Human Islet Amyloid Polypeptide Oligomers Disrupt Cell Coupling, Induce Apoptosis, and Impair Insulin Secretion in Isolated Human Islets

Ritzel, Robert; Meier, Juris J.; Lin, Chia Yu; Veldhuis, Johannes D.; Butler, Peter C.

doi:10.2337/db06-0734

Cited by 172 publications

(159 citation statements)

References 46 publications

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“…Intracellular amyloid-like aggregates have also been reported in human and hIAPP-overexpressing transgenic mouse islets transplanted into type 1 diabetic mice [4,9,44,45] hIAPP aggregates appear to be more toxic than large fibrils and are probably the major mediators of beta cell death [19][20][21]46]. Despite convincing evidence implicating a membrane interaction in the cytotoxicity of exogenous synthetic hIAPP aggregates [19,46,47], the mode of this interaction is still unclear. Our studies show that prevention of hIAPP aggregation and interaction with beta cells by the amyloid-binding dye Congo Red, markedly reduces caspase-3 activation and apoptosis in INS-1 beta cells, supporting the notion that interaction of extracellular hIAPP aggregates with beta cell membranes induces caspase-3 activation and apoptosis.…”

Section: Discussionmentioning

confidence: 98%

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: Discussionmentioning

confidence: 98%

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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“…IAPP is produced in the β-cells and inhibits insulin secretion (14)(15)(16). IAPP of the human form may form fibrils leading to islet amyloid deposition, β-cell dysfunction and type 2 diabetes (17,18). We have previously shown that mice with β -cell specific overexpression of hIAPP have severe glucose intolerance and defective insulin response to gastric glucose (12).…”

Section: Introductionmentioning

confidence: 99%

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

Åhrén

Winzell

Wierup

et al. 2007

Regulatory Peptides

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Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with β-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3µmol/mouse daily) to female mice with β-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated.Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located α-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with specific ß cell transgenic overexpression of human IAPP.

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“…In type II diabetes, IAPP forms amyloid deposits that are correlated with ␤-cell death (16). Recent transgenic models, e.g., the HIP rat, strongly support a role for IAPP in diabetic pathology (17). Residues 20-29 of IAPP, SNNFGAILSS, referred to here as IAPP [20][21][22][23][24][25][26][27][28][29] , have previously been shown to form amyloid independently of the rest of the sequence (18)(19)(20).…”

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confidence: 99%

Fiber-dependent amyloid formation as catalysis of an existing reaction pathway

Ruschak¹,

Miranker

2007

Proc. Natl. Acad. Sci. U.S.A.

203

251

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A central component of a number of degenerative diseases is the deposition of protein as amyloid fibers. Self-assembly of amyloid occurs by a nucleation-dependent mechanism that gives rise to a characteristic sigmoidal reaction profile. The abruptness of this transition is a variable characteristic of different proteins with implications to both chemical mechanism and the aggressiveness of disease. Because nucleation is defined as the rate-limiting step, we have sought to determine the nature of this step for a model system derived from islet amyloid polypeptide. We show that nucleation occurs by two pathways: a fiber-independent (primary) pathway and a fiber-dependent (secondary) pathway. We first show that the balance between primary and secondary contributions can be manipulated by an external interface. Specifically, in the presence of this interface, the primary mechanism dominates, whereas in its absence, the secondary mechanism dominates. Intriguingly, we determine that both the reaction order and the enthalpy of activation of the two nucleation processes are identical. We interrogate this coincidence by global analysis using a simplified model generally applicable to protein polymerization. A physically reasonable set of parameters can be found to satisfy the coincidence. We conclude that primary and secondary nucleation need not represent different processes for amyloid formation. Rather, they are alternative manifestations of the same, surfacecatalyzed nucleation event.amylin ͉ fibers ͉ islet amyloid polypeptide ͉ nucleation T he noncovalent, fibrous self-assembly of proteins, including hemoglobin S, actin, microtubules, and amyloid fibers, occurs by a nucleation-dependent mechanism (1-5). If polymer product formation is monitored as a function of time in a reaction where all of the protein is initially monodisperse, there is a lag phase in which little product is formed, followed by a period of rapid growth (2). Such observations are consistent with a rate-limiting step in which change occurs to a high-energy intermediate known as the nucleus. In many systems such as actin, collagen, and microtubules, the nucleus is modeled as an oligomeric species that is in a highly unfavorable equilibrium with monomer (1, 3-6). The nucleus may also be a high-energy conformation of monomer, such as that reported for polyglutamine (7). Regardless, the rate-limiting step involves a nucleus because it is defined as the species with the highest free energy and therefore lowest population (1, 4).This model of nucleation alone cannot account for the high apparent cooperativity of conversion observed in many systems. Historically, hemoglobin S was the first biological polymerization reaction to demonstrate a transition time that is much shorter than its preceding lag phase (8). This same phenomenon is commonly reported for amyloid systems including islet amyloid polypeptide (IAPP) from type II diabetes (9), A␤ from Alzheimer's (10), PrP from the mammalian prion (11), and Sup35 from the yeast prion (12, 13), as well as mode...

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Human Islet Amyloid Polypeptide Oligomers Disrupt Cell Coupling, Induce Apoptosis, and Impair Insulin Secretion in Isolated Human Islets

Cited by 172 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

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

Fiber-dependent amyloid formation as catalysis of an existing reaction pathway

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