Combination of DPP-4 inhibitor and PPARγ agonist exerts protective effects on pancreatic β-cells in diabetic db/db mice through the augmentation of IRS-2 expression.

We investigated the effects of long- and short-term treatment with pioglitazone (Pio) and/or alogliptin (Alo) on β-cells in diabetic db/db mice. Six-week-old male db/db mice received Pio (25 mg/kg, oral) and/or Alo (30 mg/kg, oral) for 4 weeks and for 2 days. Blood glucose levels were decreased after 4-week intervention, but not after 2-day intervention. Pio increased adiponectin levels, and Alo decreased glucagon levels and increased active GlP-1 levels. Insulin sensitivity was restored by Pio. After 4-week treatment, β-cell mass was increased (over 2-fold increase) and expression levels of various β-cell-related factors were restored. Expression levels of IRS-2 and various downstream factors were up-regulated by Pio and Alo after 2-day and 4-week intervention. In addition, mRNA and protein levels of IRS-2 and various downstream factors were up-regulated in MIN6 cells after 24-h exposure to Pio and exendin-4. These results suggest that Pio and Alo additively up-regulate IRS-2 expression independently of the alteration of glycemic control. Taken together, combination of Pio and Alo exerts protective effects on β-cells in diabetic db/db mice, at least in part, through the augmentation of IRS-2 expression.