Effects of beta cell granule components on human islet amyloid polypeptide fibril formation

Westermark, Per; Li, Zhan Chun; Westermark, Gunilla T.; Leckström, Arnold; Steiner, Donald F.

doi:10.1016/0014-5793(95)01512-4

Cited by 184 publications

(229 citation statements)

References 21 publications

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“…Indeed, because the simple addition of h-IAPP to islets causes cell-to-cell disruption, it might be questioned, what are the mechanisms present in healthy islets that prevent recently secreted h-IAPP from forming toxic oligomers? One possible factor is the associated high insulin content discharged from the insulin secretory vesicle since insulin inhibits h-IAPP amyloid formation in an aqueous environment (37). Also, the acidic pH in the secretory vesicle may be sufficient in the immediate site of exocytosis to prevent h-IAPP oligomerization (38).…”

Section: Discussionmentioning

confidence: 99%

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

Ritzel¹,

Meier²,

Lin³

et al. 2007

Diabetes

173

154

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Insulin secretion from the 2,000 -3,000 ␤-cells in an islet is a highly synchronized activity with discharge of insulin in coordinate secretory bursts at approximately 4-min intervals. Insulin secretion progressively declines in type 2 diabetes and following islet transplantation. Both are characterized by the presence of islet amyloid derived from islet amyloid polypeptide (IAPP). In the present studies, we examined the action of extracellular human IAPP (h-IAPP) on morphology and function of human islets. Because oligomers of h-IAPP are known to cause membrane disruption, we questioned if application of h-IAPP oligomers to human islets would lead to disruption of islet architecture (specifically cell-to-cell adherence) and a decrease in coordinate function (e.g., increased entropy of insulin secretion and diminished coordinate secretory bursts). Both hypotheses are affirmed, leading to a novel hypothesis for impaired insulin secretion in type 2 diabetes and following islet transplantation, specifically disrupted cell-to-cell adherence in islets through the actions of membrane-disrupting IAPP oligomers. Diabetes 56:65-71, 2007

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Section: Discussionmentioning

confidence: 99%

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

Ritzel¹,

Meier²,

Lin³

et al. 2007

Diabetes

173

154

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“…If our hypothesis is correct, i.e., if hIAPP fibril growth causes membrane damage, then one would predict that inhibition of hIAPP fibril growth would also inhibit hIAPP-induced membrane leakage. To test this, we have chosen insulin as a biologically relevant, potent inhibitor of hIAPP fibril formation (29)(30)(31). The mechanism of inhibition of hIAPP fibril formation by insulin is most likely related to strong binding of the insulin B-chain to hIAPP (32).…”

Section: Seeding Reduces the Lag Time Of Hiapp-induced Membrane Damagementioning

confidence: 99%

Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane

Engel

Khemtémourian²,

Kleijer³

et al. 2008

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

437

482

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Fibrillar protein deposits (amyloid) in the pancreatic islets of Langerhans are thought to be involved in death of the insulinproducing islet ␤ cells in type 2 diabetes mellitus. It has been suggested that the mechanism of this ␤ cell death involves membrane disruption by human islet amyloid polypeptide (hIAPP), the major constituent of islet amyloid. However, the molecular mechanism of hIAPP-induced membrane disruption is not known. Here, we propose a hypothesis that growth of hIAPP fibrils at the membrane causes membrane damage. We studied the kinetics of hIAPP-induced membrane damage in relation to hIAPP fibril growth and found that the kinetic profile of hIAPP-induced membrane damage is characterized by a lag phase and a sigmoidal transition, which matches the kinetic profile of hIAPP fibril growth. The observation that seeding accelerates membrane damage supports the hypothesis. In addition, variables that are well known to affect hIAPP fibril formation, i.e., the presence of a fibril formation inhibitor, hIAPP concentration, and lipid composition, were found to have the same effect on hIAPP-induced membrane damage. Furthermore, electron microscopy analysis showed that hIAPP fibrils line the surface of distorted phospholipid vesicles, in agreement with the notion that hIAPP fibril growth at the membrane and membrane damage are physically connected. Together, these observations point toward a mechanism in which growth of hIAPP fibrils, rather than a particular hIAPP species, is responsible for the observed membrane damage. This hypothesis provides an additional mechanism next to the previously proposed role of oligomers as the main cytotoxic species of amyloidogenic proteins.amylin ͉ amyloid cytotoxicity ͉ large unilamellar vesicles ͉ protein-membrane interaction ͉ type 2 diabetes mellitus T ype 2 diabetes mellitus (DM2) is characterized histopathologically by the presence of fibrillar amyloid deposits in the pancreatic islets of Langerhans. Amyloid cytotoxicity is thought to be an early mechanism involved in death of insulin-producing islet ␤ cells in DM2 (1). The main component of islet amyloid, and the actual fibril-forming molecule, is a 37-amino acid peptide called human islet amyloid polypeptide (hIAPP) or amylin, which is produced together with insulin in the pancreatic islet ␤-cells. It is thought that ␤ cells of DM2 patients are somehow killed through hIAPP-induced damage of the ␤ cell membrane (2). However, our knowledge of the mechanism of hIAPP-induced membrane damage is extremely sparse. It is not known how cytotoxic hIAPP species interact with cellular membranes and induce cell death. Furthermore, it is not established whether cytotoxic hIAPP species are formed before contacting the membrane or whether a membrane environment is in fact required for the formation of cytotoxic hIAPP species.The prevailing view is that membrane damage and concomitant ␤ cell death are caused by cytotoxic hIAPP oligomers (2-9). There are indications that these oligomers form ion channels (2, 3), as has been suggeste...

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“…5 Note that amylin aggregates are commonly found as amyloid deposits in pancreatic islets from diabetic patients. 6 While the causative relationship between aggregation of human amylin peptide and Type II diabetes is not known, it has been established that aggregates of human amylin can induce apoptopic cell-death of the insulin producing β-cells. 2 Perhaps more importantly, recent experiments have shown that the main toxic species are the pre-fibrillar, early stage oligomers of the peptide.…”

Section: Introductionmentioning

confidence: 99%

α-helix to β-hairpin transition of human amylin monomer

Singh

Chiu

Reddy

et al. 2013

The Journal of Chemical Physics

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The human islet amylin polypeptide is produced along with insulin by pancreatic islets. Under some circumstances, amylin can aggregate to form amyloid fibrils, whose presence in pancreatic cells is a common pathological feature of Type II diabetes. A growing body of evidence indicates that small, early stage aggregates of amylin are cytotoxic. A better understanding of the early stages of the amylin aggregation process and, in particular, of the nucleation events leading to fibril growth could help identify therapeutic strategies. Recent studies have shown that, in dilute solution, human amylin can adopt an α-helical conformation, a β-hairpin conformation, or an unstructured coil conformation. While such states have comparable free energies, the β-hairpin state exhibits a large propensity towards aggregation. In this work, we present a detailed computational analysis of the folding pathways that arise between the various conformational states of human amylin in water. A free energy surface for amylin in explicit water is first constructed by resorting to advanced sampling techniques. Extensive transition path sampling simulations are then employed to identify the preferred folding mechanisms between distinct minima on that surface. Our results reveal that the α-helical conformer of amylin undergoes a transformation into the β-hairpin monomer through one of two mechanisms. In the first, misfolding begins through formation of specific contacts near the turn region, and proceeds via a zipping mechanism. In the second, misfolding occurs through an unstructured coil intermediate. The transition states for these processes are identified. Taken together, the findings presented in this work suggest that the inter-conversion of amylin between an α-helix and a β-hairpin is an activated process and could constitute the nucleation event for fibril growth.

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Effects of beta cell granule components on human islet amyloid polypeptide fibril formation

Cited by 184 publications

References 21 publications

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

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

Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane

α-helix to β-hairpin transition of human amylin monomer

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