A Simple Matter of Life and Death—The Trials of Postnatal Beta-Cell Mass Regulation

Tarabra, Elena; Pelengaris, Stella; Khan, Michael

doi:10.1155/2012/516718

Cited by 34 publications

(34 citation statements)

References 277 publications

(303 reference statements)

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“…The balance in the pancreatic β-cells is pivotal in a right β-cell mass maintenance which would affect the function of β-cells. The β-cell mass is increased by neogenesis (differentiation from precursor cells), proliferation, and β-cell hypertrophy (increased cell size) and is decreased by β-cell death, primarily through apoptosis and β-cell atrophy (decreased cell size) (Tarabra et al 2012). A previous study has pointed out that the molecular mechanisms of CR delays the onset of age-related disease and extends life span in mammals, which may be associated with the alleviation of cellular apoptosis (Koubova and Guarente 2003).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that age correlates with decreased proliferative activity and enhanced sensitivity to glucose-induced β-cell apoptosis (Maedler et al 2006). The β-cell proliferation was detected to gradually decline with aging by 0.5%~ 2% (Ackermann and Gannon 2007) and the imbalance between β-cell proliferation and apoptosis would finally result in β-cell dysfunction and consequently diabetes onset (Tarabra et al 2012). Therefore, seeking a feasible way to restore the β-cell mass and its functionality that decreased with increasing age would be quite important in delaying the onset of diabetes.…”

mentioning

confidence: 99%

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Calorie Restriction from a Young Age Preserves the Functions of Pancreatic β Cells in Aging Rats

Zhao

et al. 2012

Tohoku J. Exp. Med.

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Calorie restriction (CR) is a simple method for delaying aging process, extending lifespan, and preventing the onset of aging-related diseases, such as diabetes. However, the mechanism, by which CR influences β-cell functions during the aging process, still remains unclear. In this study, sixteen 8-week-old male Sprague-Dawley rats were randomized to control group with food intake ad libitum and CR group fed with 70% of food intake of the control group. Twenty-four weeks later, the body weights of the rats with CR were significantly lower with the smaller amounts of perirenal and epididymal fats, compared to those of control rats. The β-cell activity, as judged by the early insulin secretion in the intraperitoneal glucose tolerance test, was significantly higher in the CR group than that in control animals. Moreover, CR animals showed the increased β-cell mass and proliferation of β-cells in pancreas. The plasma level of malondialdehyde was lower in CR rats than that in control rats, while the activities of superoxide dismutase, catalase and glutathione peroxidase in plasma were higher in CR rats than control rats. These results indicate that aging is associated with the increases in oxidative stress, which was, however, alleviated by CR. In conclusion, CR from a young age preserves the principal β-cell function of early insulin secretion in rats probably by stimulating the β-cell proliferation. Our observations provide the evidence for clinical significance of CR in preventing β-cell dysfunction during the aging process, which may delay the onset of aging-related disease, including diabetes in humans.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Calorie Restriction from a Young Age Preserves the Functions of Pancreatic β Cells in Aging Rats

Zhao

et al. 2012

Tohoku J. Exp. Med.

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“…Adult β cells have a low intrinsic replicative rate but retain some capacity for expansion in response to physiological perturbations such as pregnancy and obesity (3,4). A better understanding of molecular pathways that activate β-cell proliferation may help to define strategies for replacement of functional β-cell mass in both major forms of diabetes.…”

mentioning

confidence: 99%

Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors

Tessem¹,

Moss

Chao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

118

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Loss of functional β-cell mass is a hallmark of type 1 and type 2 diabetes, and methods for restoring these cells are needed. We have previously reported that overexpression of the homeodomain transcription factor NK6 homeobox 1 (Nkx6.1) in rat pancreatic islets induces β-cell proliferation and enhances glucosestimulated insulin secretion, but the pathway by which Nkx6.1 activates β-cell expansion has not been defined. Here, we demonstrate that Nkx6.1 induces expression of the nuclear receptor subfamily 4, group A, members 1 and 3 (Nr4a1 and Nr4a3) orphan nuclear receptors, and that these factors are both necessary and sufficient for Nkx6.1-mediated β-cell proliferation. Consistent with this finding, global knockout of Nr4a1 results in a decrease in β-cell area in neonatal and young mice. Overexpression of Nkx6.1 and the Nr4a receptors results in increased expression of key cell cycle inducers E2F transcription factor 1 and cyclin E1. Furthermore, Nkx6.1 and Nr4a receptors induce components of the anaphasepromoting complex, including ubiquitin-conjugating enzyme E2C, resulting in degradation of the cell cycle inhibitor p21. These studies identify a unique bipartite pathway for activation of β-cell proliferation, suggesting several unique targets for expansion of functional β-cell mass.

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“…Effect of OTUB2 on insulin secretion To determine whether knockdown of OTUB2 also affects insulin secretion, glucose-stimulated insulin secretion (GSIS) was examined in MIN6 cells and intact human islets, either untreated or treated with cytokines-conditions known to inhibit GSIS [1]. As shown in Fig.…”

Section: Effect Of Otub2 Sirnas On Viability Of Beta Cellsmentioning

confidence: 99%

“…Pancreatic beta cell dysfunction underlies essentially all major forms of diabetes [1]. In type 1 diabetes, cell death is caused by an autoimmune assault against beta cells by infiltrating lymphocytes resulting in autoimmune destruction, insulin deficiency and hyperglycaemia [2].…”

Section: Introductionmentioning

confidence: 99%

Otubain 2 is a novel promoter of beta cell survival as revealed by siRNA high-throughput screens of human pancreatic islets

et al. 2013

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Aims/hypothesis Pro-inflammatory cytokines induce death of beta cells and hamper engraftment of transplanted islet mass. Our aim was to reveal novel genes involved in this process, as a platform for innovative therapeutic approaches. Methods Small interfering RNA (siRNA) high-throughput screening (HTS) of primary human islets was employed to identify novel genes involved in cytokine-induced beta cell apoptosis. Dispersed human islets from nine human donors, treated with a combination of TNF-α, IL-1β and IFN-γ were transfected with ∼730 different siRNAs. Caspase-3/7 activity was measured, results were analysed and potential anti-and pro-apoptotic genes were identified. Results Dispersed human pancreatic islets appeared to be suitable targets for performance of siRNA HTS. Using this methodology we found a number of potential pro-and antiapoptotic target hits that have not been previously associated with pancreatic beta cell death. One such hit was the deubiquitinating enzyme otubain 2 (OTUB2). OTUB2 knockdown increased caspase-3/7 activity in MIN6 cells and primary human islets and inhibited insulin secretion and increased nuclear factor-κB (NF-κB) activity both under basal conditions and following cytokine treatment. Conclusions Use of dispersed human islets provides a new platform for functional HTS in a highly physiological system. Employing this technique enabled the identification of OTUB2 as a novel promoter of viability and insulin secretion in human beta cells. OTUB2 acts through the inhibition of NF-κB signalling, which is deleterious to beta cell survival. siRNA screens of human islets may therefore identify new targets, such as OTUB2, for therapeutic intervention in type 1 diabetes and islet transplantation.

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A Simple Matter of Life and Death—The Trials of Postnatal Beta-Cell Mass Regulation

Cited by 34 publications

References 277 publications

Calorie Restriction from a Young Age Preserves the Functions of Pancreatic β Cells in Aging Rats

Calorie Restriction from a Young Age Preserves the Functions of Pancreatic β Cells in Aging Rats

Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors

Otubain 2 is a novel promoter of beta cell survival as revealed by siRNA high-throughput screens of human pancreatic islets

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