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

Cai, Erica P.; Luk, Cynthia T.; Wu, Xiaohong; Schroer, Stephanie A.; Shi, Sally Yu; Sivasubramaniyam, Tharini; Brunt, Jara J.; Zacksenhaus, Eldad; Woo, Minna

doi:10.1007/s00125-014-3381-y

Cited by 11 publications

(12 citation statements)

References 51 publications

(72 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Discussionsupporting

confidence: 60%

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

Bourouh

Courty

Pasquetti

et al. 2021

Preprint

View full text Add to dashboard Cite

Compromised β-cell function contributes to type 2 diabetes (T2D) development. The glucagon like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential toward T2D treatment, notably by improving β-cell functions. Recent data have shown that the transcription factor E2f1, besides its role as a cell cycle regulator, is involved in glucose homeostasis by modulating β-cell mass, function and identity. Here, we demonstrate a crosstalk between the E2F1, phosphorylation of retinoblastoma protein (pRb) and Glp-1 signaling pathways. We found that β-cell specific E2f1 deficient mice (E2f1β-/-) presented with impaired glucose homeostasis and decreased glucose stimulated-insulin secretion mediated by exendin 4 (i.e., GLP1R agonist), which were associated with decreased expression of Glp1r encoding Glp-1 receptor (GLP1R) in E2f1β-/- pancreatic islets. Decreasing E2F1 transcriptional activity with an E2F inhibitor in islets from nondiabetic humans decreased GLP1R levels and blunted the incretin effect of exendin 4 on insulin secretion. Conversely, overexpressing E2f1 in pancreatic β cells increased Glp1r expression associated with enhanced insulin secretion mediated by GLP1R agonist. Interestingly, kinome analysis of mouse islets demonstrated that an acute treatment with exendin 4 increased pRb phosphorylation and subsequent E2f1 transcriptional activity. This study suggests a molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways that modulates insulin secretion and glucose homeostasis.

show abstract

Section: Discussionsupporting

confidence: 60%

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

Bourouh

Courty

Pasquetti

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Fujita

Kozawa

Iwahashi

et al. 2018

J of Diabetes Invest

View full text Add to dashboard Cite

Aims/IntroductionPancreatic α‐cell area and the α‐ to β‐cell area ratio (α/β) might be associated with glucose tolerance. The aim was to clarify how these histological parameters change as glucose tolerance deteriorates.Materials and MethodsWe analyzed pancreatic tissues obtained from pancreatectomies of 43 patients. We evaluated the relationships between α‐cell area or the α/β and various clinical parameters. Additionally, we analyzed α‐cell proliferation and the expression patterns of various pancreatic transcription factors.ResultsThe α/β in individuals with longstanding (previously diagnosed) type 2 diabetes (0.36 ± 0.12) was higher than that in those with normal glucose tolerance (0.18 ± 0.10; P < 0.01), impaired glucose tolerance (0.17 ± 0.12; P < 0.05) and newly diagnosed diabetes (0.17 ± 0.12; P < 0.05). In all participants, glycated hemoglobin (HbA1c) correlated with relative α‐cell area (P = 0.010). Diabetes duration (P = 0.004), HbA1c (P < 0.001) and plasma glucose levels (P = 0.008) were significantly correlated with the α/β in single regression analyses, and diabetes duration was the only independent and significant determinant in stepwise multiple regression analyses (P = 0.006). The α‐cell Ki67‐positive ratio in patients with HbA1c ≥6.5% was significantly higher than that in patients with HbA1c <6.5% (P = 0.022). We identified β‐cells that expressed aristaless‐related homeobox and α‐cells that did not express aristaless‐related homeobox at all glucose tolerance stages. Aristaless‐related homeobox and NK homeobox 6.1 expression patterns varied in insulin and glucagon double‐positive cells.ConclusionsThe pancreatic α/β increases after type 2 diabetes onset and correlates with diabetes duration. This change might occur through α‐cell proliferation and phenotypic changes in pancreatic endocrine cells.

show abstract

“…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.…”

Section: Discussionmentioning

confidence: 96%

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

Mulder

Havinga

Kluiver

et al. 2019

Journal of Endocrinology

View full text Add to dashboard Cite

MicroRNAs have emerged as essential regulators of beta cell function and beta cell proliferation. One of these microRNAs, miR-132, is highly induced in several obesity models and increased expression of miR-132 in vitro modulates glucose-stimulated insulin secretion. The aim of this study was to investigate the therapeutic benefits of miR-132 overexpression on beta cell function in vivo. To overexpress miR-132 specifically in beta cells, we employed adeno-associated virus (AAV8)-mediated gene transfer using the rat insulin promoter in a double-stranded, self-complementary AAV vector to overexpress miR-132. Treatment of mice with dsAAV8-RIP-mir132 increased miR-132 expression in beta cells without impacting expression of miR-212 or miR-375. Surprisingly, overexpression of miR-132 did not impact glucose homeostasis in chow-fed animals. Overexpression of miR-132 did improve insulin secretion and hence glucose homeostasis in high-fat diet-fed mice. Furthermore, miR-132 overexpression increased beta cell proliferation in mice fed a high-fat diet. In conclusion, our data show that AAV8

show abstract

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

Cited by 11 publications

References 51 publications

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

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

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

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

Contact Info

Product

Resources

About