Dipeptidyl peptidase IV inhibitor MK-0626 attenuates pancreatic islet injury in tacrolimus-induced diabetic rats.

Abstract

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-0626 was an effective antidiabetic agent that exerted antioxidative and antiapoptotic effects via enhanced GLP-1 signaling in TAC-induced diabetics.

• Authors: Long Jin, Sun Woo Lim, Kyoung Chan Doh, Shang Guo Piao, Jian Jin, Seong Beom Heo, Byung Ha Chung, Chul Woo Yang
• Journal: PloS one (PLoS One) Vol. 9 Issue 6 Pg. e100798 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24959755 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dipeptidyl-Peptidase IV Inhibitors
• Protective Agents
• 8-Hydroxy-2'-Deoxyguanosine
• Deoxyguanosine
• Tacrolimus

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Animals
• DNA Damage (drug effects)
• Deoxyguanosine (analogs & derivatives, blood, urine)
• Diabetes Mellitus, Experimental
• Dipeptidyl-Peptidase IV Inhibitors (pharmacology)
• Islets of Langerhans (drug effects, pathology)
• Male
• Protective Agents (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Tacrolimus (adverse effects)