Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

Abstract

Aims/hypothesis Diabetes mellitus is characterised by beta cell loss and alpha cell expansion. Analogues of glucagonlike peptide-1 (GLP-1) are used therapeutically to antagonise these processes; thus, we hypothesised that the related cell cycle regulators retinoblastoma protein (Rb) and p107 were involved in GLP-1 action. Methods We used small interfering RNA and adenoviruses to manipulate Rb and p107 expression in insulinoma and alpha-TC cell lines. In vivo we examined pancreas-specific Rb knockout, whole-body p107 knockout and Rb/p107 doubleknockout mice.Results Rb, but not p107, was downregulated in response to the GLP-1 analogue, exendin-4, in both alpha and beta cells. Intriguingly, this resulted in opposite outcomes of cell cycle arrest in alpha cells but proliferation in beta cells. Overexpression of Rb in alpha and beta cells abolished or attenuated the effects of exendin-4 supporting the important role of Rb in GLP-1 modulation of cell cycling. Similarly, in vivo, Rb, but not p107, deficiency was required for the beta cell proliferative response to exendin-4. Consistent with this finding, Rb, but not p107, was suppressed in islets from humans with diabetes, suggesting the importance of Rb regulation for the compensatory proliferation that occurs under insulin resistant conditions. Finally, while p107 alone did not have an essential role in islet homeostasis, when combined with Rb deletion, its absence potentiated apoptosis of both alpha and beta cells resulting in glucose intolerance and diminished islet mass with ageing. Conclusions/interpretation We found a central role of Rb in the dual effects of GLP-1 in alpha and beta cells. Our findings highlight unique contributions of individual Rb family members to islet cell proliferation and survival.

A crosstalk between E2F1 and GLP-1 signaling pathways modulates insulin secretion

“…Here, we report that E2F1 transcription factor, primarily known to control cell cycle progression (52), plays a key role in pancreatic b-cell function through the control of Glp-1 signaling, both in mice and human islets. Following previous studies demonstrating that E2F1-pRb pathway controls pancreatic b-cell mass (18,36,53,54) and function (17,55), we identify here a new role for this transcription factor linking this pathway to the druggable Glp-1 signaling. Indeed, we demonstrate that the specific loss of E2f1 expression in b cells leads to impaired oral glucose tolerance, both under chow and upon metabolic stress, associated to a loss of insulin secretion in response to glucose, despite normal Glp-1 circulating levels.…”

Human pancreatic α‐ to β‐cell area ratio increases after type 2 diabetes onset

“…Macrophages and granulocytes, which produce and secrete interleukin‐6, are found in islets of Goto–Kakizaki rats, which are often used as a non‐obese diabetic model. In contrast, glucagon‐like peptide‐1 accelerated β‐cell proliferation and reduced α‐cell proliferation by downregulating retinoblastoma protein. The decreased incretin effect associated with impaired glucose tolerance might also promote α‐cell proliferation.…”

AAV8-mediated gene transfer of microRNA-132 improves beta cell function in mice fed a high-fat diet

“…Interestingly, exendin-4, a GLP-1 agonist known to induce beta cell proliferation in mice, has been shown to decrease RB expression. Further study revealed that this decreased Rb expression is necessary for the beta cell proliferation stimulating effect of exendin-4 (Cai et al 2014). GLP-1 agonists increase miR-132 expression in beta cells (Shang et al 2015), suggesting that miR-132 plays a central role in the adaptive beta cell response to obesity and GLP-1.…”