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.
© 2012 Blackwell Publishing Ltd.