The insulin molecule

Insulin was first identified as an anti-diabetic factor in 1921, and was introduced clinically the following year. Its complete amino acid sequence was determined in 1951. Although mature insulin is a dimeric structure, it is synthesized as a single polypeptide precursor, i.e. preproinsulin. This 108 amino acid polypeptide contains a 23 amino acid signal sequence at its amino terminal end. This guides it through the endoplasmic reticulum membrane, where the signal sequence is removed by a specific peptidase.

Proinsulin-containing vesicles bud off from the endoplasmic reticulum and fuse with the golgi apparatus. Subsequently, proinsulin-containing vesicles (clathrin-coated secretory vesicles), in turn, bud off from the golgi. As they move away from the golgi, they lose their clathrin coat, becoming non-coated secretory vesicles. These vesicles serve as a storage form of insulin in the P-cell. Elevated levels of blood glucose, or other appropriate signals, cause the vesicles to fuse with the plasma membrane, thereby releasing their contents into the blood via the process of exocytosis.

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.

Mature insulin consists of two polypeptide chains connected by two interchain disulfide linkages. The A-chain contains 21 amino acids, whereas the larger B-chain is composed of 30 residues. Insulins from various species conform to this basic structure, while varying slightly in their amino acid sequence. Porcine insulin (5777 Da) varies from the human form (5807 Da) by a single amino acid, whereas bovine insulin (5733 Da) differs by three residues.

C-peptide (34 residues)

C-peptide (34 residues)

Proteolysis

Figure 11.1 Proteolytic processing of proinsulin, yielding mature insulin, as occurs within the coated secretory granules

Figure 11.1 Proteolytic processing of proinsulin, yielding mature insulin, as occurs within the coated secretory granules

Although a high degree of homology is evident between insulins from various species, the same is not true for proinsulins, as the C peptide sequence can vary considerably. This has therapeutic implications, as the presence of proinsulin in animal-derived insulin preparations can potentially elicit an immune response in humans.

Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

Get My Free Ebook


Post a comment