Biphasic effect of insulin on beta cell apoptosis depending on glucose deprivation

Guillén, Carlos; Bartolomé, Alberto; Nevado, Carmen; Benito, Manuel

doi:10.1016/j.febslet.2008.10.020

Cited by 19 publications

(15 citation statements)

References 29 publications

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“…This notion is consistent with previous findings that have shown that insulin can increase ROS levels in target cells (Goldstein et al 2005b), probably via the NOX family of NADPH oxidases (Guichard et al 2008), several members of which 230:3 are expressed in pancreatic islets (Guichard et al 2008). Insulin was also reported to induce apoptosis in glucosedeprived β cells (Guillen et al 2008) and potentiate the deleterious effects of H 2 O 2 on β cell survival (Sampson et al 2010). Of special interest in this regard is our finding that insulin increased the expression of iNos and Trb3, factors whose expression is known to be increased by cytokines in pancreatic β cells (Kanki et al 2009, Humphrey et al 2010, Kanwar 2010, Quintana-Lopez et al 2013.…”

Section: :3supporting

confidence: 81%

“…Most studies attribute any deleterious effects of this association to overproduction of insulin by the β cells that eventually results in a classical induction of ER stress, UPR and eventual death of the β cell (Fonseca et al 2011). Although the concentrations used in this study are unlikely to be attained in the blood during hyperinsulinemia, they are in accord with those used in other studies regarding insulin effects on its target tissues (Biswas et al 2007, Guillen et al 2008, Du & Ding 2009. Furthermore, some studies report levels as high as 700-800 pM (Movassat et al 1997, Remington et al 2015.…”

Section: :3supporting

confidence: 76%

“…It was also shown that chronic insulin treatment of RINm pancreatic β cell line increases LDH release and potentiates the deleterious effects of H 2 O 2 on cell survival (Sampson et al 2010). Consistent with these findings, insulin has a proapoptotic effect on β cells exposed to glucose deprivation (Guillen et al 2008), conditions that reduce the cellular redox potential.…”

Section: Introductionsupporting

confidence: 71%

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Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Bucris

Beck

Boura‐Halfon

et al. 2016

Journal of Endocrinology

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Insulin resistance results from impaired insulin signaling in target tissues that leads to increased levels of insulin required to control plasma glucose levels. The cycle of hyperglycemia and hyperinsulinemia eventually leads to pancreatic β cell deterioration and death by a mechanism that is yet unclear. Insulin induces ROS formation in several cell types. Furthermore, death of pancreatic β cells induced by oxidative stress could be potentiated by insulin. Here, we investigated the mechanism underlying this phenomenon. Experiments were done on pancreatic β cell lines (Min-6, RINm, INS-1), isolated mouse and human islets, and on cell lines derived from nonpancreatic sources. Insulin (100 nM) for 24 h selectively increased the production of ROS in pancreatic β cells and isolated pancreatic islets, but only slightly affected the expression of antioxidant enzymes. This was accompanied by a time-and dose-dependent decrease in cellular reducing power of pancreatic β cells induced by insulin and altered expression of several ER stress response elements including a significant increase in Trb3 and a slight increase in iNos. The effect on iNos did not increase NO levels. Insulin also potentiated the decrease in cellular reducing power induced by H 2 O 2 but not cytokines. Insulin decreased the expression of MCL-1, an antiapoptotic protein of the BCL family, and induced a modest yet significant increase in caspase 3/7 activity. In accord with these findings, inhibition of caspase activity eliminated the ability of insulin to increase cell death. We conclude that prolonged elevated levels of insulin may prime apoptosis and cell death-inducing mechanisms as a result of oxidative stress in pancreatic β cells.

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Section: :3supporting

confidence: 81%

Section: :3supporting

confidence: 76%

Section: Introductionsupporting

confidence: 71%

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Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Bucris

Beck

Boura‐Halfon

et al. 2016

Journal of Endocrinology

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“…It was recently reported that insulin has a biphasic effect on b cell survival that appears to depend on glucose level, being pro-apoptotic in glucose-deprived cells [15]. The mechanism of this effect, whether via IR or some other pathway, was not investigated.…”

Section: Discussionmentioning

confidence: 98%

“…Indeed, insulin may protect different cells from cell death through activation of a PI3-kinase pathway. It was recently reported that insulin also has a proapoptotic effect on b cells which was dependent on glucose deprivation [15]. Insulin has been shown to induce ROS production in several cell types (see [16], effects of which on cell death may vary.…”

Section: Introductionmentioning

confidence: 99%

Insulin increases H2O2-induced pancreatic beta cell death

et al. 2010

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Insulin resistance results, in part, from impaired insulin signaling in insulin target tissues. Consequently, increased levels of insulin are necessary to control plasma glucose levels. The effects of elevated insulin levels on pancreatic beta (β) cell function, however, are unclear. In this study, we investigated the possibility that insulin may influence survival of pancreatic β cells. Studies were conducted on RINm, RINm5F and Min-6 pancreatic β-cells. Cell death was induced by treatment with H(2)O(2), and was estimated by measurements of LDH levels, viability assay (Cell-Titer Blue), propidium iodide staining and FACS analysis, and mitochondrial membrane potential (JC-1). In addition, levels of cleaved caspase-3 and caspase activity were determined. Treatment with H(2)O(2) increased cell death; this effect was increased by simultaneous treatment of cells with insulin. Insulin treatment alone caused a slight increase in cell death. Inhibition of caspase-3 reduced the effect of insulin to increase H(2)O(2)-induced cell death. Insulin increased ROS production by pancreatic β cells and increased the effect of H(2)O(2). These effects were increased by inhibition of IR signaling, indicative of an effect independent of the IR cascade. We conclude that elevated levels of insulin may act to exacerbate cell death induced by H(2)O(2) and, perhaps, other inducers of apoptosis.

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Mechanisms of Pancreatic β-Cell Apoptosis in Diabetes and Its Therapies

Johnson

Luciani

2010

Advances in Experimental Medicine and Biology

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Diabetes occurs when beta-cells no longer function properly or have been destroyed. Pancreatic beta-cell death by apoptosis contributes significantly in both autoimmune type 1 diabetes and type 2 diabetes. Pancreatic beta-cell death can be induced by multiple stresses in both major types of diabetes. There are also several rare forms of diabetes, including Wolcott-Rallison syndrome, Wolfram syndrome, as well as some forms of maturity onset diabetes of the young that are caused by mutations in genes that may play important roles in beta-cell survival. The use of islet transplantation as a treatment for diabetes is also limited by excessive beta-cell apoptosis. Mechanistic insights into the control of pancreatic beta-cell apoptosis are therefore important for the prevention and treatment of diabetes. Indeed, a substantial quantity of research has been dedicated to this area over the past decade. In this chapter, we review the factors that influence the propensity of beta-cells to undergo apoptosis and the mechanisms of this programmed cell death in the initiation and progression of diabetes.

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Biphasic effect of insulin on beta cell apoptosis depending on glucose deprivation

Cited by 19 publications

References 29 publications

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Insulin increases H2O2-induced pancreatic beta cell death

Mechanisms of Pancreatic β-Cell Apoptosis in Diabetes and Its Therapies

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