Islet Amyloid Formed From Diabetes-Associated Peptide May Be Pathogenic in Type-2 Diabetes

Clark, Anne; Lewis, Claire E.; Willis, Antony C.; Cooper, Garth J. S.; Morris, John F.; Reid, Kenneth B.M.; Turner, R. C.

doi:10.1016/s0140-6736(87)90825-7

Cited by 329 publications

(204 citation statements)

References 25 publications

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“…IAPP was first isolated from amyloid deposits in an insulin-producing pancreatic tumor and from pancreatic islet amyloid in patients with type 2 diabetes mellitus (31,32). Highest levels of this protein are normally encountered in pancreatic beta cells.…”

Section: Genechip Analysis Of Genes Regulated By Rnai Knockdown Of Mamentioning

confidence: 99%

RNA interference of achaete–scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites

Wang²,

Stormo³

et al. 2004

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

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We have previously characterized a transgenic mouse model (CR2-TAg) of metastatic prostate cancer arising in the neuroendocrine (NE) cell lineage. Biomarkers of NE differentiation in this model are expressed in conventional adenocarcinoma of the prostate with NE features. To further characterize the pathways that control NE proliferation, differentiation, and survival, we established prostate NE cancer (PNEC) cell lines from CR2-TAg prostate tumors and metastases. GeneChip analyses of cell lines harvested at different passages, and as xenografted tumors, indicated that PNECs express consistent features ex vivo and in vivo and share a remarkable degree of similarity with primary CR2-TAg prostate NE tumors. PNECs express mAsh1, a basic helix-loop-helix (bHLH) transcription factor essential for NE cell differentiation in other tissues. RNA interference knockdown of mAsh1, GeneChip comparisons of treated and control cell populations, and a computational analysis of down-regulated genes identified 12 transcriptional motifs enriched in the gene set. Affected genes, including Adcy9, Hes6, Iapp1, Ndrg4, c-Myb, and Mesdc2, are enriched for a palindromic E-box motif, CAGCTG, indicating that it is a physiologically relevant mAsh1 binding site. The enrichment of a c-Myb binding site and the finding that c-Myb is down-regulated by mAsh1 RNA interference suggest that mAsh1 and c-Myb are in the same signaling pathway. Our data indicate that mAsh1 negatively regulates the cell cycle (e.g., via enhanced Cdkn2d, Bub1 expression), promotes differentiation (e.g., through effects on cAMP), and enhances survival by inhibiting apoptosis. PNEC cell lines should be generally useful for genetic and͞or pharmacologic studies of the regulation of NE cell proliferation, differentiation, and tumorigenesis.neuroendocrine cell biology ͉ mouse prostate neuroendocrine cancer cell lines ͉ mAsh1 ͉ functional genomics ͉ phylogenetic footprinting T he prostate is a tubuloaveolar gland lined with a slowly renewing epithelium composed of three cell lineages. Secretory luminal cells predominate. Lineage progenitors appear to reside in a basal cell layer underlying luminal cells. A small population of scattered neuroendocrine (NE) cells produce dendrite-like processes that extend over several cell diameters to contact members of the other two epithelial lineages. Although they export a number of neuropeptides (1-3), the precise role played by NE cells in normal prostate physiology remains unclear.Pure NE tumors of the prostate are rare but, like most NE cell cancers, are very aggressive. Conventional adenocarcinoma of the human prostate (CaP) can display features of focal NE differentiation (NED) even when initiation does not occur in NE cells. The reported frequency of NED in CaP ranges from 30% to 100% depending on the study design and the biomarker panel used to define the phenotype (4-6). Recent findings indicate that NED correlates with poor prognosis and androgen-independent growth (7-9).The mechanisms governing development of NED in CaP are obscur...

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Section: Genechip Analysis Of Genes Regulated By Rnai Knockdown Of Mamentioning

confidence: 99%

RNA interference of achaete–scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites

Wang²,

Stormo³

et al. 2004

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

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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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“…Islet amyloid polypeptide, (amylin) is the major component of the insoluble pancreatic amyloid fibrils present in Type II diabetes [11,12]. It is a normally soluble 37-amino-acid peptide synthesised in betacells, co-localised with insulin in beta-cell granules [13] and co-secreted in response to beta-cell secretagogues [14,15].…”

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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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Islet Amyloid Formed From Diabetes-Associated Peptide May Be Pathogenic in Type-2 Diabetes

Cited by 329 publications

References 25 publications

RNA interference of achaete–scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites

RNA interference of achaete–scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites

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

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

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