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Several studies have suggested that diabetes is associated with defective insulin degrading enzyme (IDE) production and stimulation of IDE may improve blood sugar control. PNC has proven that Cyclo-Z (also known as Glucometa) is a potent stimulator of IDE synthesis. We have examined anti-diabetic activities of Cyclo-Z in five different animal models: 1) Streptozotocin-induced diabetic rats (Type 1 model); 2) ob/ob mice (Type 2 diabetes with obesity); 3) Goto-Kakizaki (G-K) rats (Type 2 diabetes without obesity); 4) aging Sprague-Dawley rats (naturally induced human insulin resistance-like or mild-Type 2 diabetes) and 5) high carbohydrate fed mice (over eating induced diabetes). 

Our colleagues at the VA Greater Los Angeles Healthcare System demonstrated that Cydo-Z treatment increased IDE synthesis in human Amyloid protein transgenic mice and stimulated degradation of Amyloid b protein and insulin. A 3 month pilot study of human subjects who used Pro-Z which contains various zinc metabolism stimulating agents showed significantly improved oral glucose tolerance test (OG1T) (measurement of insulin sensitivity) and decreased Hemoglobin A1c levels (measurement of average blood glucose concentration during the last three months).  Urine glucose levels (indication of improved blood glucose control) were significantly decreased, while fasting blood glucose insignificantly decreased. In our formal FDA standard phase 1 clinical trial, acute high dose of Cydo-Z before breakfast in 12 healthy subjects significantly reduced blood glucose levels at 8 hours even after breakfast and lunch. In a pilot efficacy study, postprandial blood glucose levels, Hemoglobin A1c levels, and insulin requirement significantly decreased in 17 out of 18 diabetic subjects during 6 months. However, the physician noted that the remaining subject showed signs of improvement after more than 7 months of treatment. Some subjects stopped insulin injections completely after the 6 month treatment period. 

Blood Glucose Control
IDE, a zinc enzyme, plays a major role in the degradation of internalized insulin, which is needed to maintain insulin sensitivity. If endosomal IDE levels are inadequate, un-degraded insulin will remain in the cytosol and interfere with insulin signal transduction to translocation glucose transporter-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 un-degraded insulin in the cells. Genetically type 2 diabetic GatoKakizaki (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 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 (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.

Background Studies
Specifically, our background studies with animal models indicate that the optimal dose of Cyclo-Z for the improvement of three hour Average above Fasting blood Glucose Concentration (TAFGC)=accurate measurement of OGTT is 0.5 mg CHP plus 10 mg zinc/kg BW for acute treatment. The optimal daily dose for blood glucose lowering rate for 2 weeks is 0.5 mg CHP plus 10 mg zinc/l in the drinking water for genetically diabetic G-K rats, which is equivalent to 0.1 mg CHP plus 2 mg zinc/Kg BW/day based on the calculation of the known amount of CHP and zinc containing water intake per day. Blood glucose levels also significantly decreased in obese ob/ob mice with the same dose (0.1 mg CHP plus 2 mg zinc /kg BW/day). Therefore, Cyclo-Z dose for the treatment of diabetes must be carefully monitored depending on the need of diabetes treatment. When insulin resistant aged S-D rats were given acute bolus of 1.0 mg CHP plus 10 mg zinc/kg BW, improved TAFGC was maintained at least one week, while the improvement of TAFGC was lost within 24 hours in G-K rats. These data suggest that the blood glucose lowering effect of Cyclo-Z treatment may be more effective and better maintained in obesity induced diabetic subjects. These pre-clinical studies with various animal models and human studies suggest that Cyclo-Z may be a very effective diabetes treatment agent.

Glucometa (also known as Cyclo-Z) contains Cyclo (his-pro) plus zinc and has demonstrated to be significantly effective in the prevention and natural treatment of diabetes. While Pro-Z contains a lesser amount of Cyclo (his-pro), it contains other components that influence zinc metabolism and diabetes.