Type IIB PKA is highly expressed in β cells and controls cell proliferation via regulating Cyclin D1 expression

β cell number is maintained mainly by cell proliferation and cell apoptosis. Protein kinase A (PKA) pathway is an important intracellular signalling-mediating β cell proliferation. However, the precise roles of PKA isoforms are not well-defined. We found that the RIIB subunit of PKA is expressed specifically by β cells of mouse and human islets. Sixty percent pancreatectomy caused increased β cell proliferation. Deletion of type IIB PKA by disruption of RIIB expression further promoted β cell proliferation, leading to enhanced β cell mass expansion. RIIB KO mice also showed increased insulin levels and improved glucose tolerance. Mechanistically, activation of type IIB PKA decreased Cyclin D1 levels and inhibition of RIIB expression increased Cyclin D1 levels. Consistently, activation of type IIB PKA inhibited cell cycle entry. These results suggest that type IIB PKA plays a pivotal role in β cell proliferation via regulating Cyclin D1 expression.