Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes.

Kahn, Steven E.; Andrikopoulos, Sof; Verchere, C. Bruce

doi:10.2337/diabetes.48.2.241

Cited by 455 publications

(411 citation statements)

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“…Obese insulin-resistant subjects have slightly increased circulating IAPP and insulin [37] and TM expressing hIAPP have plasma concentrations of IAPP of 37 to 333 pmol/l compared with 10±103 pmol/l in non-transgenic mice [6,7,8,22,38,39]. Factors additional to IAPP concentrations are, however, required for amyloid formation in vivo in TM; an obese genetic back-ground or treatment to increase insulin resistance or both appears to be a prerequisite for fibril formation [40]. Recent studies in diabetic cats have shown more extensive islet amyloid in animals treated with sulphonyureas compared with those in which islet secretion was reduced by insulin therapy, providing further support for a role for increased beta-cell stimulation in islet amyloid formation [41].…”

Section: Discussionmentioning

confidence: 99%

Amyloid fibril formation is progressive and correlates with beta-cell secretion in transgenic mouse isolated islets

et al. 1999

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Amyloid deposits are found in the islets of Langerhans of up to 96 % of patients with Type II (non-insulin-dependent) diabetes mellitus [1,2] but the relation of islet amyloid to the syndrome of diabetes is not clear. Amyloid deposition precedes the onset of hyperglycaemia in cats and monkeys [3,4] suggesting a primary aetiological role of amyloid in these species. The severity of islet amyloidosis in diabetic patients at autopsy is, however, greatest in those who have progressed from sulphonylurea to insulin treatment [5] and the degree of amyloid deposition is associated with a decrease of beta-cell function in monkeys [4] implicating islet amyloid in islet dysfunction in the later stages of the disease. An increased incidence of amyloid deposition in vivo in some strains Diabetologia (1999) Abstract Aims/hypothesis. Amyloid fibrils are formed in islets isolated from transgenic mice expressing the gene for human islet amyloid polypeptide (IAPP) by an unknown mechanism. This model of islet amyloidosis in Type II (non-insulin-dependent) diabetes mellitus has been used to investigate the temporal and glucose dependency of fibril formation. Methods. To determine the time course and nature of amyloid-like accumulations and the role of glucose, transgenic mouse islets were cultured for 2±12 days in medium containing glucose (4.2 mmol/l, 11.1 mmol/l or 16.7 mmol/l) or 3.3 mmol/l glucose plus non-glucose secretagogues, 10 mmol/l leucine, 10 mmol/l leucine + 0.1 mmol/l tolbutamide, 10 mmol/l alpha-ketoisocaproic acid + 10 mmol/l glutamine. The extent of fibril formation was determined by quantitative immuno-electron microscopy. Insulin and islet amyloid polypeptide secretion into the media was measured by radioimmunoassay. Results. Extracellular amyloid fibrils immunoreactive for islet amyloid polypeptide were visible initially after 6 days of culture in 11.1 mmol/l glucose and formed 2.3 ± 0.8 % of the islet area after 12 days; small accumulations of intracellular fibrils and amorphous extracellular islet amyloid polypeptide-immunoreactive material were present at 6±12 days. Beta-cell secretion was increased significantly by 16.7 mmol/l glucose and by alpha-ketoisocaproic acid + glutamine. The proportion of fibrillar amyloid (amyloid area/islet area%) correlated with the amount of insulin (r = 0.55, p < 0.05) and IAPP (r = 0.5, p < 0.05) in the culture media. Evidence of cellular damage was present in less than 10 % cells and correlated with the degree of fibril deposition (r = 0.8, p < 0.0001). Conclusion/interpretation. These data suggest that islet amyloid polypeptide amyloid is formed primarily at extracellular sites in isolated transgenic mouse islets and progressive fibril formation correlates with beta-cell secretion. [Diabetologia (1999[Diabetologia ( ) 42: 1219± 1227

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Section: Discussionmentioning

confidence: 99%

Amyloid fibril formation is progressive and correlates with beta-cell secretion in transgenic mouse isolated islets

et al. 1999

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“…30,32,33 IAPP aggregates to form islet amyloid in type-2 diabetes; a process which is widely believed to contribute to b-cell death in the disease. 23,28,29,32,[34][35][36][37][38][39][40] Recent studies also highlight a potentially important role for IAPP amyloid formation in the failure of islet cell grafts. [41][42][43] There is widespread interest in developing inhibitors of amyloid formation and compounds which can disaggregate preformed amyloid.…”

Section: Introductionmentioning

confidence: 99%

Morin hydrate inhibits amyloid formation by islet amyloid polypeptide and disaggregates amyloid fibers

2012

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The polypeptide hormone Islet Amyloid Polypeptide (IAPP, amylin) is responsible for islet amyloid formation in type-2 diabetes and in islet cell transplants, where it may contribute to graft failure. Human IAPP is extremely amyloidogenic and fewer inhibitors of IAPP amyloid formation have been reported than for the Alzheimer's Ab peptide or for a-synuclein. The ability of a set of hydroxyflavones to inhibit IAPP amyloid formation was tested. Fluorescence detected thioflavin-Tbinding assays are the most popular methods for measuring the kinetics of amyloid formation and for screening potential inhibitors; however, we show that they can lead to false positives with hydroxyflavones. Several of the compounds inhibit thioflavin-T fluorescence, but not amyloid formation; a result which highlights the hazards of relying solely on thioflavin-T assays to screen potential inhibitors. Transmission electron microscopy (TEM) and right-angle light scattering show that Morin hydrate (2 0 ,3,4 0 ,5,7-Pentahydroxyflavone) inhibits amyloid formation by human IAPP and disaggregates preformed IAPP amyloid fibers. In contrast, Myricetin, Kaempferol, and Quercetin, which differ only in hydroxyl groups on the B-ring, are not effective inhibitors. Morin hydrate represents a new type of IAPP amyloid inhibitor and the results with the other compounds highlight the importance of the substitution pattern on the B-ring.

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“…to be toxic to cultured β-cells (4), and has been proposed to play a significant role in the pathogenesis of type 2 diabetes by contributing to the destruction of β-cells in the later stages of the disease (5)(6)(7). Studies with transgenic mice that express human amylin suggest that amyloid could develop uniformly throughout the islets of the pancreas from an early stage of the disease (8).…”

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Peptide Conformation and Supramolecular Organization in Amylin Fibrils: Constraints from Solid-State NMR

et al. 2007

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The 37-residue amylin peptide, also known as islet amyloid polypeptide, forms fibrils that are the main peptide or protein component of amyloid that develops in the pancreas of type 2 diabetes patients. Amylin also readily forms amyloid fibrils in vitro that are highly polymorphic under typical experimental conditions. We describe a protocol for the preparation of synthetic amylin fibrils that exhibit a single predominant morphology, which we call a striated ribbon, in electron microscope and atomic force microscope images. Solid state nuclear magnetic resonance (NMR) measurements on a series of isotopically labeled samples indicate a single molecular structure within the striated ribbons. We use scanning transmission electron microscopy and several types of one-dimensional and two-dimensional solid state NMR techniques to obtain constraints on the peptide conformation and supramolecular structure in these amylin fibrils, and derive molecular structural models that are consistent with the experimental data. The basic structural unit in amylin striated ribbons, which we call the protofilament, contains four-layers of parallel β-sheets, formed by two symmetric layers of amylin molecules. The molecular structure of amylin protofilaments in striated ribbons closely resembles the protofilament in amyloid fibrils with similar morphology formed by the 40-residue β-amyloid peptide that is associated with Alzheimer's disease. Keywordsislet amyloid polypeptide; type 2 diabetes; amyloid fibril structure; electron microscopy; atomic force microscopy Amylin, also called islet amyloid polypeptide or IAPP, is a 37-residue peptide that is cosecreted with insulin by the β-cells of pancreas. The normal biological effects of amylin secretion include inhibition of glucagon secretion and reduction of the rate of gastric emptying, effects that contribute to the maintenance of postprandial glucose homeostasis (1). Amylin is the major peptide or protein component of the islet amyloid found in the pancreas of approximately 90% of type 2 (or non-insulin-dependent) diabetes patients (2,3). Fibrillar amylin has been shown * Corresponding author: Dr. Robert Tycko, National Institutes of Health, Building 5, Room 112, Bethesda, MD 20892-0520. phone 301-402-8272. fax 301-496-0825. e-mail robertty@mail.nih.gov.Supporting Information Available HPLC chromatograms from the purification of both reduced and oxidized amylin by reverse-phase chromatography ( Figure S1); FPLC chromatograms from the purification of both human and rodent amylin by size-exclusion chromatography ( Figure S2); 1D 13 C spectra of amylin fibrils with various isotopic labeling patterns, in lyophilized and rehydrated conditions ( Figures S3-S5); Table of 13 C NMR chemical shifts in amylin fibrils, TALOS predictions of backbone torsion angles based on these shifts, and torsion angles determined from 15 N fpRFDR-CT measurements (Table S1). This material is freely available on the World Wide Web at http://www.acs.org. to be toxic to cultured β-cells (4), and has been propo...

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Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes.

Cited by 455 publications

References 0 publications

Amyloid fibril formation is progressive and correlates with beta-cell secretion in transgenic mouse isolated islets

Amyloid fibril formation is progressive and correlates with beta-cell secretion in transgenic mouse isolated islets

Morin hydrate inhibits amyloid formation by islet amyloid polypeptide and disaggregates amyloid fibers

Peptide Conformation and Supramolecular Organization in Amylin Fibrils: Constraints from Solid-State NMR

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