scholarly journals Lipid accelerating the fibril of islet amyloid polypeptide aggravated the pancreatic islet injury in vitro and in vivo

2018 ◽  
Vol 17 (1) ◽  
Author(s):  
Xiao-Dan Mo ◽  
Li-Ping Gao ◽  
Qing-Jun Wang ◽  
Jie Yin ◽  
Yu-Hong Jing
Keyword(s):  
Pancreatic Islet ◽  
Islet Amyloid Polypeptide ◽  
Islet Amyloid

scholarly journals Human Islet Amyloid Polypeptide Fibril Binding to Catalase: A Transmission Electron Microscopy and Microplate Study

2010 ◽  
Vol 10 ◽  
pp. 879-893 ◽  
Author(s):  
Nathaniel G. N. Milton ◽  
J. Robin Harris
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Β ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Transmission Electron

The diabetes-associated human islet amyloid polypeptide (IAPP) is a 37-amino-acid peptide that forms fibrilsin vitroandin vivo. Human IAPP fibrils are toxic in a similar manner to Alzheimer's amyloid-β (Aβ) and prion protein (PrP) fibrils. Previous studies have shown that catalase binds to Aβ fibrils and appears to recognize a region containing the Gly-Ala-Ile-Ile sequence that is similar to the Gly-Ala-Ile-Leu sequence found in human IAPP residues 24-27. This study presents a transmission electron microscopy (TEM)—based analysis of fibril formation and the binding of human erythrocyte catalase to IAPP fibrils. The results show that human IAPP 1-37, 8-37, and 20-29 peptides form fibrils with diverse and polymorphic structures. All three forms of IAPP bound catalase, and complexes of IAPP 1-37 or 8-37 with catalase were identified by immunoassay. The binding of biotinylated IAPP to catalase was high affinity with a KDof 0.77nM, and could be inhibited by either human or rat IAPP 1-37 and 8-37 forms. Fibrils formed by the PrP 118-135 peptide with a Gly-Ala-Val-Val sequence also bound catalase. These results suggest that catalase recognizes a Gly-Ala-Ile-Leu—like sequence in amyloid fibril-forming peptides. For IAPP 1-37 and 8-37, the catalase binding was primarily directed towards fibrillar rather than ribbon-like structures, suggesting differences in the accessibility of the human IAPP 24-27 Gly-Ala-Ile-Leu region. This suggests that catalase may be able to discriminate between different structural forms of IAPP fibrils. The ability of catalase to bind IAPP, Aβ, and PrP fibrils demonstrates the presence of similar accessible structural motifs that may be targets for antiamyloid therapeutic development.

scholarly journals Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
Author(s):  
Rehana Akter ◽  
Ping Cao ◽  
Harris Noor ◽  
Zachary Ridgway ◽  
Ling-Hsien Tu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Death ◽  
Type 1 Diabetes ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Formation ◽  
Islet Amyloid

The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes toβ-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formationin vivoorin vitroare not understood and the mechanisms of IAPP inducedβ-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms ofβ-cell death, the relevance of reductionist biophysical studies to the situationin vivo, the molecular mechanism of amyloid formationin vitroandin vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy.

scholarly journals Amyloid Formation in Response to β Cell Stress Occurs In Vitro, but Not In Vivo, in Islets of Transgenic Mice Expressing Human Islet Amyloid Polypeptide

1995 ◽  
Vol 1 (5) ◽  
pp. 542-553 ◽  
Author(s):  
Gunilla Westermark ◽  
Michelle Benig Arora ◽  
Niles Fox ◽  
Raymond Carroll ◽  
Shu Jin Chan ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Cell Stress ◽  
Amyloid Formation ◽  
Β Cell ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

Diazoxide pretreatment improves pancreatic islet survival in vitro and functionality in vivo

2018 ◽  
Author(s):  
Michiel Nijhoff ◽  
Francoise Carlotti ◽  
Marten Engelse ◽  
Koning Eelco de
Keyword(s):  
Pancreatic Islet ◽  
Islet Survival

scholarly journals Pancreatic beta-cell granule peptides form heteromolecular complexes which inhibit islet amyloid polypeptide fibril formation

2004 ◽  
Vol 377 (3) ◽  
pp. 709-716 ◽  
Author(s):  
Emma T. A. S. JAIKARAN ◽  
Melanie R. NILSSON ◽  
Anne CLARK
Keyword(s):  
Type 2 Diabetes ◽  
Amyloid Fibrils ◽  
Secretory Granules ◽  
Pancreatic Beta Cell ◽  
Islet Amyloid Polypeptide ◽  
Fibril Formation ◽  
Islet Amyloid ◽  
Β Sheet

Islet amyloid polypeptide (IAPP), or ‘amylin’, is co-stored with insulin in secretory granules of pancreatic islet β-cells. In Type 2 diabetes, IAPP converts into a β-sheet conformation and oligomerizes to form amyloid fibrils and islet deposits. Granule components, including insulin, inhibit spontaneous IAPP fibril formation in vitro. To determine the mechanism of this inhibition, molecular interactions of insulin with human IAPP (hIAPP), rat IAPP (rIAPP) and other peptides were examined using surface plasmon resonance (BIAcore), CD and transmission electron microscopy (EM). hIAPP and rIAPP complexed with insulin, and this reaction was concentration-dependent. rIAPP and insulin, but not pro-insulin, bound to hIAPP. Insulin with a truncated B-chain, to prevent dimerization, also bound hIAPP. In the presence of insulin, hIAPP did not spontaneously develop β-sheet secondary structure or form fibrils. Insulin interacted with pre-formed IAPP fibrils in a regular repeating pattern, as demonstrated by immunoEM, suggesting that the binding sites for insulin remain exposed in hIAPP fibrils. Since rIAPP and hIAPP form complexes with insulin (and each other), this could explain the lack of amyloid fibrils in transgenic mice expressing hIAPP. It is likely that IAPP fibrillogenesis is inhibited in secretory granules (where the hIAPP concentration is in the millimolar range) by heteromolecular complex formation with insulin. Alterations in the proportions of insulin and IAPP in granules could disrupt the stability of the peptide. The increase in the proportion of unprocessed pro-insulin produced in Type 2 diabetes could be a major factor in destabilization of hIAPP and induction of fibril formation.

scholarly journals Graphene quantum dots against human IAPP aggregation and toxicity in vivo

Nanoscale ◽  
2018 ◽  
Vol 10 (42) ◽  
pp. 19995-20006 ◽  
Author(s):  
Miaoyi Wang ◽  
Yunxiang Sun ◽  
Xueying Cao ◽  
Guotao Peng ◽  
Ibrahim Javed ◽  
...  
Keyword(s):  
Quantum Dots ◽  
Islet Amyloid Polypeptide ◽  
Graphene Quantum Dots ◽  
Human Islet ◽  
Zebrafish Embryos ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

Graphene quantum dots are biocompatible zero-dimensional nanostructures, which displayed a potency in rescuing zebrafish embryos from the toxicity of human islet amyloid polypeptide.

Endothelin-1 and pancreatic islet vasculature: studies in vivo and on isolated, vascularly perfused pancreatic islets

2007 ◽  
Vol 292 (6) ◽  
pp. E1616-E1623 ◽  
Author(s):  
En Yin Lai ◽  
A. Erik G. Persson ◽  
Birgitta Bodin ◽  
Örjan Källskog ◽  
Arne Andersson ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pancreatic Islet ◽  
Vascular Reactivity ◽  
Blood Perfusion ◽  
Receptor Subtype ◽  
Endothelin 1 ◽  
Islet Blood Flow ◽  
Endothelin B

Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor, which also stimulates insulin release. The aim of the present study was to evaluate whether exogenously administered ET-1 affected pancreatic islet blood flow in vivo in rats and the islet arteriolar reactivity in vitro in mice. Furthermore, we aimed to determine the ET-receptor subtype that was involved in such responses. When applying a microsphere technique for measurements of islet blood perfusion in vivo, we found that ET-1 (5 nmol/kg) consistently and markedly decreased total pancreatic and especially islet blood flow, despite having only minor effects on blood pressure. Neither endothelin A (ETA) receptor (BQ-123) nor endothelin-B (ETB) receptor (BQ-788) antagonists, alone or in combination, could prevent this reduction in blood flow. To avoid confounding interactions in vivo, we also examined the arteriolar vascular reactivity in isolated, perfused mouse islets. In the latter preparation, we demonstrated a dose-dependent constriction in response to ET-1. Administration of BQ-123 prevented this, whereas BQ-788 induced a right shift in the response. In conclusion, the pancreatic islet vasculature is highly sensitive to exogenous ET-1, which mediates its effect mainly through ETA receptors.

scholarly journals Loss of perlecan heparan sulfate glycosaminoglycans lowers body weight and decreases islet amyloid deposition in human islet amyloid polypeptide transgenic mice

2019 ◽  
Vol 32 (2) ◽  
pp. 95-102
Author(s):  
Andrew T Templin ◽  
Mahnaz Mellati ◽  
Raija Soininen ◽  
Meghan F Hogan ◽  
Nathalie Esser ◽  
...  
Keyword(s):  
Body Weight ◽  
Transgenic Mice ◽  
Heparan Sulfate ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Deposition ◽  
Secretory Product ◽  
Cell Area ◽  
Β Cell ◽  
Islet Amyloid

Abstract Islet amyloid is a pathologic feature of type 2 diabetes (T2D) that is associated with β-cell loss and dysfunction. These amyloid deposits form via aggregation of the β-cell secretory product islet amyloid polypeptide (IAPP) and contain other molecules including the heparan sulfate proteoglycan perlecan. Perlecan has been shown to bind amyloidogenic human IAPP (hIAPP) via its heparan sulfate glycosaminoglycan (HS GAG) chains and to enhance hIAPP aggregation in vitro. We postulated that reducing the HS GAG content of perlecan would also decrease islet amyloid deposition in vivo. hIAPP transgenic mice were crossed with Hspg2Δ3/Δ3 mice harboring a perlecan mutation that prevents HS GAG attachment (hIAPP;Hspg2Δ3/Δ3), and male offspring from this cross were fed a high fat diet for 12 months to induce islet amyloid deposition. At the end of the study body weight, islet amyloid area, β-cell area, glucose tolerance and insulin secretion were analyzed. hIAPP;Hspg2Δ3/Δ3 mice exhibited significantly less islet amyloid deposition and greater β-cell area compared to hIAPP mice expressing wild type perlecan. hIAPP;Hspg2Δ3/Δ3 mice also gained significantly less weight than other genotypes. When adjusted for differences in body weight using multiple linear regression modeling, we found no differences in islet amyloid deposition or β-cell area between hIAPP transgenic and hIAPP;Hspg2Δ3/Δ3 mice. We conclude that loss of perlecan exon 3 reduces islet amyloid deposition in vivo through indirect effects on body weight and possibly also through direct effects on hIAPP aggregation. Both of these mechanisms may promote maintenance of glucose homeostasis in the setting of T2D.

Effect of Fusidic Acid on Pancreatic Islet Allograft Rejection

1997 ◽  
Vol 6 (1) ◽  
pp. 39-45 ◽  
Author(s):  
Josá F. Mendola ◽  
Helena Corominola ◽  
Enric Esmatjes ◽  
Alex Saenz ◽  
Laureano Fernandez-Cruz ◽  
...  
Keyword(s):  
Pancreatic Islet ◽  
Fusidic Acid ◽  
Allograft Rejection ◽  
Diabetic Rats ◽  
Allograft Survival ◽  
Islet Allograft ◽  
Islet Allografts ◽  
Acinar Tissue

We examined in fully mismatched rats, the survival of pancreatic islet allografts in recipients treated with either fusidic acid (FA), an antistaphyllococcal antibiotic that has been shown to possess an immunosuppressive effect in vitro and in vivo, or cyclosporin-A (CsA). Islets were isolated by collagenase digestion, separated from acinar tissue by handpicking under a dissecting microscope and transplanted into the liver by portal vein injection of streptozotocin(STZ)-induced diabetic rats. The results indicated that while a temporary immunosuppression with CsA achieved an indefinite islet allograft survival, FA administered to recipients daily was not able to prevent islet allograft rejection across a major histocompatibility barrier. We conclude that despite the fact that fusidic acid has been claimed to act as an immunosuppressant drug in vitro with effects similar to those of CsA, unlike CsA, FA given either orally or by s.c. injection was not effective to prolong islet allograft survival in vivo. Copyright © 1997 Elsevier Science Inc.

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