator of endogenous insulin production.

The specific stimulus for insulin release involves fluctuations in the serum glucose levels and to a much lesser extent levels of other substrates. Glucose enters the pancreatic p-cell via glucose transporter isoform (GLUT) 4 glucose transporters, is quickly phosphory-lated to glucose-6-phosphate, and triggers an intracellu-lar influx of calcium ions that promotes fusion of the insulin-containing secretory granules with the cell membrane (exocytosis).

Insulin is continuously secreted at a low basal level during fasting, but a postprandial rise in serum glucose or amino acid levels can augment blood levels of insulin severalfold. Other nutrients (e.g., arginine, leucine) and several hormones (e.g., glucagon, growth hormone, secretin, gastrin cholecystokinin, pancre-ozymin, adrenocorticotropin) modulate insulin release. The autonomic nervous system also participates in the regulation of the rate of insulin secretion, with the islets of Langerhans receiving both cholinergic and adrenergic innervation. Insulin secretion is enhanced by vagal (cholinergic) and diminished by sympathetic (adrenergic) stimulation.

Glucose-induced stimulation of insulin release from cells is biphasic. The initial rapid rise in insulin that follows a rise in glucose is termed the first phase of insulin release and is thought to reflect the release of the presynthesized insulin in the storage granules; a more delayed and prolonged rise in insulin secretion follows. This second phase of insulin secretion is due to an up-regulation of insulin expression and production. The first phase of insulin secretion is often blunted in diabetes.

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