Research in mice suggests that transiently blocking insulin-degrading enzyme (IDE) may represent a feasible approach for treating type 2 diabetes. Scientists at the Mayo Clinic and Scripps Research Institute in Florida have found that knocking out the protease, which is the primary enzyme responsible for breaking down excess insulin in the body, has beneficial effects on very young animals, but a continued lack of IDE eventually leads to the mice developing a diabetic phenotype.
While their findings suggest targeting IDE for diabetes therapy will require fine-tuning, they also help provide some answers as to why previous studies on the effects of IDE knockdown have yielded conflicting results. Lead author Malcolm A. Leissring, Ph.D., from Mayo’s department of neuroscience, and colleagues, report their research in PLoS One. Their paper is titled “Deletion of Insulin-Degrading Enzyme Elicits Antipodal, Age-Dependent Effects on Glucose and Insulin Tolerance.”
Despite IDE’s key role in insulin metabolism, little work has directly addressed the zinc metalloprotease’s role in regulating insulin and glucose homeostasis in vivo, Dr. Leissring and colleagues note. Moreover, studies that have been carried out have yielded contradictory results. Early work supported the expectation that IDE inhibition would increase the half-life of circulating insulin, an effect that could be beneficial for the treatment of diabetes. More recent research in two different animal models, however, suggested that blocking IDE activity can induce a diabetic phenotype.
To try and provide answers to this conundrum, the researchers further investigated the effects of IDE inhibition on insulin and glucose homeostasis longitudinally during the first six months of life. Both IDE-knockout animals and their wild-type littermates were monitored repeatedly at two, four, and six months of age to determine multiple diabetes-related parameters.
As expected, fasting serum insulin levels in the IDE-knockout mice were about threefold higher than those in wild-type controls at all ages. However, just about every other effect of IDE deficiency varied dependent on the animals’ age. Compared with their wild-type littermates, basal glucose levels in the knockout mice were significantly lower at two months of age, were unchanged at four months of age, and significantly increased at six months. Body mass also followed this trend: two-month-old IDE knockouts were significantly lighter than their age-matched normal littermates, while six-month-old knockouts were significantly heavier than age-matched wild-type animals.
In fact, at six months of age, IDE-knockouts exhibited profound glucose intolerance, whereas at two months of age these animals not only lacked glucose intolerance, but actually exhibited modest, but statistically significant improvements in glucose removal compared with the age-matched wild-type mice, the authors report. Consistent with a transition from glucose tolerance to intolerance over time, at four months old the knockout animals displayed an intermediate phenotype. The same trend held true for insulin tolerance: IDE-knockouts demonstrated significant insulin intolerance at six months of age, largely normal tolerance at four months of age, and statistically significant improvements in insulin tolerance at two months, relative to the wild-type mice.
On the basis of these results, the researchers hypothesized that the diabetic phenotype in older IDE-deficient mice may represent a compensatory response to chronically elevated circulating insulin levels. When they looked at the numbers of insulin receptors in the IDE-knockout and wild-type animals, they found that at two months of age both animal cohorts had comparable insulin receptor levels in all tissues. However, by six months of age the IDE-knockout animals showed significantly lower levels of insulin receptors in all examined tissues including muscle, adipose tissue, and liver. Adipocytes from the IDE-deficient mice showed substantial impairments in insulin-stimulated glucose uptake.
“Taken together, these findings have significant implications for both the etiology and the potential treatment of diabetes, and corroborate several studies suggesting that insulin resistance can arise as a secondary consequence of primary persistant hyperinsulinemia,” the researchers state.
However, they stress, although the new findings appear to offer “a neat explanation” for the development of a diabetic phenotype in IDE-knockout animals, much more study will be needed before firm conclusions can be drawn. At present it’s not possible to exclude the possibility that deletion of IDE triggers changes in other insulin-signaling components that in turn elicit the compensatory hyperinsulinemia.
Nevertheless, the team writes, “from a therapeutic perspective, our results support the idea that pharmacologic inhibition of IDE, properly implemented, may represent a viable—even attractive—therapeutic approach to the treatment of diabetes." Such a treatment could take the form of a short-acting, partial inhibitors of IDE that would exert similar effects to those of sulfonylureas or other secretagogues in terms of absolute levels of circulating insulin, while still maintaining a normal cycle of secretion. In theory such IDE inhibitors might have advantages over secretagogues, as they would not affect pancreatic function itself, just how much insulin is allowed to remain in the system. Moreover, because hyperinsulinemia takes time to develop following prolonged IDE inhibition, such drugs would hopefully have minimal overdose-related risks. “This compared favorably with many other anti-diabetic medications that can be harmful or even lethal if taken in excess,” the authors stress.
Dr. Leissring’s team has previously developed a first generation of peptide hydroxamate IDE inhibitors, and is currently working to generate improved versions that would be stable enough to test in animal models.