E2F1 transcription factor mediates a link between fat and islets to promote β cell proliferation in response to acute insulin resistance

Shirakawa, Jun; Togashi, Yuichi; Basile, Giorgio; Okuyama, Tomoko; Inoue, Ryota; Fernandez, Megan; Kyohara, Mayu; Jesus, Dario F. De; Goto, Nobuaki; Zhang, Wei; Tsuno, Takahiro; Kin, Tatsuya; Hui, Pei; Dreyfuss, Jonathan M.; Shapiro, A. M. James; Peng, Yi; Terauchi, Yasuo; Kulkarni, Rohit

doi:10.1016/j.celrep.2022.111436

Cited by 17 publications

(7 citation statements)

References 48 publications

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“…Considering relative abundances of these subsets in unchallenged mice (Figure 4C), we designated β-1 and β-2 cells as normal-OxPhos and normal-proteostasis, respectively. β-4 cells expressed genes involved in DNA replication and cell division, indicating these β-cells are proliferating as is well-documented to occur in response to increased workload 12,41 . Remaining β-cell subsets induced by S961 treatment (β-3 and β-5) both overexpressed genes associated with translation and protein glycosylation, with the majority-population β-5 cells further expressing a signature of protein processing in the ER and β-3 cells expressing a signature of OxPhos and ROS.…”

Section: Resultsmentioning

confidence: 75%

Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2

Wortham,

Ramms,

Zeng

et al. 2024

Preprint

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Selective and controlled expansion of endogenous β-cells has been pursued as a potential therapy for diabetes. Ideally, such therapies would preserve feedback control of β-cell proliferation to avoid excessive β-cell expansion and an increased risk of hypoglycemia. Here, we identified a regulator of β-cell proliferation whose inactivation results in controlled β-cell expansion: the protein deacetylase Sirtuin 2 (SIRT2). Sirt2 deletion in β-cells of mice increased β-cell proliferation during hyperglycemia with little effect in homeostatic conditions, indicating preservation of feedback control of β-cell mass. SIRT2 restrains proliferation of human islet β-cells cultured in glucose concentrations above the glycemic set point, demonstrating conserved SIRT2 function. Analysis of acetylated proteins in islets treated with a SIRT2 inhibitor revealed that SIRT2 deacetylates enzymes involved in oxidative phosphorylation, dampening the adaptive increase in oxygen consumption during hyperglycemia. At the transcriptomic level, Sirt2 inactivation has context-dependent effects on β-cells, with Sirt2 controlling how β-cells interpret hyperglycemia as a stress. Finally, we provide proof-of-principle that systemic administration of a GLP1-coupled Sirt2-targeting antisense oligonucleotide achieves β-cell selective Sirt2 inactivation and stimulates β-cell proliferation under hyperglycemic conditions. Overall, these studies identify a therapeutic strategy for increasing β-cell mass in diabetes without circumventing feedback control of β-cell proliferation.

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Section: Resultsmentioning

confidence: 75%

Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2

Wortham,

Ramms,

Zeng

et al. 2024

Preprint

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“…Administration of the insulin receptor antagonist S961 imparts hyperinsulinism and marked hyperglycemia in male mice ( Figure 2A ) ( 24 – 26 ) with a concomitant reduction of islet β cell MafA protein and mRNA levels ( Figure 2B and data not shown). Four days of S961 treatment also stimulated the production of a rare Gast + cell population ( Figure 2C ).…”

Section: Resultsmentioning

confidence: 96%

Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity

Cha,

Tong,

Walker

et al. 2023

JCI Insight

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Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β cells, characterized by inappropriate production of other islet cell–enriched hormones. Here, we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin + (Gast + ) cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a GAST + gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a potentially novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively. Here, we discuss the possibility that induction of Gast/GAST and other non–β cell hormones, by reduction in the levels of these transcription factors, represents a dysfunctional β cell signature.

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“…As S961 and OSI‐906 administration inhibit systemic IR phosphorylation, the activation of IR is dispensable for β‐cell replication in response to acute insulin resistance. Indeed, S961‐induced β‐cells were not suppressed in knockout mice of IR and IRS‐2 37 . The FoxO1‐mediated insulin signal was also found to be dispensable for β‐cell compensation induced by S961 13,30 .…”

Section: Compensatory β‐Cell Proliferation In Acute and Chronic Insul...mentioning

confidence: 98%

“…As this liver‐derived circulating protease inhibitor‐mediated β‐cell proliferation is blunted by IR deficiency in β‐cells 12 , IR signaling might mediate serpin B1 action in terms of β‐cell replication in response to chronic liver insulin resistance. In contrast, adipocyte‐derived serum factors likely promote β‐cell replication under S961‐induced acute insulin resistance through the activation of E2F1 and the FoxM1/PLK1/CENP‐A pathway, independent of IR 37 . Based on this evidence, different tissues might contribute to adaptive β‐cell proliferation depending on chronic or acute conditions (Figure 3).…”

Section: Interorgan Network To Regulate Adaptive β‐Cell Proliferationmentioning

confidence: 99%

“…β‐Cell proliferation persists in OSI‐906‐treated mice after normalization of blood glucose levels by sodium–glucose cotransporter 2 inhibition, suggesting that glucose/glucokinase‐mediated insulin signaling is also unnecessary 38 . The β‐cell proliferation induced by acute models (i.e., S961, OSI‐906 or partial pancreatectomy) is mediated by M phase‐related cell cycle genes (e.g., cyclin B1 and Birc5) and the FoxM1/PLK1/CENP‐A pathway 33 , 37 , but not IRS‐2 or cyclin D2, which are induced in the chronic DIO model. In this way, there are distinct signaling pathways that evoke adaptive β‐cell proliferation between acute and chronic insulin resistance models (Figure 3 ).…”

Section: Compensatory β‐Cell Proliferation In Acute and Chronic Insul...mentioning

confidence: 99%

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Signaling pathways that regulate adaptive β‐cell proliferation for the treatment of diabetes

Shirakawa

2023

J of Diabetes Invest

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The decline in β‐cell mass due to the failure of β‐cell compensation is one cause of the development of type 2 diabetes. Therefore, elucidation of the mechanism by which an adaptive increase in β‐cell mass occurs in vivo will lead to the development of a cure for diabetes. Insulin and insulin receptor (IR)‐mediated signaling pathways play an important role in the mechanism that increases β‐cell mass by compensatory β‐cell proliferation in response to chronic insulin resistance. However, whether IR is required for compensatory β‐cell proliferation remains controversial in some situations. It might be possible that IR acts as a scaffold for the signaling complex independent of its ligand. It has also been reported that the forkhead box protein M1/polo‐like kinase 1/centromere protein A pathway plays a central role in adaptive β‐cell proliferation during diet‐induced obesity, hyperglycemia, pregnancy, aging and acute insulin resistance. We recently reported that the cross‐talk of islets with fat tissue, in addition to the liver, through humoral factors is involved in adaptive β‐cell proliferation. This accommodative response of β‐cell proliferation through adipocytes was observed particularly under an acute insulin resistance state in an IR/insulin signal‐independent and forkhead box protein M1/polo‐like kinase 1/centromere protein A pathway‐dependent manner. A remaining barrier for the treatment of human diabetes using β‐cells is the differences between human and rodent islets. In this review, the focus is on signaling pathways that regulate adaptive β‐cell proliferation for the treatment of diabetes considering the abovementioned issues.

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E2F1 transcription factor mediates a link between fat and islets to promote β cell proliferation in response to acute insulin resistance

Cited by 17 publications

References 48 publications

Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2

Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2

Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity

Signaling pathways that regulate adaptive β‐cell proliferation for the treatment of diabetes

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