High-throughput Functional Genomics Identifies Regulators of Primary Human Beta Cell Proliferation

Robitaille, Karine; Rourke, Jillian L.; McBane, Joanne E.; Fu, Accalia; Baird, Stephen; Du, Qiujiang; Kin, Tatsuya; Shapiro, A. M. James; Screaton, Robert A.

doi:10.1074/jbc.m115.683912

Cited by 39 publications

(51 citation statements)

References 49 publications

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“…156,157 Phosphatase and tensin homolog (PTEN) activation, which contributes to β-cell failure in mouse models of type 2 diabetes, 158 was increased in Mir155 -/-Ldlr -/-mice (Figure 36). Moreover, glucose transporter (Glut)2-dependent pathways and pathways related to cyclic adenosine monophosphate (AMP), GLP-1, and glucose-dependent insulinotropic polypeptide (GIP) signaling were inhibited, suggesting impaired glucose uptake and insulin secretion (Figure 36).…”

Section: Effect Of Mir-155 On Global Gene Expression In Pancreatic Ismentioning

confidence: 99%

Hyperlipidemia-Induced MicroRNA-155-5p Improves β-Cell Function by TargetingMafb

et al. 2017

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A high-fat diet increases bacterial lipopolysaccharide (LPS) in the circulation and thereby stimulates glucagon-like peptide 1 (GLP-1)–mediated insulin secretion by upregulating interleukin-6 (IL-6). Although microRNA-155-5p (miR-155-5p), which increases IL-6 expression, is upregulated by LPS and hyperlipidemia and patients with familial hypercholesterolemia less frequently develop diabetes, the role of miR-155-5p in the islet stress response to hyperlipidemia is unclear. In this study, we demonstrate that hyperlipidemia-associated endotoxemia upregulates miR-155-5p in murine pancreatic β-cells, which improved glucose metabolism and the adaptation of β-cells to obesity-induced insulin resistance. This effect of miR-155-5p is because of suppression of v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B, which promotes β-cell function through IL-6–induced GLP-1 production in α-cells. Moreover, reduced GLP-1 levels are associated with increased obesity progression, dyslipidemia, and atherosclerosis in hyperlipidemic Mir155 knockout mice. Hence, induction of miR-155-5p expression in β-cells by hyperlipidemia-associated endotoxemia improves the adaptation of β-cells to insulin resistance and represents a protective mechanism in the islet stress response.

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Section: Effect Of Mir-155 On Global Gene Expression In Pancreatic Ismentioning

confidence: 99%

Hyperlipidemia-Induced MicroRNA-155-5p Improves β-Cell Function by TargetingMafb

et al. 2017

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“…While several of these have clear activity in rodent islets, none have proven useful in stimulating human β-cell proliferation. This inability to stimulate human β-cell proliferation has led to intense efforts by several groups to use high-throughput small-molecule screening approaches to identify compounds or small molecules that stimulate β-cell proliferation [8–11]. Interestingly, recent, independent discoveries have identified the dual-specificity tyrosine-regulated kinase-1a (DYRK1A) as the likely target of compounds such as harmine and 5-iodotubercidin, both of which stimulate adult human β-cell proliferation [9,10].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, recent, independent discoveries have identified the dual-specificity tyrosine-regulated kinase-1a (DYRK1A) as the likely target of compounds such as harmine and 5-iodotubercidin, both of which stimulate adult human β-cell proliferation [9,10]. Another group was able to stimulate adult human β-cell proliferation using a RNA interference strategy to silence cell cycle-dependent kinase inhibitors CDKN2C/p18 or CDKN1A/p21 and suggested that p18 and p21 may be attractive targets to promote β-cell proliferation [8]. Efforts to identify additional compounds and to optimize identified compounds are underway.…”

Section: Introductionmentioning

confidence: 99%

Replicative capacity of β-cells and type 1 diabetes

Saunders

Powers

2016

Journal of Autoimmunity

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Efforts to restore β-cell number or mass in type 1 diabetes (T1D) must combine an intervention to stimulate proliferation of remaining β-cells and an intervention to mitigate or control the β-cell-directed autoimmunity. This review highlights features of the β-cell, including it being part of a pancreatic islet, a mini-organ that is highly vascularized and highly innervated, and efforts to promote β-cell proliferation. In addition, the β-cell in T1D exists in a microenvironment with interactions and input from other islet cell types, extracellular matrix, vascular endothelial cells, neuronal projections, and immune cells, all of which likely influence the β-cell’s capacity for replication. Physiologic β-cell proliferation occurs in human and rodents in the neonatal period and early in life, after which there is an age-dependent decline in β-cell proliferation, and also as part of the β-cell’s compensatory response to the metabolic challenges of pregnancy and insulin resistance. This review reviews the molecular pathways involved in this β-cell proliferation and highlights recent work in two areas: 1) Investigators, using high-throughput screening to discover small molecules that promote human β-cell proliferation, are now focusing on the dual-specificity tyrosine-regulated kinase-1a and cell cycle-dependent kinase inhibitors CDKN2C/p18 or CDKN1A/p21 as targets of compounds to stimulate adult human β-cell proliferation. 2) Local inflammation, macrophages, and the local β-cell microenvironment promote β-cell proliferation. Future efforts to harness the responsible mechanisms may lead to new approaches to promote β-cell proliferation in T1D.

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“…They also suggest that human β cells are more resistant to proliferation than the β cells of Rats. Recently, High-Throughput Screening methods (HTS) suggested p18 and p21 to be the prime candidates for the proliferation of beta cells [162]. …”

Section: Control Of Cell Cycle Molecules Upon β Cell Proliferationmentioning

confidence: 99%

The Making of Pancreatic β Cells: Advances and Apprehensions

Radha¹,

Muniraj

Rasu³

2016

IJPPE

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Abstract. Diabetes is a dreadful disease, which in its acute stages, causes severe multiple organ failure. It is also one of the world's oldest diseases. Type 1 Diabetes is characterized by the absence of insulin and exogenous insulin dependency. Stem cell therapy is one of the promises of this era, as there are numerous studies on Rodents, Frogs, Zebra fish, Dog and Chick, elucidating the wide array of genes, transcription factors, signaling pathways and compounds, which could promote β cell neogenesis, regeneration, differentiation and trans-differentiation. Even though, a recent PubMed search on the keyword 'Pancreatic beta cell proliferation' revealed around 3000 reports, this review focuses on the trends attempted in recent years and infers certain critical aspects in the observations.

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High-throughput Functional Genomics Identifies Regulators of Primary Human Beta Cell Proliferation

Cited by 39 publications

References 49 publications

Hyperlipidemia-Induced MicroRNA-155-5p Improves β-Cell Function by TargetingMafb

Hyperlipidemia-Induced MicroRNA-155-5p Improves β-Cell Function by TargetingMafb

Replicative capacity of β-cells and type 1 diabetes

The Making of Pancreatic β Cells: Advances and Apprehensions

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