Novel insulin analogues and its mitogenic potential

Abstract

Insulin analogues were developed to modify the structure of the human insulin molecule in order to more accurately approximate the endogenous secretion of insulin. With the help of recombinant technology and site-directed mutagenesis, the insulin molecule can be modified to either delay or shorten absorption time, providing better insulin treatment options and facilitating the achievement of glycaemic goals. Changing the structure of the insulin molecule, however, may significantly alter both its metabolic and mitogenic activity. Multiple factors such as residence time on the receptor, dissociation rate, rate of receptor internalization and the degree of phosphorylation of signalling proteins can affect the mitogenic potencies of insulin analogues. Changes in the structure of the insulin have raised concern about the safety of the insulin analogues. For example, questions have emerged about the relationship between the use of insulin lispro and insulin glargine and the progression of diabetic retinopathy. Two studies have shown progression of retinopathy with the use of insulin lispro. However, others have not confirmed these results, and causality could not be proven as progression of retinopathy can occur with rapid improvement in glycaemic control, and methods of assessments among studies were not consistent. Therefore, we examine the metabolic and mitogenic characteristics of the three insulin analogues, insulin lispro, insulin aspart and insulin glargine, that are currently on the market, as well as the two insulin analogues, insulin glulisine and insulin detemir, that are soon going to be available for clinical use.

Does diabetes therapy influence the risk of cancer?

“…Curiously, this fact is not mentioned in the original report [44], which concludes with the statement that insulin glargine has a safety profile that, apart from reduced nocturnal hypoglycaemia, is 'otherwise similar to NPH insulin'. Equally curious, a later review also cites the same paper as documenting a three step or greater retinopathy progression in 7.5% of those on insulin glargine vs 2.7% of those on NPH (p<0.05) [45]. Since IGF-1 has a role in normal retinal vascular function and disease [46], this observation raised the possibility that insulin glargine might also have mitogenic effects on the vascular endothelium.…”

Obesity, type 2 diabetes, and cancer: the insulin and IGF connection

“…In order to create the insulin analogs, human insulin has been modified to more accurately mimic the endogenous secretion of insulin. Altering the structure of the insulin molecule can alter and enhance its mitogenic activity (Zib & Raskin 2006). The potential for increased cancer risk in patients treated with insulin analogs became a cause of alarm after a German study showed a dose-dependent increase in cancer risk in patients treated with one such analog, insulin glargine, compared with human insulin (Hemkens et al 2009).…”

Insulin treatment in pregnancy

“…A significant concern regarding the use of the long-acting insulin analogs, has been the mitogenic potential of these analogues [Weinstein et al, 2007;Zib and Raskin, 2006]. Long-term clinical studies are needed to evaluate the use of insulin glargine or insulin detemir in pregnancy, both of which are currently classified Category C.…”