Combined treatment with a dipeptidyl peptidase-IV inhibitor (sitagliptin) and an angiotensin II type 1 receptor blocker (losartan) promotes islet regeneration via enhanced differentiation of pancreatic progenitor cells.

AIM

The existence of pancreatic progenitor cells (PPCs) with differentiation capacity in the adult pancreas has rendered that promotion of islet regeneration is feasible. The dipeptidyl peptidase-IV inhibitor sitagliptin and the angiotensin II type 1 receptor (AT(1) receptor) blocker losartan have a common target action in the pancreata. Thus, we evaluated the synergistic/additive effects of these two drugs on the differentiation of islet progenitors.

METHODS

The acute and chronic effects of sitagliptin and losartan, individually or in combination, on islet regeneration in vivo were investigated by using a streptozotocin-induced type 1 diabetes mouse model. Their effects were also examined on an in vitro PPCs model derived from human foetal pancreas.

RESULTS

A chronic combination treatment enhanced glucose tolerance in diabetic mice associated with an increased ratio of β cells to islet; an acute combination treatment resulted in a marked increase in the production of neurogenin 3 (NGN3(+)) cells in proximity to CK7(+) ductal cell and an increased presence of insulin(+) /CK7(+) cells. The in vitro study revealed that a combination treatment significantly enhanced mRNA expression of NGN3, NKX6.1 and PDX-1 during PPCs differentiation into human islet-like cell clusters (ICCs). Despite no apparent changes in insulin release, the combined treatment resulted in increasing production of peroxisome proliferator-activated receptor γ (PPARγ) during PPC differentiation.

CONCLUSIONS

These data indicate that combined sitagliptin-losartan treatment can improve islet function by promoting the differentiation of PPCs into ICCs, perhaps via a mechanism involving PPARγ production, and could thereby, contribute to islet regeneration.