Abstract
The dipeptidyl peptidase-4 inhibitor linagliptin promotes β-cell survival and insulin secretion by prolonging endogenous glucagon-like peptide 1 (GLP-1) action and therefore helps to maintain normoglycemia in diabetic patients. The effect of linagliptin on glucagon-producing α cells, however, was not clear. In this study, we investigated whether linagliptin had any effects on α cells with regard to their proliferation and hormonal production using type 1 diabetes mouse models, including streptozotocin-induced and nonobese diabetes mice. After diabetes development, the mice were either untreated or treated with linagliptin or insulin for up to 6 weeks. Our results showed that linagliptin significantly increased circulating GLP-1 levels in both type 1 diabetes models, but therapeutic benefit was detected in nonobese diabetes mice only. Circulating C-peptide and glucagon levels (nonfasting) were not significantly altered by linagliptin treatment in either model. In addition, we found that linagliptin did not increase α-cell proliferation compared with the untreated or insulin-treated controls as assessed by in vivo 5-bromo-2'-deoxyuridine labeling assay. Finally, we examined whether linagliptin treatment altered GLP-1 vs glucagon expression in pancreatic α cells. Immunohistochemistry assays showed that linagliptin treatment resulted in detection of GLP-1 in more α cells than in control groups, suggesting linagliptin was able to increase intraislet GLP-1 presence, presumably by inhibiting GLP-1 degradation. In summary, this study indicates that linagliptin would not confer adverse effect on α cells, such as causing α cell hyperplasia, and instead may facilitate a blood glucose-lowering effect by increasing GLP-1 presence in α cells.