Amylin-Induced Cytotoxicity Is Associated with Activation of Caspase-3 and MAP Kinases

Rumora, Lada; Hadžija, Mirko; Barišić, Karmela; Maysinger, Dušica; Grubiić, Tihana Zanić

doi:10.1515/bc.2002.196

Cited by 30 publications

(41 citation statements)

References 42 publications

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“…Previous in vitro studies have suggested different mechanisms for hIAPP toxicity, including formation of non-selective ion channel-like structures [19][20][21][22][23], activation of the caspase pathways [24,25], and interaction of hIAPP fibrils with components of beta cell membranes, such as heparan sulphate proteoglycan [26,27] or touch receptors [28]. 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).…”

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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confidence: 99%

“…Even in advanced diabetes, islets lacked amyloid deposits. In islets from nontransgenic mice, glucagon and somatostatin cells were present mainly at the periphery and insulin cells were mainly in the core; in contrast, all three cell types were distributed throughout the islet in transgenic animals.[ 25,28,29 Pro]human amylin transgenic mice developed neither ␤-cell degeneration nor glucose intolerance.CONCLUSIONS-Overexpression of fibrillogenic human amylin in these human amylin transgenic mice caused ␤-cell degeneration and diabetes through mechanisms independent from both peripheral insulin resistance and islet amyloid. These findings are consistent with ␤-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.…”

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confidence: 99%

“…RESEARCH DESIGN AND METHODS-We characterized the phenotypes of independent transgenic mouse lines that display pancreas-specific expression of human amylin or a nonaggregating homolog, [ 25,28,29 Pro]human amylin, in an FVB/n background.…”

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confidence: 99%

“…[ 25,28,29 Pro]human amylin transgenic mice developed neither ␤-cell degeneration nor glucose intolerance.…”

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confidence: 99%

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Spontaneous Diabetes in Hemizygous Human Amylin Transgenic Mice That Developed Neither Islet Amyloid nor Peripheral Insulin Resistance

et al. 2008

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OBJECTIVES-We sought to 1) Determine whether solublemisfolded amylin or insoluble-fibrillar amylin may cause or result from diabetes in human amylin transgenic mice and 2) determine the role, if any, that insulin resistance might play in these processes.RESEARCH DESIGN AND METHODS-We characterized the phenotypes of independent transgenic mouse lines that display pancreas-specific expression of human amylin or a nonaggregating homolog, [ 25,28,29 Pro]human amylin, in an FVB/n background.RESULTS-Diabetes occurred in hemizygous human amylin transgenic mice from 6 weeks after birth. Glucose tolerance was impaired during the mid-and end-diabetic phases, in which progressive ␤-cell loss paralleled decreasing pancreatic and plasma insulin and amylin. Peripheral insulin resistance was absent because glucose uptake rates were equivalent in isolated soleus muscles from transgenic and control animals. Even in advanced diabetes, islets lacked amyloid deposits. In islets from nontransgenic mice, glucagon and somatostatin cells were present mainly at the periphery and insulin cells were mainly in the core; in contrast, all three cell types were distributed throughout the islet in transgenic animals.[ 25,28,29 Pro]human amylin transgenic mice developed neither ␤-cell degeneration nor glucose intolerance.CONCLUSIONS-Overexpression of fibrillogenic human amylin in these human amylin transgenic mice caused ␤-cell degeneration and diabetes through mechanisms independent from both peripheral insulin resistance and islet amyloid. These findings are consistent with ␤-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.

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Islet amyloid toxicity: From genesis to counteracting mechanisms

Marmentini

Branco

Boschero

et al. 2021

Journal Cellular Physiology

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Islet amyloid polypeptide (IAPP or amylin) is a hormone co-secreted with insulin by pancreatic β-cells and is the major component of islet amyloid. Islet amyloid is found in the pancreas of patients with type 2 diabetes (T2D) and may be involved in β-cell dysfunction and death, observed in this disease. Thus, investigating the aspects related to amyloid formation is relevant to the development of strategies towards β-cell protection. In this sense, IAPP misprocessing, IAPP overproduction, and disturbances in intra-and extracellular environments seem to be decisive for IAPP to form islet amyloid. Islet amyloid toxicity in β-cells may be triggered in intra-and/or extracellular sites by membrane damage, endoplasmic reticulum stress, autophagy disruption, mitochondrial dysfunction, inflammation, and apoptosis. Importantly, different approaches have been suggested to prevent islet amyloid cytotoxicity, from inhibition of IAPP aggregation to attenuation of cell death mechanisms. Such approaches have improved β-cell function and prevented the development of hyperglycemia in animals. Therefore, counteracting islet amyloid may be a promising therapy for T2D treatment.

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Amylin-Induced Cytotoxicity Is Associated with Activation of Caspase-3 and MAP Kinases

Cited by 30 publications

References 42 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

Spontaneous Diabetes in Hemizygous Human Amylin Transgenic Mice That Developed Neither Islet Amyloid nor Peripheral Insulin Resistance

Islet amyloid toxicity: From genesis to counteracting mechanisms

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