Dual Effect of <i>Raptor</i> on Neonatal β-Cell Proliferation and Identity Maintenance

Wang, Yanqiu; Sun, Jian; Ni, Qicheng; Nie, Aifang; Gu, Yuchao; Wang, Shu; Zhang, Weizhen; Ning, Guang; Wang, Weiqing; Wang, Qidi

doi:10.2337/db19-0166

Cited by 12 publications

(14 citation statements)

References 64 publications

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“…Note that proliferation rates in these latter group were higher than those reported for p14 Wisp1 − / − pups (Fig. 3a, b), consistent with the rapid drop in beta cell proliferation that occurs during the first postnatal weeks 36,37 . No changes in Igf-1, osteoprogeterin or osteopontin were observed in mice treated with rmWisp1 as compared to saline controls ( Supplementary Fig.…”

Section: Resultssupporting

confidence: 81%

Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells

et al. 2020

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Expanding the mass of pancreatic insulin-producing beta cells through re-activation of beta cell replication has been proposed as a therapy to prevent or delay the appearance of diabetes. Pancreatic beta cells exhibit an age-dependent decrease in their proliferative activity, partly related to changes in the systemic environment. Here we report the identification of CCN4/Wisp1 as a circulating factor more abundant in pre-weaning than in adult mice. We show that Wisp1 promotes endogenous and transplanted adult beta cell proliferation in vivo. We validate these findings using isolated mouse and human islets and find that the beta cell trophic effect of Wisp1 is dependent on Akt signaling. In summary, our study reveals the role of Wisp1 as an inducer of beta cell replication, supporting the idea that the use of young blood factors may be a useful strategy to expand adult beta cell mass.

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Section: Resultssupporting

confidence: 81%

Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells

et al. 2020

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“…66,67 At present, some study used RIP-Cre mice as controls. 68 However, a number of studies had also shown that RIP-Cre have comparable glucose tolerance tests and insulin secretion as Loxp mice, and Loxp mice and even wild-type mice had been widely used as control mice [40][41][42][43][44][45][46][47][48][69][70][71] in study involving β cell specific knockout of genes triggered by RIP-Cre. In addition, although FAM3A-deficience impairs while FAM3A overexpression increases insulin secretion in primary mouse islets and β cell lines under basal glucose concentration, BKO mice has comparable insulin and blood glucose levels in fasting status as control mice.…”

Section: Discussionmentioning

confidence: 99%

“…40,41 PCR and agarose gel electrophoresis assays were used to characterize mouse genotypes. It had been reported that Ins2-Cre mice (RIP-Cre) exhibited normal insulin secretion and glucose metabolism as flox/flox and wild-type mice, 40,[42][43][44][45] which had been widely used as control mice in studies involving Ins2triggered 42,44-49 β cell specific knockout of genes. In the current study, the flox/flox mice had been used as control mice.…”

Section: Fam3a Gene Knockout (Bko) Micementioning

confidence: 99%

“…To directly evaluate the roles of FAM3A in insulin expression and secretion, β cell specific FAM3A knockout mice (BKO mice) were generated by crossing FAM3A-Loxp mice with Ins2-Cre mice (Supplemental Figure 3A,B). Although there is concern that Cre may impact β cell functions, it had also been reported that Ins2-Cre mice (RIP-Cre) exhibited normal insulin secretion and glucose metabolism as flox/ flox (Loxp) and wild-type mice, 40,[42][43][44][45] and Loxp mice had been widely used as control mice in studies involving RIP-Cre-triggered β cell specific knockout of genes. 42,[44][45][46][47][48][49] Our preliminary experiments revealed that there was no significant difference in OGTT between Loxp mice and RIP-Cre mice (Supplemental Figure 3C), so the Loxp mice had been used as control mice in the current study.…”

Section: Fam3a Gene Deficiency Markedly Impaired Insulin Secretion mentioning

confidence: 99%

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FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

et al. 2020

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So far, the mechanism that links mitochondrial dysfunction to PDX1 inhibition in the pathogenesis of pancreatic β cell dysfunction under diabetic condition remains largely unclear. This study determined the role of mitochondrial protein FAM3A in regulating PDX1 expression in pancreatic β cells using gain‐ and loss‐of function methods in vitro and in vivo. Within pancreas, FAM3A is highly expressed in β, α, δ, and pp cells of islets. Islet FAM3A expression was correlated with insulin expression under physiological and diabetic conditions. Mice with specific knockout of FAM3A in islet β cells exhibited markedly blunted insulin secretion and glucose intolerance. FAM3A‐deficient islets showed significant decrease in PDX1 expression, and insulin expression and secretion. FAM3A overexpression upregulated PDX1 and insulin expressions, and augmented insulin secretion in cultured islets and β cells. Mechanistically, FAM3A enhanced ATP production to elevate cellular Ca2+ level and promote insulin secretion. Furthermore, FAM3A‐induced ATP release activated CaM to function as a co‐activator of FOXA2, stimulating PDX1 gene transcription. In conclusion, FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic β cells. Inhibition of FAM3A will trigger mitochondrial dysfunction to repress PDX1 and insulin expressions.

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“…Early postnatal life is a critical period for acquiring the appropriate number of functional β cells needed to sustain the metabolic needs of the adult organism [ 1 ]. The β-cell population expands dramatically during the perinatal period due to increased proliferation [ [2] , [3] , [4] ], which rapidly declines until reaching low replication values maintained throughout adulthood (cells in cycle: ≈1% in rodents and <0.2% in humans) [ 5 ]. In concert with their expansion, neonatal β cells up-regulate the expression of identity and functionality genes and develop the capability to regulate insulin secretion in response to high glucose (GSIS), which is the hallmark of their mature state [ [6] , [7] , [8] , [9] ].…”

Section: Introductionmentioning

confidence: 99%

Gsα-dependent signaling is required for postnatal establishment of a functional β-cell mass

Serra-Navarro

Fernández-Ruiz

García‐Alamán

et al. 2021

Molecular Metabolism

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Objective Early postnatal life is a critical period for the establishment of the functional β-cell mass that will sustain whole-body glucose homeostasis during the lifetime. β cells are formed from progenitors during embryonic development but undergo significant expansion in quantity and attain functional maturity after birth. The signals and pathways involved in these processes are not fully elucidated. Cyclic adenosine monophosphate (cAMP) is an intracellular signaling molecule that is known to regulate insulin secretion, gene expression, proliferation, and survival of adult β cells. The heterotrimeric G protein Gs stimulates the cAMP-dependent pathway by activating adenylyl cyclase. In this study, we sought to explore the role of Gs-dependent signaling in postnatal β-cell development. Methods To study Gs-dependent signaling, we generated conditional knockout mice in which the α subunit of the Gs protein (Gsα) was ablated from β-cells using the Cre deleter line Ins1 Cre . Mice were characterized in terms of glucose homeostasis, including in vivo glucose tolerance, glucose-induced insulin secretion, and insulin sensitivity. β-cell mass was studied using histomorphometric analysis and optical projection tomography. β-cell proliferation was studied by ki67 and phospho-histone H3 immunostatining, and apoptosis was assessed by TUNEL assay. Gene expression was determined in isolated islets and sorted β cells by qPCR. Intracellular cAMP was studied in isolated islets using HTRF-based technology. The activation status of the cAMP and insulin-signaling pathways was determined by immunoblot analysis of the relevant components of these pathways in isolated islets. In vitro proliferation of dissociated islet cells was assessed by BrdU incorporation. Results Elimination of Gsα in β cells led to reduced β-cell mass, deficient insulin secretion, and severe glucose intolerance. These defects were evident by weaning and were associated with decreased proliferation and inadequate expression of key β-cell identity and maturation genes in postnatal β-cells. Additionally, loss of Gsα caused a broad multilevel disruption of the insulin transduction pathway that resulted in the specific abrogation of the islet proliferative response to insulin. Conclusion We conclude that Gsα is required for β-cell growth and maturation in the early postnatal stage and propose that this is partly mediated via its crosstalk with insulin signaling. Our findings disclose a tight connection between these two pathways in postnatal β cells, which may have implications for using cAMP-raising agents to promote β-cell regeneration and maturation in diabetes.

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Dual Effect of Raptor on Neonatal β-Cell Proliferation and Identity Maintenance

Cited by 12 publications

References 64 publications

Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells

Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

Gsα-dependent signaling is required for postnatal establishment of a functional β-cell mass

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