A variety of factors, including other pancreatic hormones, are known to influence insulin secretion. The primary physiological regulator of insulin secretion, however, is the blood glucose concentration.
Proinsulin Synthesis. The gene for insulin is located on the short arm of chromosome 11 in humans. Like other hormones and secretory proteins, insulin is first synthesized by ribosomes of the rough ER as a larger precursor peptide that is then converted to the mature hormone prior to secretion (see Chapter 31).
The insulin gene product is a 110-amino acid peptide, preproinsulin. Proinsulin consists of 86 amino acids (Fig. 35.2); residues 1 to 30 constitute what will form the B chain of insulin, residues 31 to 65 form the connecting peptide, and residues 66 to 86 constitute the A chain. (Note that "connecting peptide" should not be confused with "C-peptide.") In the process of converting proinsulin to insulin, two pairs of basic amino acid residues are clipped out of the proinsulin molecule, resulting in the formation of insulin and C-peptide, which are ultimately secreted from the beta cell in equimolar amounts.
It is of clinical significance that insulin and C-peptide are co-secreted in equal amounts. Measurements of circulating C-peptide levels may sometimes provide important information regarding beta cell secretory capacity that could not be obtained by measuring circulating insulin levels alone.
Insulin Secretion. Table 35.1 lists the physiologically relevant regulators of insulin secretion. As indicated previ ously, an elevated blood glucose level is the most important regulator of insulin secretion. In humans, the threshold value for glucose-stimulated insulin secretion is a plasma glucose concentration of approximately 100 mg/dL (5.6 mmol/L).
Based on studies using isolated animal pancreas preparations maintained in vitro, it has been determined that insulin is secreted in a biphasic manner in response to a marked increase in blood glucose. An initial burst of insulin secretion may last 5 to 15 minutes, resulting from the secretion of preformed insulin secretory granules. This response is followed by more gradual and sustained insulin secretion that results largely from the synthesis of new insulin molecules.
In addition to glucose, several other factors serve as important regulators of insulin secretion (see Table 35.1). These include dietary constituents, such as amino acids and fatty acids, as well as hormones and drugs. Among the amino acids, arginine is the most potent secretagogue for insulin. Among the fatty acids, long-chain fatty acids (16 to 18 carbons) generally are considered the most potent stimulators of insulin secretion. Several hormones secreted by the gastrointestinal tract, including gastric inhibitory pep-tide (GIP), gastrin, and secretin, promote insulin secretion. An oral dose of glucose produces a greater increment in insulin secretion than an equivalent intravenous dose because oral glucose promotes the secretion of GI hormones that
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