Therefore, these preparations are used to maintain basal insulin levels (i.e.

Insulin complexed to zinc ions dissociates only slowly into insulin monomers. **Two changes have been made.Ĭitation: Endocrine-Related Cancer 19, 5 10.1530/ERC-12-0026 For insulin detemir, threonine at position 30 of the B-chain is removed and a 14-carbon fatty acid chain is added to position 29 of the B-chain. For insulin glargine, aspartic acid at position 21 in the A-chain had been replaced for glycine and the B-chain contains two extra amino acids (two arginines) at positions 31 and 32. For insulin glulisine, the asparagine at position 3 and lysine at position 29 in the B-chain are replaced by lysine and glutamic acid. For insulin aspart, the proline at position 28 in the B-chain is replaced by aspartic acid. For insulin lispro, proline at the position 28 and lysine at position 29 in the B-chain of human insulin are interchanged. Modifications made on the insulin backbone to produce short-acting insulin analogues are indicated in black, modifications made to produce long-acting insulin analogues are indicated in grey.

There are six cysteines, and so three disulphide bridges are formed: two between the A- and B-chains (between A7 and B7, and A20 and B19), and one within the A-chain (A6 and A11). These form between thiol groups (-SH) on cysteine residues. The three-dimensional structure of insulin is further stabilised by disulphide bridges. At one end of each chain (the N terminal end) is an amino group, and at the other end (the C terminal end) is a carboxylic acid group. The primary structure of human insulin is formed by 21 amino acids in the A-chain and 30 amino acids in the B-chain. Human insulin is a peptide hormone composed of 51 amino acids and has a molecular weight of 5808 Da. Monomers are the biologically active forms that bind to the insulin receptor (IR). This process provides efficient spatial storage within the beta-cell vesicles, but dilution upon exocytosis ensures immediate dissociation into dimers (association of two insulin molecules) and finally into monomers. An adaptation of beta-cell insulin production is the self-association of insulin molecules, at high concentrations, in conjunction with zinc ions into hexamers ( Emdin et al. In the body, insulin exists as monomers, dimers and as hexamers (consisting of six monomers which self-associate in conjunction with zinc ions).

The human insulin molecule is secreted by the pancreas and consists of two polypeptide chains A and B that are linked by two disulphide bridges ( Fig. These methods have permitted the production of limitless quantities of human insulin for therapeutic use. In the late-80s of the past century, methods were developed that allowed insulin to be made in the laboratory. It has saved the lives of many who would otherwise have died, but its unforeseen effect was to transform an acute, rapidly fatal illness into a chronic disease with serious long-term complications ( Tattersall 2003). The discovery of insulin by Banting and Best in 1922 represented a milestone in clinical medicine. The introduction of insulin analogues in the treatment of diabetes More detailed information is required to elucidate the exact mechanisms as to how insulin analogues may activate the IR and IGF1R and how this activation may be linked to mitogenesis. In addition, recent data suggest that insulin (or insulin analogues)-mediated stimulation of IRs may play a key role in the progression of human cancer. At present, there are several uncertainties which make it very difficult to answer this question decisively. Although it has been suggested that especially insulin analogues with an increased affinity for the IGF1R (such as insulin glargine) are more mitogenic when tested in vitro in cells expressing a high proportion of IGF1R, the question remains whether this has any clinical consequences. In vitro, all at present commercially available insulin analogues have lower affinities for the insulin receptor (IR). This hypothesis has been evaluated extensively in vitro and also in vivo by using animal models. In view of the lifelong exposure and large patient populations involved, insulin analogues with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogues may possibly induce the growth of pre-existing neoplasms. As a consequence, insulin analogues may theoretically have an increased mitogenic action compared to human insulin.

However, structural modification of the insulin molecule may result in altered binding affinities and activities to the IGF1 receptor (IGF1R). Insulin analogues have been developed in an attempt to achieve a more physiological replacement of insulin and thereby a better glycaemic control.

Analog insulin