Abstract: Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a beneficial class of antidiabetic
drugs. However, a major debate about the risk of developing pancreatitis is still existing. The aim
of the work was to study the histological and immunohistochemical eects of sitagliptin on both
endocrine and exocrine pancreases in a rat model of type 2 diabetes mellitus and to correlate
these eects with the biochemical findings. Moreover, a possible synergistic eect of sitagliptin,
in combination with metformin, was also evaluated. Fifty adult male rats were used and assigned
into five equal groups. Group 1 served as control. Group 2 comprised of untreated diabetic rats.
Group 3 diabetic rats received sitagliptin. Group 4 diabetic rats received metformin. Group 5 diabetic
rats received both combined. Treatments were given for 4 weeks after the induction of diabetes.
Blood samples were collected for biochemical assay before the sacrification of rats. Pancreases were
removed, weighed, and were processed for histological and immunohistochemical examination. In the
untreated diabetic group, the islets appeared shrunken with disturbed architecture and abnormal
immunohistochemical reactions for insulin, caspase-3, and inducible nitric oxide synthase (iNOS).
The biochemical findings were also disturbed. Morphometrically, there was a significant decrease in
the islet size and islet number. Treatment with sitagliptin, metformin, and their combination showed
an improvement, with the best response in the combined approach. No evidence of pancreatic injury
was identified in the sitagliptin-treated groups. In conclusion, sitagliptin had a cytoprotective eect
on beta-cell damage. Furthermore, the data didn’t indicate any detrimental eects of sitagliptin on
the exocrine pancreas.