Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus

Lorenzo, Alfredo; Razzaboni, Bronwyn L.; Weir, Gordon C.; Yankner, Bruce A.

doi:10.1038/368756a0

Cited by 781 publications

(634 citation statements)

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“…Our data shows that IAPP fibril formation in hIAPP TM isolated islets is progressive, largely extracellular and is related to the level of secretion of beta-cell products rather than to the specific concentration of glucose in the media. There is relatively little evidence of cell damage resulting from biosynthetic IAPP fibrils developing over 6 days compared with that reported for synthetic IAPP fibrils added to cultured cells [10] but there is evidence for some cytotoxic effects of amyloid deposition.…”

Section: Discussionmentioning

confidence: 84%

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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: 84%

“…This could be explained by the proposed cytotoxic role of amyloid: fibrils formed from human synthetic islet amyloid polypeptide (IAPP) have been shown to be cytotoxic to pancreatic islet cells in vitro [10].…”

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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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“…3,4 The progressive formation of islet amyloid leads to a decrease in β-cell mass. 5 The toxicity of fibrillar IAPP was first demonstrated in the early 1990s, 6 but more recent studies suggest that oligomeric assemblies could be the proximate cytotoxic species in T2D. 3,7 A number of mechanisms behind the toxicity of IAPP oligomers have been proposed, 8 but recent biophysical studies have focused on the ability of IAPP to disrupt model membranes, as reviewed recently.…”

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confidence: 99%

Kinetic Profile of Amyloid Formation in the Presence of an Aromatic Inhibitor by Nuclear Magnetic Resonance

Liu

Gaines

Robbins

et al. 2012

ACS Med. Chem. Lett.

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The self-assembly of amyloid proteins into β-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are potential inhibitors of β-sheet formation. How these compounds affect the kinetics of self-assembly studied by thioflavin T (ThT) fluorescence is not understood primarily because their presence interferes with ThT fluorescence. Here, we show that by plotting peak intensities from nuclear magnetic resonance (NMR) against incubation time, kinetic profiles in the presence of the polyphenol can be obtained from which kinetic parameters of self-assembly can be easily determined. In applying this technique to the selfassembly of the islet amyloid polypeptide in the presence of curcumin, a biphenolic compound found in turmeric, we show that the kinetic profile is atypical in that it shows a prenucleation period during which there is no observable decrease in NMR peak intensities. KEYWORDS: amyloid, ThT fluorescence, curcumin, NMR A total of 27 proteins have been identified to form the extracellular β-sheet containing amyloid fibrils associated with human amyloidoses. 1 These include the amyloid-β protein (Aβ) in Alzheimer's disease, α-synuclein in Parkinson's disease, and the islet amyloid polypeptide (IAPP) in type 2 diabetes (T2D). In spite of the large differences in the primary structure of the precursor proteins, the mature fibrils possess common characteristics including unbranched, 10 nm wide morphology as determined by electron microscopy, the ability to bind Congo red and exhibit green birefringence, and X-ray diffraction patterns consistent with cross-β-sheet. 1 Mechanistic studies of fibril formation in hydro have shown that Aβ, α-synuclein, and IAPP undergo a random coil to β-sheet conformational transition. 2 IAPP is a 37-residue polypeptide ( Figure 1A) that is cosecreted with insulin by β-cells of the islets of Langerhans in the pancreas. Molecular biological, biophysical, and genetic evidence support a central role for IAPP in β-cell death and dysfunction associated with T2D. 3,4 The progressive formation of islet amyloid leads to a decrease in β-cell mass. 5 The toxicity of fibrillar IAPP was first demonstrated in the early 1990s, 6 but more recent studies suggest that oligomeric assemblies could be the proximate cytotoxic species in T2D. 3,7 A number of mechanisms behind the toxicity of IAPP oligomers have been proposed, 8 but recent biophysical studies have focused on the ability of IAPP to disrupt model membranes, as reviewed recently. 3 A missense mutation involving the substitution of serine at position 20 with glycine ( Figure 1A) has been linked to an early onset, more severe form of T2D. 9 The mutant polypeptide aggregates faster 10,11 and is more toxic than wildtype IAPP. 10 Together, these findings suggest that molecules that significantly delay or completely inhibit IAP...

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“…Amyloid deposit of human islet amyloid polypeptide (hIAPP) in pancreatic islets is closely associated with the pathology of type 2 diabetes by promoting pancreatic b-cell death [1][2][3][4]. Therefore, preventing hIAPP fibrillogenesis has been a primary strategy in development of therapeutic drugs for type 2 diabetes [5] and related studies have attracted much attention of researchers.…”

Section: Introductionmentioning

confidence: 99%

A hIAPP‐derived all‐d‐amino‐acid inhibits hIAPP fibrillation efficiently at membrane surface by targeting α‐helical oligomeric intermediates

Wang

Lei

et al. 2014

FEBS Letters

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Edited by Sandro Sonnino ) is demonstrated to inhibit hIAPP fibril formation efficiently both at the phospholipid membrane and in bulk solution. The inhibitor terminates hIAPP aggregation to the a-helical oligomeric intermediates at the membrane surface, whereas it stops the aggregation at the stage of b-sheet oligomeric intermediates in bulk solution. This is the first evidence that the inhibition mechanism of the inhibitor at membrane surface is significantly different from that in bulk solution. Structured summary of protein interactions:hIAPP and hIAPP bind by transmission electron microscopy (View interaction) hIAPP and hIAPP bind by atomic force microscopy (View interaction) hIAPP and hIAPP bind by fluorescence technology (View interaction) hIAPP and hIAPP bind by dynamic light scattering (View interaction)

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Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus

Cited by 781 publications

References 27 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

Kinetic Profile of Amyloid Formation in the Presence of an Aromatic Inhibitor by Nuclear Magnetic Resonance

A hIAPP‐derived all‐d‐amino‐acid inhibits hIAPP fibrillation efficiently at membrane surface by targeting α‐helical oligomeric intermediates

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