Insulin-degrading enzyme: is it suitable for diabetes treatment?

This article refers to:

Modulation of insulin degrading enzyme activity and liver cell proliferation

Insulin-degrading enzyme (IDE) or insulysin or insulinase was discovered by Tomizawa and Halsey¹ by its ability to degrade insulin. Today it is known that IDE is a zinc-dependent metalloproteinase, with a molecular weight of some 110 kDa, making it one of the large metalloproteinases. Several studies showed that the enzyme is present in cells in a dimeric form. It is highly conserved and even the E. coli protease III shows 27% identity and some 50% homology.² IDE is widely distributed in mammalian tissues and largely cytosolic, whereas it has also a peroxisomal target sequence and is present also in peroxisomes.

It is assumed that IDE is the principal protease responsible for the degradation and, therefore, also the inactivation of insulin. This raises the question of the substrate specificity of the enzyme. On the one hand it is known, that IDE is able to degrade a number of polypeptides, making it have a wide substrate specificity. To the substrates of IDE are counted today besides insulin also amylin, calcitonin, atrial natriuretic peptide, glucagon and others. On the other hand peptides of the same molecular weight range, as glucagon-like peptide 1, somatostatin or bradykinin are not substrates of the enzyme. This would lead to the conclusion that the catalytical chamber size, which fits peptides up to 70 amino acids, is not the only substrate-selectivity criteria. Interestingly, most – if not all – of the IDE substrates are in the one or other way amyloidogenic. All substrates are peptides with a range up to 7 or 8 kDa, except single reports on a role of IDE in the degradation of oxidized proteins, perhaps within peroxisomes.³ However, this line of research was not followed, since the general opinion overtook that the proteasomal system is responsible for the degradation of oxidized proteins.⁴ However, the earlier results of IDE playing a role in the degradation of oxidized proteins might be hampered by the fact that IDE seems to have a role in proteasomal activation.⁵ So, it seems agreeable that IDE is primarily involved in the degradation of small proteins or amyloid-forming polypeptides. This is also underlined by the fact that IDE knock out animals have a high level of amyloid-β peptide and are hyperinsulinaemic and obtain a glucose intolerance.

Therefore, it seems to be reasonable clear that IDE is the principal peptidase responsible for insulin degradation and processing in cells. However, the real importance for this in vivo is still not well described.

Due to the insulin-degrading function of IDE it is reasonable to use inhibitors of IDE for the stabilization of the insulin levels as a therapeutic option in treating type-2-diabetes. But, nevertheless, it should be remarked that also function of IDE in development and differentiation were described, perhaps via the activation of the proteasome. So, side effects can be expected. Pivovarova and coauthors describe here an effect of IDE knock-down or the low IDE levels in type-2 diabetics liver samples. Both models were accompanied by disturbances in the p53 pathway, which might affect tumorigenesis in the liver.⁶ Whether this is a direct effect of IDE or mediated by changes in the proteasome-ubiquitin system is not clear. Certainly the effects of inhibition of IDE have to be carefully investigated – not only in liver, but also in other tissues, as brain and pancreatic islands – in order to make this a suitable future strategy of type 2 diabetes treatment.