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

Wong, Way W.; Scott, David W.; Chuang, Chia Lin; Zhang, Shaoping; Liu, Hong; Ferreira, Athena; Saafi, Etuate L.; Choong, Y.S.; Cooper, Garth J. S.

doi:10.2337/db06-1755

Cited by 28 publications

(44 citation statements)

References 33 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.…”

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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“…Because the major difference in body weight between amylin knockout and wild-type mice occurred mainly within the first 3 to 4 months of life, the same may also hold true for animals overexpressing amylin. Another recent article with mice that were transgenic for the overexpression of human amylin did not report data on eating and body weight (Wong et al, 2008).…”

Section: A Genetic Models Of Amylin Deficiency or Overexpressionmentioning

confidence: 99%

Amylin: Pharmacology, Physiology, and Clinical Potential

Hay¹,

Chen²,

Lutz³

et al. 2015

Pharmacol Rev

302

297

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“…On the other hand, extracellular amyloid peptides have been shown to trigger CD95 (FAS) death receptor signalling [18] and elicit suicidal cell death or apoptosis of pancreatic ß-cells [12,13,[19][20][21][22][23][24][25][26][27][28][29] fostering the development of diabetes mellitus [1,[30][31][32]. Accordingly, diabetes develops in hemizygous human amylin transgenic mice [33]. Conversely, suppression of proislet amyloid polypeptide enhances survival of pancreatic islet cells [34].…”

Section: Introductionmentioning

confidence: 97%

Sphingomyelinase dependent apoptosis following treatment of pancreatic beta-cells with amyloid peptides Aß1-42 or IAPP

et al. 2009

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Amyloid peptides interfere with survival of pancreatic beta-cells. In some cells apoptosis is paralleled by ceramide-dependent alterations of ion channel activity. The purpose of the present study was to elucidate the dependence of amyloid peptides Abeta(1-42) and islet amyloid polypeptide (IAPP)-induced cell death on ceramide formation and ion channel activity in murine pancreatic islet cells. As disclosed by TUNEL (terminal dUTP nick-end labelling) and cleaved caspase 3 staining, apoptotic cell death was induced by Abeta(1-42), IAPP and exogenously added C2-ceramide in islet cells from wild type mice. In islet cells from acid sphingomyelinase-deficient mice (ASMKO) Abeta(1-42) and IAPP but not exogenously added N-acetyl-D-sphingosine (C2-ceramide, 20 microM) failed to stimulate apoptosis. Immunofluorescent staining revealed a stimulatory effect of Abeta(1-42) on ceramide formation. According to patch clamp experiments, administration of Abeta(1-42) and IAPP significantly decreased outwardly rectifying whole cell currents in wild type but not in ASMKO islet cells. C2-ceramide but not inactive di-ceramide (20 microM) mimicked the inhibitory effect on Kv channel current. In conclusion, amyloid peptides induce apoptosis of pancreatic islet cells at least in part through activation of acid sphingomyelinase resulting in production of ceramide and subsequent inhibition of ion channel activity.

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

Cited by 28 publications

References 33 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

Amylin: Pharmacology, Physiology, and Clinical Potential

Sphingomyelinase dependent apoptosis following treatment of pancreatic beta-cells with amyloid peptides Aß1-42 or IAPP

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