Blood Glucose Control: Insulin degrading enzyme (IDE), a zinc enzyme, plays a major role in the degradation of internalized insulin, which is necessary for maintaining insulin sensitivity. If endosomal IDE levels are inadequate, undegraded insulin will remain in the cytosol and interferes with insulin signal transduction to translocate glucose transporter-4 (GLUT-4) to the cell membrane for glucose uptake. Diabetic animals and humans are zinc deficient due to impaired intestinal zinc absorption and hyperzincuria. This zinc deficiency is likely to contribute to insulin resistance by decreasing IDE synthesis and thereby accumulating undegraded insulin in the cells. Genetically type 2 diabetic Goto-Kakizaki (G-K) rats are defective in IDE gene expression. Polymorphism in the IDE gene is also associated with type 2 diabetes in Europeans and in Asians. Insulin downstream targeting of insulin receptor signaling in the brain is associated with IDE function. Cyclo (his-pro) (CHP) plus zinc (Cyclo-Z) enhanced IDE synthesis in brain tissues and stimulated insulin degradation. It has been proven that Cyclo-Z significantly stimulated intestinal zinc absorption and muscles tissue zinc uptake in rats and glucose uptake in isolated muscle tissue. CHP or zinc alone is somewhat effective, but Cyclo-Z treatment significantly reduced blood glucose levels and improved oral glucose tolerance (OGT) while reducing plasma insulin levels in a CHP concentration dependent manner in genetically IDE–deficient diabetic G-K rats, in insulin resistant aged obese Sprague-Dawley rats, and in obese diabetic ob/ob mice. These available literatures and our preliminary data suggest a strong potentiality that Cyclo-Z ameliorates insulin resistant humans mainly by stimulating IDE synthesis.

Body Weight Control: Cyclo-Z treatment also significantly decreased body weight (BW) or BW gain in obese and overweight animals while decreasing plasma leptin levels. Although obese subjects generally develop hyperinsulinemia (pre-diabetic), only 22% of diabetic subjects are not directly associated with Body Mass Index. Thus, obese diabetic subjects are also expected to benefit from the Cyclo-Z treatment as evidenced in the animal study. IDE deficiency causes hyperinsulinemia and hyperinsulinemia is one of the major causes of obesity, since insulin increases fat accumulation in adipocytes. Hyperinsulinemia in obesity is caused mainly by decreased insulin clearance in the plasma. Impaired internalized insulin digestion induces accumulation of inactive insulin fragments in the cells, which is associated with significant impairment of insulin receptor signal transduction mechanisms, resulting in insulin resistant, hyperinsulinemia, and obesity. Monocyte insulin levels from obese patients were more than four fold higher compared to cells from normal subjects. Similarly, plasma insulin levels in obese subjects are about 69% higher than in normal subjects. The impaired insulin clearance in obese humans and the contrasting increase in insulin clearance with weight loss has been demonstrated. The decreased insulin clearance in obese subjects is mainly due to the elevated free fatty acids which inhibit insulin degrading enzyme (IDE) synthesis. Therefore, it appears that one of the plausible methods to treat obesity may be to reduce plasma and cellular insulin levels by stimulating IDE synthesis.

Alzheimer’s disease (AD): Amyloid beta protein accumulation in the brain is the main cause of AD. Although several kinds of mutations in the Amyloid protein precursor (APP) gene and apoE genes have been identified to be the cause of AD development, the majority of AD incidence is induced by age-related undefined cause, which is mostly related to the metabolic diseases. Numerous epidemiological studies suggest that type 2 diabetes characterized as glucose intolerance, obesity, and hyperinsulinemia is associated with a 2- to 6 -fold increased risk for AD. There is some evidence that insulin itself may significantly accelerate APP/Aβ trafficking from the trans-Golgi network to plasma membrane for Aβ generation. However, the most important approach in understanding the mechanisms of AD induction is to establish the relationship of IDE with Aβ, which is now intensely studied by many researchers from the evidence that IDE activity in the brain is negatively correlated with Aβ content and that IDE expression is decreased in the AD brain. There is now general consensus that insulin may provoke amyloid accumulation by limiting Aβ degradation via direct competition for IDE which is the only enzyme that degrades both insulin and Aβ.