GLP-1 RA treatment improves the secretory function and proliferation of pancreatic β-cells with ABCC8 dysfunction

Abstract

Abstract Purpose: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are used to treat type 2 diabetes, but whether GLP-1 RAs have therapeutic effects on diabetes associated with ABCC8dysfunction remains elusive. Methods: We created pancreatic MIN6 cells that overexpressed wild-type and mutant ABCC8. We assessed their proliferation using MTT and measured insulin and C-peptide secretion through ELISA. Additionally, we studied the proliferation and insulin/C-peptide secretion of pancreatic β-cells in mice with adeno-associated virus (AAV) carrying wild-type and mutant Abcc8. Furthermore, we investigated the impact of a GLP-1 RA (liraglutide) on the proliferation and secretory function of MIN6 cells and pancreatic β-cells in T1DM mice expressing mutant ABCC8 using ELISA and immunofluorescence. Results: We found that MIN6 cells that overexpress wild-type ABCC8 secrete more insulin and C-peptide than control cells, while MIN6 cells expressing mutant ABCC8 secrete lower levels of insulin and C-peptide than control cells. In the fasting T1DM mice, overexpression of wild-type ABCC8 accelerated glucose consumption, repressed glucagon level, and elevated insulin and C-peptide secretion. By contrast, overexpression of mutant ABCC8 slightly impaired insulin and C-peptide secretion in MIN6 cells and reduced expression of insulin in the pancreatic β-cells of T1DM mice. In addition, we observed that treatment of MIN6 cells and T1DM mice that overexpress mutant ABCC8 with liraglutide can substantially stimulate the proliferation and secretory function of the affected pancreatic β-cells. Conclusion: GLP-1 RA is a promising therapeutic option for the treatment of diabetes caused by ABCC8 dysfunction.