Oxidative stress is induced by islet amyloid formation and time-dependently mediates amyloid-induced beta cell apoptosis

Zraika, Sakeneh; Hull, Rebecca L.; Udayasankar, Jayalakshmi; Aston-Mourney, Kathryn; Subramanian, Shoba L.; Kisilevsky, Robert; Szarek, Walter A.; Kahn, Steven E.

doi:10.1007/s00125-008-1255-x

Cited by 198 publications

(207 citation statements)

References 46 publications

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“…It is, however, not clear which of these mechanism(s) contribute to hIAPP-induced beta cell death in primary islets, in which the level of endogenously produced hIAPP (pmol/l) is several fold lower [4,29] than that used in vitro (μmol/l). Recent studies using transgenic rodents have demonstrated that endoplasmic reticulum (ER) stress caused by formation of intracellular hIAPP fibrils [30,31] and oxidative stress [32] also contribute to cytotoxic effects of hIAPP. It therefore appears that, at least in vitro, hIAPPinduced beta cell apoptosis involves different mechanisms, although these mechanisms may share the same apoptotic signalling pathways.…”

Section: Introductionmentioning

confidence: 99%

Differences between amyloid toxicity in alpha and beta cells in human and mouse islets and the role of caspase-3

Law

Kieffer

et al. 2010

Diabetologia

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Aims/hypothesis Type 2 diabetes is characterised by decreased beta cell mass and islet amyloid formation. Islet amyloid formed by aggregation of human islet amyloid polypeptide (hIAPP) is associated with beta cell apoptosis. We used human and transgenic mouse islets in culture to examine whether deletion of caspase-3 protects islets from apoptosis induced by endogenously produced and exogenously applied hIAPP and compared hIAPP toxicity in islet alpha and beta cells. Methods Human and wild-type or caspase-3 knockout mouse islet cells were treated with hIAPP. Rat insulinoma INS-1 cells were similarly cultured with hIAPP and the amyloid inhibitor Congo Red or caspase-3 inhibitor. Human and hIAPP-expressing caspase-3 knockout mouse islets were cultured to form amyloid fibrils and assessed for beta and alpha cell apoptosis, beta cell function and caspase-3 activation.Results hIAPP-treated INS-1 cells had increased caspase-3 activation and apoptosis, both of which were reduced by inhibitors of amyloid or caspase-3. Similarly, hIAPP-treated human and mouse islet beta cells had elevated active caspase-3-and TUNEL-positive cells, whereas mouse islet cells lacking caspase-3 had markedly lower beta cell but comparable alpha cell apoptosis. During culture, human islets that formed amyloid had higher active caspase-3-and TUNEL-positive beta cells than those without detectable amyloid. Finally, cultured hIAPP-expressing mouse islets lacking caspase-3 had markedly lower beta cell apoptosis than those expressing caspase-3, associated with an increase in islet beta cell/alpha cell ratio, insulin content and glucose response. Conclusions/interpretation Prevention of caspase-3 activation protects islet beta cells from apoptosis induced by fibrillogenesis of endogenously secreted and exogenously applied hIAPP. Islet beta cells are more susceptible to hIAPP toxicity than alpha cells cultured under the same conditions.

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Section: Introductionmentioning

confidence: 99%

Differences between amyloid toxicity in alpha and beta cells in human and mouse islets and the role of caspase-3

Law

Kieffer

et al. 2010

Diabetologia

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“…Of the two risk factors, evidence is accumulating that β-cell dysfunction, and the consequent inability to maintain appropriately elevated insulin secretion in the face of insulin resistance, is likely the more important factor precipitating the development of T2DM. 1 Several physiologic stressors have been proposed to explain the cause of this β-cell impairment, including glucolipotoxicity, 2 cytokines released from adipocytes and activated macrophages, 3,4 and islet amyloid deposition 5,6 among others (reviewed in ref. 7).…”

Section: β-Cell Dysfunction In Type 2 Diabetes Mellitusmentioning

confidence: 99%

Deoxyhypusine synthase haploinsufficiency attenuates acute cytokine signaling

et al. 2011

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“…heparan sulphate proteoglycans) [24]; inducing endoplasmic reticulum stress [25] and oxidative stress [26]; and disruption of the endoplasmic reticulum-associated degradation (ERAD)/ubiquitin/proteasome system [27] and autophagy/ lysosomal pathway [28]. Although several mechanisms, at least in vitro, are involved in hIAPP-induced beta cell apoptosis, some of these may share the same apoptotic signalling pathways.…”

Section: Introductionmentioning

confidence: 99%

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

et al. 2014

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Aims/hypothesis Reduced beta cell mass due to increased beta cell apoptosis is a key defect in type 2 diabetes. Islet amyloid, formed by the aggregation of human islet amyloid polypeptide (hIAPP), contributes to beta cell death in type 2 diabetes and in islet grafts in patients with type 1 diabetes. In this study, we used human islets and hIAPP-expressing mouse islets with beta cell Casp8 deletion to (1) investigate the role of caspase-8 in amyloid-induced beta cell apoptosis and (2) test whether caspase-8 inhibition protects beta cells from amyloid toxicity. Methods Human islet cells were cultured with hIAPP alone, or with caspase-8, Fas or amyloid inhibitors. Human islets and wild-type or hIAPP-expressing mouse islets with or without caspase-8 expression (generated using a Cre/loxP system) were cultured to form amyloid. Caspase-8 and -3 activation, Fas and FLICE inhibitory protein (FLIP) expression, islet beta cell and amyloid area, IL-1β levels, and the beta:alpha cell ratio were assessed. Results hIAPP treatment induced activation of caspase-8 and -3 in islet beta cells (via Fas upregulation), resulting in apoptosis, which was markedly reduced by blocking caspase-8, Fas or amyloid. Amyloid formation in cultured human and hIAPP-expressing mouse islets induced caspase-8 activation, which was associated with Fas upregulation and elevated islet IL-1β levels. hIAPP-expressing mouse islets with Casp8 deletion had comparable amyloid, IL-1β and Fas levels with those expressing hIAPP and Casp8, but markedly lower beta cell apoptosis, higher beta:alpha cell ratio, greater beta cell area, and enhanced beta cell function. Conclusions/interpretation Beta cell Fas upregulation by endogenously produced and exogenously applied hIAPP aggregates promotes caspase-8 activation, resulting in beta cell apoptosis. The prevention of amyloid-induced caspase-8 activation enhances beta cell survival and function in islets.

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Oxidative stress is induced by islet amyloid formation and time-dependently mediates amyloid-induced beta cell apoptosis

Cited by 198 publications

References 46 publications

Differences between amyloid toxicity in alpha and beta cells in human and mouse islets and the role of caspase-3

Differences between amyloid toxicity in alpha and beta cells in human and mouse islets and the role of caspase-3

Deoxyhypusine synthase haploinsufficiency attenuates acute cytokine signaling

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

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