Dipeptidyl Peptidase IV Inhibitor MK-0626 Attenuates Pancreatic Islet Injury in Tacrolimus-Induced Diabetic RatsReport as inadecuate




Dipeptidyl Peptidase IV Inhibitor MK-0626 Attenuates Pancreatic Islet Injury in Tacrolimus-Induced Diabetic Rats - Download this document for free, or read online. Document in PDF available to download.

Background

Tacrolimus TAC-induced pancreatic islet injury is one of the important causes of new-onset diabetes in transplant recipients. This study was performed to evaluate whether a dipeptidyl peptidase IV DPP IV inhibitor is effective in improving TAC-induced diabetes mellitus by reducing pancreatic islet injury.

Methods

Rats were treated with TAC 1.5 mg-kg, subcutaneously and the DPP IV inhibitor MK-0626 10 or 20 mg-kg, oral gavage for 4 weeks. The effect of MK-0626 on TAC-induced diabetes was evaluated by assessing pancreatic islet function, histopathology. TAC-induced incretin dysfunction was also examined based on active glucagon-like peptide-1 GLP-1 levels in the serum after glucose loading. The protective effect of MK-0626 was evaluated by measuring markers of oxidative stress, oxidative resistance, and apoptosis. To determine whether enhanced GLP-1 signaling is associated with these protective effects, we measured the expression of the GLP-1 receptor GLP-1R and the effect of the GLP-1 analog exendin-4 on cell viability and oxidative stress in isolated islets.

Results

MK-0626 treatment attenuated TAC-induced pancreatic islet dysfunction and islet morphology. TAC treatment led to a defect in active GLP-1 secretion; however, MK-0626 reversed these effects. TAC treatment increased the level of 8-hydroxy-2′-deoxyguanosine 8-OHdG, the number of apoptotic death, and the level of active caspase-3, and decreased the level of manganese superoxide dismutase and heme oxygenase-1; MK-0626 treatment reversed these changes. MK-0626 treatment restored the expression of GLP-1R, and direct administration of exendin-4 to isolated islets reduced TAC-induced cell death and 8-OHdG expression.

Conclusions

The DPP IV inhibitor MK-0626wasan effective antidiabetic agent that exerted antioxidative and antiapoptotic effects via enhanced GLP-1 signaling in TAC-induced diabetics.



Author: Long Jin , Sun Woo Lim , Kyoung Chan Doh, Shang Guo Piao, Jian Jin, Seong Beom Heo, Byung Ha Chung, Chul Woo Yang

Source: http://plos.srce.hr/



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