Glucagon-like peptide 1 (GLP-1) has been shown to play important roles in maintaining beta-cell functions, such as insulin secretion and proliferation. While expression levels of GLP-1 receptor (Glp1r) are compromised in the islets of diabetic rodents, it remains unclear when and to what degree Glp1r mRNA levels are decreased during the progression of diabetes. In this study, we performed real-time PCR with the islets of db/db diabetic mice at different ages, and found that the expression levels of Glp1r were comparable to those of the islets of nondiabetic db/misty controls at the age of four weeks, and were significantly decreased at the age of eight and 12 weeks. To investigate whether restored expression of Glp1r affects the diabetic phenotypes, we generated the transgenic mouse model Pdx1(PB)-CreER (TM); CAG-CAT-Glp1r (beta Glp1r) that allows for induction of Glp1r expression specifically in 13 cells. Whereas the expression of exogenous Glp1r had no measurable effect on glucose tolerance in nondiabetic beta Glp1r;db/misty mice, beta Glp1r;db/db mice exhibited higher glucose and lower insulin levels in blood on glucose challenge test than control db/db littermates. In contrast, four weeks of treatment with exendin-4 improved the glucose profiles and increased serum insulin levels in beta Glp1r;db/db mice, to significantly higher levels than those in control db/db mice. These differential effects of exogenous Glp1r in nondiabetic and diabetic mice suggest that downregulation of Glp1r might be required to slow the progression of D-cell failure under diabetic conditions. (C) 2016 Elsevier Inc. All rights reserved.