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

Abstract

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.

Control of human pancreatic beta cell kinome by glucagon‐like peptide‐1 receptor biased agonism

“…The mitogen‐activated protein kinase (MAPK) signalling pathway was highlighted as the most enriched pathway for both PTK and STK analyses, in agreement with previous reports linking MAPK family activities to pancreatic beta cell function 27 . For instance, PKA‐activated MAPKs play a crucial role in accelerating the cell cycle, which is associated with maintenance of beta cell mass 28 . According to the Venn diagram analysis of the kinases implicated (Figure 3C,D), there are 13 Tyr kinases and 15 Ser/Thr kinases common to all our top selected KEGG pathways.…”

“…27 For instance, PKA-activated MAPKs play a crucial role in accelerating the cell cycle, which is associated with maintenance of beta cell mass. 28…”

Control of human pancreatic beta cell kinome by GLP-1R biased agonism

“…The MAPK signalling pathway was highlighted as the most enriched pathway for both PTK and STK analyses, in agreement with previous reports linking MAPK family activities to pancreatic beta cell function (27). For instance, PKA-activated MAPKs play a crucial role in accelerating the cell cycle, which is associated with maintenance of beta cell mass (28). According to the Venn diagram analysis of the kinases implicated (Figure 3C, D), there are 13 Tyr kinases and 15 Ser/Thr kinases common to all our top selected KEGG pathways.…”

Empagliflozin attenuates liver fibrosis in high‐fat diet/streptozotocin‐induced mice by modulating gut microbiota

“…Liver samples were lysed using radioimmunoprecipitation assay (RIPA) lysis buffer (Beyotime) and protease inhibitor (Beyotime), and protein concentration was determined using a BCA Protein Assay Kit (Beyotime). Western blot analysis was performed as described previously 42 . The antibodies used for protein quantification were as follows: α‐SMA (Signalway Antibody#40482, 1:1000 dilution), Col 1 (Proteintech#66761‐1‐Ig, 1:2000 dilution), HSP90 (Proteintech#60318‐1‐Ig, 1:10000 dilution) along with secondary antibody HRP‐conjugated goat anti‐rabbit (Beyotime#A0208, 1:1000 dilution) or mouse (Proteintech#SA00001‐1, 1:10000 dilution) IgG.…”

“…Western blot analysis was performed as described previously. 42 The antibodies used for protein quantification were as follows: Taxon abundance at the genus level was compared by Kruskal test using R software (4.1.1). Alpha and beta diversity were evaluated using QIIME software.…”