Autocrine Regulation of Single Pancreatic β-Cell Survival

Navarro-Tableros, Víctor; Sánchez-Soto, M. Carmen; García, Santiago Rodríguez; Hiriart, Marcia

doi:10.2337/diabetes.53.8.2018

Cited by 62 publications

(63 citation statements)

References 35 publications

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“…Here we present evidence that insulin released by the islets in culture activates Akt in an autocrine manner to mediate islet survival. We demonstrate that treatment with an antiinsulin antibody decreased Akt phosphorylation and induced cell death, similar to findings in dispersed rat islets where treatment with anti-insulin antibody increased the amount of TUNEL (TdT-mediated dUTP-biotin nick end labelling)-positive cells [40]. We also demonstrate that inhibition of insulin reception blocks Akt phosphorylation and leads to cell death.…”

Section: Discussionsupporting

confidence: 84%

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Autocrine insulin action activates Akt and increases survival of isolated human islets

et al. 2006

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Aims/hypothesis The phosphatidylinositol 3-kinase (PI3K)/ Akt pathway plays a critical role in promoting the survival of pancreatic beta cells. Akt becomes activated in isolated human islets following overnight culture despite significant levels of cell death. The aim of the current study was to identify the cause of the observed increase in Akt phosphorylation in isolated islets. We hypothesised that a factor secreted by the islets in culture was acting in an autocrine manner to activate Akt. Methods In order to identify the stimulus of the PI3K/Akt pathway in culture, we examined the effects of different culture conditions on Akt phosphorylation and islet survival during the immediate post-isolation period. Results We demonstrated that islet-conditioned medium induced Akt phosphorylation in freshly isolated human islets, whereas frequent medium replacement decreased Akt phosphorylation. Following overnight culture, islet-conditioned medium contained significantly elevated levels of insulin, indicating that insulin may be responsible for the observed increase in Akt phosphorylation. Indeed, treatment with an anti-insulin antibody or with inhibitors of insulin receptor/IGF receptor 1 kinase activity suppressed Akt phosphorylation, leading to decreased islet survival. In addition, dispersion of islets into single cells also suppressed Akt phosphorylation and induced islet cell death, indicating that islet integrity is also required for maximal Akt phosphorylation. Conclusions/interpretation Our findings demonstrate that insulin acts in an autocrine manner to activate Akt and mediate the survival of isolated human islets. These findings provide new information on how culturing islets prior to transplantation may be beneficial to their survival by allowing for autocrine activation of the pro-survival Akt pathway.

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Section: Discussionsupporting

confidence: 84%

“…Previous studies have also demonstrated high levels of cell death in dispersed islet cultures [40,44]. One explanation for the increase in cell death upon dispersion of islets into single cells is the loss of contact with the extracellular matrix (ECM), which is mediated by the integrin receptor family.…”

Section: Discussionmentioning

confidence: 99%

Autocrine insulin action activates Akt and increases survival of isolated human islets

et al. 2006

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“…Because insulin is an HNF-1alpha target gene [9,10] and has been implicated in autocrine survival signalling in insulin-secreting cells [33][34][35], we next determined whether apoptosis activation by DN-HNF-1alpha was paralleled by changes in Ins1 gene transcription. Quantitative PCR analysis of Ins1 mRNA expression demonstrated a rapid and prominent downregulation of Ins1 mRNA expression after the induction of DN-HNF-1alpha (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This is due to defects in nutrient-secretion coupling and ATP production [6,9,10]. Insulin release serves as an important autocrine survival signal for the pancreatic beta cells [33,35]. It also activates Ins1 gene transcription via the insulin receptor/PI-3K/p70 S6 kinase pathway [34].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of protein kinase B/Akt-1 mediates INS-1 insulinoma cell apoptosis induced by dominant-negative suppression of hepatocyte nuclear factor-1alpha function

et al. 2006

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Aims/hypothesis: Inactivating mutations in Tcf1, which encodes the transcription factor hepatocyte nuclear factor (HNF)-1alpha, cause maturity-onset diabetes of the young-3. We have previously shown that a dominantnegative mutant (DN-HNF-1alpha) renders INS-1 insulinoma cells sensitive to the mitochondrial apoptosis pathway, but the underlying alterations in signal transduction remain unknown. Materials and methods: Using a reverse tetracycline-dependent transactivator system, DN-HNF-1alpha-induced apoptosis was assessed by immunoblotting and caspase assays. Alterations in AKT1 kinase/ protein kinase B (AKT1) survival signalling during DN-HNF-1alpha-induced apoptosis were investigated by phospho-specific immunodetection and transient transfection experiments. Results: Induction of DN-HNF-1alpha caused significant changes in the activation-specific phosphorylation status of AKT1 that were preceded by a downregulation of Ins1 gene transcription. Phosphorylation of AKT1 at Ser473 was dramatically reduced after 36 to 48 h of DN-HNF-1alpha induction and coincided with maximal apoptosis activation. Overexpression of a constitutively active mutant of Akt1 rescued INS-1 cells from DN-HNF1alpha-induced apoptosis, while ectopic expression of a dominant-negative mutant mimicked the effect of DN-HNF-1alpha on apoptosis activation. Pharmacological suppression of growth factor survival signalling through administration of the phosphatidylinositol-3 kinase (PI-3K) inhibitor wortmannin accelerated the induction of apoptosis by DN-HNF-1alpha. Conclusions/interpretation: These data suggest that a decrease in PI-3K/AKT1 survival signalling mediates DN-HNF-1alpha-induced apoptosis in insulinsecreting cells.

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“…The dynamic changes in the pancreas during progression of β cell death raise certain questions regarding potential autocrine regulatory effects of insulin on β cells (Navarro-Tableros et al 2004). In general, insulin acts as a growth factor that plays an antiapoptotic role and protects cells from death through activation of the PI3-kinase and ERK signaling pathways (Muller et al 2006, Jensen & De Meyts 2009, and insulin therapy can protect β cells from deterioration (Del Parigi 2008).…”

Section: Introductionmentioning

confidence: 99%

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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Autocrine Regulation of Single Pancreatic β-Cell Survival

Cited by 62 publications

References 35 publications

Autocrine insulin action activates Akt and increases survival of isolated human islets

Autocrine insulin action activates Akt and increases survival of isolated human islets

Downregulation of protein kinase B/Akt-1 mediates INS-1 insulinoma cell apoptosis induced by dominant-negative suppression of hepatocyte nuclear factor-1alpha function

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

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