Insulin and proinsulin

Yamamoto A, Hayakawa E, Lee VH (1990) Insulin and proinsulin proteolysis in mucosal homogenates of the albino rabbit Implications in peptide delivery from nonoral routes. Life Sci 47 2465-2474... 

Studies on characterizing the enzymatic barrier at each delivery site have investigated the pattern of cleavage of enkephalins, substance P, insulin and proinsulin, and have demonstrated the presence of both exo- and endo-peptidases in the various epithelial tissues. What distinguishes one route from another is probably the relative proportion of these proteases, as well as their subcellular distribution. 

Teng, C.L.D. Groves, M.J. The effect of compactional pressure on urease activity. Pharm. Res. 1988, 5, 776-780. Alur, H.H. Paher, S.I. Mitra, A.K. Johnston, T.P. Transmucosal sustained delivery of chlorpheniramine maleate in rabbits using a novel, natural mucoadhesive gum as an excipient in buccal tablets. Int. J. Pharm. 1999,188, 1-10. Kondo, S. Sugimoto, I. Moment analysis of intravenous, intraduodenal, buccal, rectal, and percutaneous nifedipine in rats. J. Pharmacobio. Dyn. 1987, 10, 462 69. Yamamoto, A. Hayakawa, E. Lee, V.H. Insulin and proinsulin proteolysis in mucosal homogenates of the albino rabbit implications in peptide delivery from nonoral routes. Life Sci. 1990, 26, 2465-2474. 

The plasma tj, insuhn normally is 5-6 minutes but may be increased in diabetics who develop anti-insulin antibodies. The tj, of proinsulin is longer than that of insulin, and proinsulin... 

D. H., Effects of GH-RIH (somatostatin) on insulin and proinsulin secretion in patients with insulinomas. Submitted for publication. 

Insulin and Amylin. Insulin is a member of a family of related peptides, the insulin-like growth factors (IGFs), including IGF-I and IGF-II (60) and amylin (75), a 37-amino acid peptide that mimics the secretory pattern of insulin. Amylin is deficient ia type 1 diabetes meUitus but is elevated ia hyperinsulinemic states such as insulin resistance, mild glucose iatolerance, and hypertension (33). Insulin is synthesized ia pancreatic P cells from proinsulin, giving rise to the two peptide chains, 4. and B, of the insulin molecule. IGF-I and IGF-II have stmctures that are homologous to that of proinsulin (see INSULIN AND OTHER ANTIDIABETIC DRUGS). 

Figure 42-12. Structure of human proinsulin. Insulin and C-peptide molecules are connected at two sites by dipeptide links. An initial cleavage by a trypsin-like enzyme (open arrows) followed by several cleavages by a car-boxypeptidase-like enzyme (solid arrows) results in the production of the heterodimeric (AB) insulin molecule (light blue) and the C-peptide.

Proinsulin is proteolytically processed in the coated secretory granules, yielding mature insulin and a 34-amino acid connecting peptide (C peptide, Figure 11.1). The C peptide is further proteolytically modified by removal of a dipeptide from each of its ends. The secretory granules thus contain low levels of proinsulin, C peptide and proteases, in addition to insulin itself. The insulin is stored in the form of a characteristic zinc-insulin hexamer, consisting of six molecules of insulin stabilized by two zinc atoms. 

FIGURE 18-12 The/af//af mutation in carboxypeptidase E (CPE) leads to secretion of proinsulin, not mature insulin, and results in diabetes. The S202P mutation within CPE results in degradation of the enzyme and defective insulin processing in the fat/fat heterozygous mouse. LDCV, large dense-core vesicle. 

Pablo ED, de la Rosa EJ. 1995. The developing CNS a scenario for the action of proinsulin, insulin and insulin-like growth factors. Trends Neurosci 18 143-150. 

IGF-1 and -2 display identical amino acid residues at 45 positions, and exhibit in excess of 60% sequence homology. Both display A and B domains, connected by a short C domain — similar to proinsulin. However, unlike in the case of proinsulin, the IGF s C domain is not subsequently removed. The predicted tertiary structure of both IGFs closely resemble that of proinsulin. The overall amino acid homology displayed between insulin and the two IGFs is in excess of 40%. 

Chromatographic or electrophoretic analysis of conventional insulins generally yields three major fractions or bands a, b and c). Fraction a contains high molecular mass material which can be removed from the product by additional recrystallization steps. The major components of fraction b are proinsulin and insulin dimers, while insulin, as well as slightly modified forms of insulin (e.g. arginine-insulin and desamido-insulin), are found in fraction c. 

Mass production of human insulin and insulin analogs by recombinant DNA techniques is carried out by inserting the human or a modified human proinsulin gene into Escherichia coli or yeast and treating the extracted proinsulin to form the insulin or insulin analog molecules. 

Site of synthesis and secretion Enzyme that degrades insulin and its source Half-life of insulin Insulin is a polypeptide hormone produced by thep cells of the islets of Langerhans of the pancreas. Its synthesis involves two inactive precursors, preproinsulin and proinsulin, which are subsequently cleaved to form the active hormone. Insulin is stored in the cytosol in granules that are released by exocytosis Insulin is degraded by the enzyme insulinase produced primarily by the liver. Insulin has a plasma half-life of approximately six minutes. 

Insulin growth factor (IGF) and the IGF-I receptor are structurally comparable to insulin and the insulin receptor. Recombinant human IGF-I has 54% identity to proinsulin. Insulin and IGF-I can bind to both receptors, but insulin can only transfer 1% of the IGF message on the IGF receptor and IGF-I only 1% of the insulin message on the insulin receptor. 

The names and structures of the twenty natural amino acids are given in Table 1.13. The International Union of Pure and Applied Chemistry (IUPAC) uses the three-letter abbreviations shown in the second column of Table 1.13 to describe amino acids. These are widely used in biological circles as well but are inappropriate when long peptide or protein sequences need to be described. For example, when proinsulin is cleaved, it forms the biologically important peptide insulin and another peptide usually called C-peptide. The human peptide consists of a linear chain of 31 amino acids that have the sequence, from amino to carboxyl, H2N-Glu-Ala-Glu-Asp-Leu-Gln-Val-Glu-Gln-Glu-Leu-Gly-Gly-Gly-Pro-Gly-Ala-Gly-Ser-Leu-Gln-Pro-Leu-Ala-Leu-Glu-Gly-Ser-Leu-Gln-OH. This is readily comprehensible to most chemists because the abbreviations are typically the first three letters of the amino acid. Thus, alanine is Ala and arginine is Arg. Aspartic acid and asparagine cannot both be named Asp so the latter is distinguished as Asn. 

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