Insulin Degrading Enzyme inhibition, a novel therapy for type 2 diabetes?

Abstract

The Insulin Degrading Enzyme (IDE) has been identified as a type 2 diabetes and Alzheimer’s disease susceptibility gene though its physiological function remains unclear. Maianti et al. (2014) now propose that an IDE inhibitor may be a promising therapeutic strategy for type 2 diabetes.

IDE (Insulin Degrading Enzyme) is a highly conserved and widely expressed Zn²⁺ metalloprotease first identified through its action to degrade insulin. IDE also degrades a variety of substrates that share in common small size (<50 amino acids) and a pattern of charged and hydrophobic residues rather than being from a particular family of proteins (Shen et al., 2006). Interest in IDE function was prompted by genome wide-association studies that suggested linkage to IDE for both type 2 diabetes (Sladek et al., 2007) and Alzheimer’s disease (Bertram et al., 2000), although linkage to the former has not always been replicated. Whether the genetic linkage of IDE with type 2 diabetes and Alzheimer’s disease is due to loss or gain of function of IDE enzyme activity also remains unclear, though investigators in the Alzheimer’s disease field have concluded that inactivation of IDE underlies the association (Farris et al., 2004). Loss of function of IDE has also been implicated in pancreatic β-cell failure as the Ide^−/− mouse has impaired insulin secretion (Steneberg et al., 2013), and an inactivating mutation in the Ide gene is responsible for failed insulin secretion in the Goto-Kakizaki (GK) rat model of type 2 diabetes (Farris et al., 2004). Moreover, genetic analysis of type 2 diabetes susceptibility variants linked the IDE gene to impaired insulinogenic index, a diabetic trait that is a measure of insulin secretion (Dimas et al., 2014). In a recent intriguing Nature paper,Maianti et al. (2014) provide compelling evidence that acute inhibition of IDE activity may be a novel therapeutic approach to restore post-prandial hyperglycemia in type 2 diabetes (Maianti et al., 2014).

Maianti et al. performed an impressive chemical and biochemical survey in order to select an optimal small-molecule modulator of IDE. After establishing ideal arrangements of the candidate structure, the potent and selective IDE inhibitor 6bK was generated. Administration of a single dose of 6bK in non-fasted mice 30 min prior to an insulin tolerance test confirmed the physiological stability and efficiency of 6bK to inhibit IDE activity in vivo. 6bK was then evaluated in lean or high fat-fed mice, given as a single dose 30 minutes prior to a glucose challenge. Acute administration of 6bK enhanced glucose tolerance to oral glucose, notably to a greater extent in high fat-fed mice. However, 6bK induced glucose intolerance when glucose was administered by intraperitoneal (i.p.) injection. Measurement of plasma levels of the main glucose-regulating hormones in high-fat fed mice after i.p glucose delivery revealed that 6bK not only increased circulating insulin, presumably by decreasing its degradation, but also, as predicted by prior structural and in vitro studies (Shen et al., 2006), glucagon and amylin (also known as islet amyloid polypeptide [IAPP]). The latter was shown to delay gastric emptying, contributing to the enhanced glucose tolerance with 6bK. In contrast, 6bK action on glucagon signaling was shown to be responsible for the hyperglycemia that follows i.p. glucose injection. In summary, acute inhibition of IDE activity in obese mice enhanced post-prandial insulin and amylin secretion, attenuating the post-prandial glycemic excursion presumably by insulin-mediated suppression of hepatic glucose release and amylin-induced delayed gastric emptying. (Figure 1).

Figure 1. Roles of IDE in glucose homeostasis, gastric emptying and regulation of amyloidogenic protein levels based on studies with pharmacological IDE inhibition or Ide knockout mice.

IDE deficit increases the abundance and signaling of the pancreatic hormones insulin, amylin and glucagon. Increased insulin improves glucose tolerance, and increased amylin levels slow post-prandial gastric emptying. On the right is shown that IDE deficit increases levels of amylin, α-synuclein and Aβ monomers which, via subsequent formation of toxic oligomers, impair secretory function and survival of pancreatic β-cells and neurons.

There is an unmet need for enhanced post-prandial glucose control in type 2 diabetes. Therefore the authors’ proposal of an IDE inhibitory therapy, perhaps in combination with a GLP-1-based therapy since GLP-1 suppression of glucagon secretion may offset increased glucagon secretion with IDE inhibition, is an intriguing one. However, there are some important questions that would need to be addressed before serious consideration can be given to this strategy as a therapy. The findings reported by Maianti et al. draw attention to the uncertainty as to how IDE influences risk for type 2 diabetes or Alzheimer’s disease, or indeed a full understanding of its physiological role. For example, does the inhibition of IDE increase insulin levels primarily by decreasing hepatic insulin clearance of insulin, and/or by decreasing degradation of insulin in β-cells to increase insulin secretion? Of greater concern, what would be the outcome of long-term use of IDE inhibition on cell viability in tissues that express amyloidogenic peptide substrates of IDE (Kurochkin, 2001)?

Maianti and colleagues considered the potential issue of an adverse effect of IDE inhibition on one such amyloidogenic peptide. They reported that there was no measurable accumulation of 6bK or increase of amyloid β-protein (Aβ) in the brain 2 hours after injection of 6bK. The pancreas did take up 6bK however, raising concerns about the potential accumulation of misfolded insulin, amylin, α-synuclein and Aβ in β-cells. Indeed, given that IDE has an apparent substrate preference for amyloidogenic proteins (proteins with a propensity to form amyloid fibrils, but of greater concern, also membrane-permeant toxic oligomers) (Kurochkin, 2001), IDE has been proposed to play a role in defending against intracellular accumulation of these proteins, as well as cellular dysfunction and apoptosis that may follow (Figure 1). To this end, inhibition of IDE has been shown to increase β-cell vulnerability to human amylin (Bennett et al., 2003). While rodent amylin is not amyloidogenic, rodent models expressing human amylin are available, and human islets can be evaluated after transplantation into immune-tolerant mice. Likewise, it would be important to evaluate the effect of long-term 6bK delivery (more than a single dose) to mice vulnerable to neurodegenerative diseases (e.g. expressing mutant α-synuclein or Aβ). Given that the alternative pathways for clearance of amyloidogenic proteins (i.e. autophagy and ubiquitin/proteasome system) decline with aging (Koga et al., 2011), evaluating the repercussions of long-term administration of 6bK in aged mice would be necessary. Moreover, it remains critical to exclude accumulation of other amyloidogenic proteins expressed in potentially vulnerable tissues, such as atrial natriuretic peptide in cardiac muscle (Kurochkin, 2001), after repeated administrations of an IDE inhibitor.

With development of this impressive new tool, Maianti et al. have opened the opportunity for new lines of investigation to shed insight into both how IDE functions in health and its linkage to diabetes, as well as whether the postulated role of IDE as a defender against amyloidogenic protein-induced toxicity is valid.