Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones

Abstract

Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes1, 2, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene3, 4, the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide−/− mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction5, 6. IDE inhibitors that are active in vivo are therefore needed to elucidate IDE’s physiological roles and to determine its potential to serve as a target for the treatment of diabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation.

Dual Exosite-binding Inhibitors of Insulin-degrading Enzyme Challenge Its Role as the Primary Mediator of Insulin Clearance in Vivo

“…This report identifies a new series of N-terminal exosite (NTE) ligands as potent IDE inhibitors and describes the effects of these molecules both in vitro and in vivo. Our results are consistent with the main findings of Maianti et al (37) but also provide additional insight into the relative importance of IDE for insulin clearance. Furthermore, we investigate the potential of IDE inhibition on enhancing insulin sensitivity in rodents.…”

“…Maianti et al (37) report several observations from animals treated with inhibitor 6bk. Compound treatment improved glucose clearance during OGTT experiments in lean and DIO mice.…”

Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment

“…Support for this mechanism of insulin resistance is indicated in the fact that inhibition of IDE with BDM44768 resulted in impaired glucose tolerance [85]. However, others have reported that IDE deficiency actually improved glucose tolerance [108] and based on this, some researchers are now proposing the use of IDE inhibitors as an anti-diabetes agent [86]. Deprez-Poulain et al [85] reported that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness in the inhibition of IDE to treat diabetes.…”

“…Many of the diabetes studies indicate that inhibition of extracellular IDE activities may be a useful method for treating diabetes [64], [65], since extracellular IDE can interfere with normal blood glucose transport by decreasing plasma insulin levels within diabetic subjects. Although, plasma insulin levels decrease to a certain amount by increasing extracellular IDE, it is the level of cytosolic IDE synthesis, not extracellular levels, that is important for the treatment of insulin resistance in diabetic subjects.…”

“…There has been disagreement in the research community regarding the interpretation of the role of IDE in the treatment of diabetes. Based on the ability to lower plasma insulin levels, many researchers concluded that IDE inactivation or inhibition of IDE synthesis may help in the control of blood glucose metabolism [64], [65]. However, more recently, researchers have reported that IDE activity is essential to maintain normal insulin sensitivity in humans [37], [94].…”