Insulin is the primary anabolic hormone that dominates regulation of metabolism during the digestive phase. Insulin is a protein hormone that belongs to the gene family that includes insulinlike growth factors I and II (IGF-I, IGF-II) and relaxin. The insulin gene encodes preproinsulin. Insulin is synthesized as preproinsulin, which is converted to proinsulin as the hormone enters the endoplasmic reticulum. Proinsulin is packaged in the
CHAPTER 39 Hormonal Regulation of Energy Metabolism 705 4 (-) ATP of cell membrane • Fig. 39.7 Glucose is the primary stimulus of insulin secretion and is enhanced by sulfonylurea drugs as well as GLP-1 analogues/DPP-4 inhibitors. See text for explanation of numbered steps in glucose-stimulated insulin secretion (GSIS).
Golgi apparatus into membrane-bound secretory granules. Proinsulin contains the AA sequence of insulin plus the C (connecting) peptide. The proteases that cleave proinsulin (proprotein convertases) are packaged with proinsulin within secretory vesicles. Proteolytic processing clips out the C peptide and generates the mature hormone, which consists of two chains, an α chain and a β chain, connected by two disulfide bridges (
Fig. 39.7). A third disulfide bridge is contained within the α chain. Insulin is stored in secretory granules in zinc-bound crystals. On stimulation, the granule’s contents are released to the outside of the cell by exocytosis. Equimolar amounts of mature insulin and C peptide are released, along with small amounts of proinsulin. C peptide has no known biological activity but is useful in assessing endogenous insulin production. C peptide is more stable in blood than insulin (making it easier to assay) and helps distinguish endogenous insulin production from injected insulin, insofar as the latter has been purified from C peptide.
Insulin has a short half-life of about 5 minutes and is cleared rapidly from the circulation. It is degraded by insulin-degrading enzyme (IDE; also called insulinase) in the liver, kidney, and other tissues. Because insulin is secreted into the hepatic portal vein, it is exposed to liver IDE before it enters the peripheral circulation. About half the insulin is degraded before leaving the liver. Thus peripheral tissues are exposed to significantly less serum insulin concentrations than the liver. Recombinant human insulin and insulin analogues with different characteristics of speed of onset and duration of action and peak activity are now available. Serum insulin levels normally begin to rise within 10 minutes after ingestion of food and reach a peak in 30 to 45 minutes. The higher serum insulin level rapidly lowers blood glucose to baseline values.
Glucose is the primary stimulus of insulin secretion (“steps” in glucose-stimulated insulin secretion described in the discussion that follows refer to