scholarly journals The Effect of Cholesterol on Membrane-Bound Islet Amyloid Polypeptide

2021 ◽  
Vol 8 ◽  
Author(s):  
Mikkel Christensen ◽  
Nils A. Berglund ◽  
Birgit Schiøtt
Keyword(s):  
Pancreatic Beta Cells ◽  
Cell Mass ◽  
Islet Amyloid Polypeptide ◽  
Beta Cell Mass ◽  
Helical Structure ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Insertion Depth ◽  
Membrane Bound

Islet amyloid polypeptide (IAPP) is a proposed cause of the decreased beta-cell mass in patients with type-II diabetes. The molecular composition of the cell-membrane is important for regulating IAPP cytotoxicity and aggregation. Cholesterol is present at high concentrations in the pancreatic beta-cells, and in-vitro experiments have indicated that it affects the amyloid formation of IAPP either by direct interactions or by changing the properties of the membrane. In this study we apply atomistic, unbiased molecular dynamics simulations at a microsecond timescale to investigate the effect of cholesterol on membrane bound IAPP. Simulations were performed with various combinations of cholesterol, phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. In all simulations, the helical structure of monomer IAPP was stabilized by the membrane. We found that cholesterol decreased the insertion depth of IAPP compared to pure phospholipid membranes, while PS lipids counteract the effect of cholesterol. The aggregation propensity has previously been proposed to correlate with the insertion depth of IAPP, which we found to decrease with the increased ordering of the lipids induced by cholesterol. Cholesterol is depleted in the vicinity of IAPP, and thus our results suggest that the effect of cholesterol is indirect.

Conformational transitions of islet amyloid polypeptide (IAPP) in amyloid formation in Vitro

1999 ◽  
Vol 287 (4) ◽  
pp. 781-796 ◽  
Author(s):  
Rakez Kayed ◽  
Jürgen Bernhagen ◽  
Norma Greenfield ◽  
Khuloud Sweimeh ◽  
Herwig Brunner ◽  
...  
Keyword(s):  
Islet Amyloid Polypeptide ◽  
Conformational Transitions ◽  
Amyloid Formation ◽  
Islet Amyloid

scholarly journals Extracellular vesicles from human pancreatic islets suppress human islet amyloid polypeptide amyloid formation

2017 ◽  
Vol 114 (42) ◽  
pp. 11127-11132 ◽  
Author(s):  
Diana Ribeiro ◽  
Istvan Horvath ◽  
Nikki Heath ◽  
Ryan Hicks ◽  
Anna Forslöw ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Extracellular Vesicles ◽  
Islet Amyloid Polypeptide ◽  
Cell Communication ◽  
Human Islet ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Amyloid Deposits

Extracellular vesicles (EVs) are small vesicles released by cells to aid cell–cell communication and tissue homeostasis. Human islet amyloid polypeptide (IAPP) is the major component of amyloid deposits found in pancreatic islets of patients with type 2 diabetes (T2D). IAPP is secreted in conjunction with insulin from pancreatic β cells to regulate glucose metabolism. Here, using a combination of analytical and biophysical methods in vitro, we tested whether EVs isolated from pancreatic islets of healthy patients and patients with T2D modulate IAPP amyloid formation. We discovered that pancreatic EVs from healthy patients reduce IAPP amyloid formation by peptide scavenging, but T2D pancreatic and human serum EVs have no effect. In accordance with these differential effects, the insulin:C-peptide ratio and lipid composition differ between EVs from healthy pancreas and EVs from T2D pancreas and serum. It appears that healthy pancreatic EVs limit IAPP amyloid formation via direct binding as a tissue-specific control mechanism.

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.

Genetic background determines the extent of islet amyloid formation in human islet amyloid polypeptide transgenic mice

2005 ◽  
Vol 289 (4) ◽  
pp. E703-E709 ◽  
Author(s):  
Rebecca L. Hull ◽  
Melissah R. Watts ◽  
Keiichi Kodama ◽  
Zhen-ping Shen ◽  
Kristina M. Utzschneider ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Genetic Background ◽  
Cell Mass ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Deposition ◽  
Human Islet ◽  
Amyloid Formation ◽  
Β Cell ◽  
Islet Amyloid ◽  
Background Strain

Genetic background is important in determining susceptibility to metabolic abnormalities such as insulin resistance and β-cell dysfunction. Islet amyloid is associated with reduced β-cell mass and function and develops in the majority of our C57BL/6J × DBA/2J (F1) male human islet amyloid polypeptide (hIAPP) transgenic mice after 1 yr of increased fat feeding. To determine the relative contribution of each parental strain, C57BL/6J (BL6) and DBA/2J (DBA2), to islet amyloid formation, we studied male hIAPP mice on each background strain (BL6, n = 13; and DBA2 n = 11) and C57BL/6J × DBA/2J F1mice ( n = 17) on a 9% (wt/wt) fat diet for 1 yr. At the end of 12 mo, islet amyloid deposition was quantified from thioflavin S-stained pancreas sections. The majority of mice in all groups developed islet amyloid (BL6: 91%, F1: 76%, DBA2: 100%). However, the prevalence (%amyloid-positive islets; BL6: 14 ± 3%, F1: 44 ± 8%, DBA2: 49 ± 9%, P < 0.05) and severity (%islet area occupied by amyloid; BL6: 0.03 ± 0.01%, F1: 9.2 ± 2.9%, DBA2: 5.7 ± 2.3%, p ≤ 0.01) were significantly lower in BL6 than F1and DBA2 mice. Increased islet amyloid severity was negatively correlated with insulin-positive area per islet, in F1( r2= 0.75, P < 0.001) and DBA2 ( r2= 0.87, P < 0.001) mice but not BL6 mice ( r2= 0.07). In summary, the extent of islet amyloid formation in hIAPP transgenic mice is determined by background strain, with mice expressing DBA/2J genes (F1and DBA2 mice) being more susceptible to amyloid deposition that replaces β-cell mass. These findings underscore the importance of genetic and environmental factors in studying metabolic disease.

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

scholarly journals Inhibition of glycosaminoglycan synthesis and protein glycosylation with WAS-406 and azaserine result in reduced islet amyloid formation in vitro

2007 ◽  
Vol 293 (5) ◽  
pp. C1586-C1593 ◽  
Author(s):  
Rebecca L. Hull ◽  
Sakeneh Zraika ◽  
Jayalakshmi Udayasankar ◽  
Robert Kisilevsky ◽  
Walter A. Szarek ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Cell Mass ◽  
Amyloid Deposition ◽  
Protein Glycosylation ◽  
Amyloid Formation ◽  
Β Cell ◽  
Islet Amyloid ◽  
Glycosaminoglycan Synthesis ◽  
Amyloid A

Deposition of islet amyloid polypeptide (IAPP) as amyloid in the pancreatic islet occurs in ∼90% of individuals with Type 2 diabetes and is associated with decreased islet β-cell mass and function. Human IAPP (hIAPP), but not rodent IAPP, is amyloidogenic and toxic to islet β-cells. In addition to IAPP, islet amyloid deposits contain other components, including heparan sulfate proteoglycans (HSPGs). The small molecule 2-acetamido-1,3,6-tri- O-acetyl-2,4-dideoxy-α-d- xylo-hexopyranose (WAS-406) inhibits HSPG synthesis in hepatocytes and blocks systemic amyloid A deposition in vivo. To determine whether WAS-406 inhibits localized amyloid formation in the islet, we incubated hIAPP transgenic mouse islets for up to 7 days in 16.7 mM glucose (conditions that result in amyloid deposition) plus increasing concentrations of the inhibitor. WAS-406 at doses of 0, 10, 100, and 1,000 μM resulted in a dose-dependent decrease in amyloid deposition (% islet area occupied by amyloid: 0.66 ± 0.14%, 0.10 ± 0.06%, 0.09 ± 0.07%, and 0.004 ± 0.003%, P < 0.001) and an increase in β-cell area in hIAPP transgenic islets (55.0 ± 2.6 vs. 60.6 ± 2.2% islet area for 0 vs. 100 μM inhibitor, P = 0.05). Glycosaminoglycan, including heparan sulfate, synthesis was inhibited in both hIAPP transgenic and nontransgenic islets (the latter is a control that does not develop amyloid), while O-linked protein glycosylation was also decreased, and WAS-406 treatment tended to decrease islet viability in nontransgenic islets. Azaserine, an inhibitor of the rate-limiting step of the hexosamine biosynthesis pathway, replicated the effects of WAS-406, resulting in reduction of O-linked protein glycosylation and glycosaminoglycan synthesis and inhibition of islet amyloid formation. In summary, interventions that decrease both glycosaminoglycan synthesis and O-linked protein glycosylation are effective in reducing islet amyloid formation, but their utility as pharmacological agents may be limited due to adverse effects on the islet.

scholarly journals Matrix Metalloproteinase-9 Reduces Islet Amyloid Formation by Degrading Islet Amyloid Polypeptide

2012 ◽  
Vol 288 (5) ◽  
pp. 3553-3559 ◽  
Author(s):  
Kathryn Aston-Mourney ◽  
Sakeneh Zraika ◽  
Jayalakshmi Udayasankar ◽  
Shoba L. Subramanian ◽  
Pattie S. Green ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Islet Amyloid Polypeptide ◽  
Matrix Metalloproteinase 9 ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Metalloproteinase 9

scholarly journals PET Imaging of GPR44 by Antagonist [11C]MK-7246 in Pigs

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 434
Author(s):  
Pierre Cheung ◽  
Bo Zhang ◽  
Emmi Puuvuori ◽  
Sergio Estrada ◽  
Mohammad A. Amin ◽  
...  
Keyword(s):  
Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Emission Tomography ◽  
Pet Tracer ◽  
Positron Emission ◽  
In Vitro Cell Lines ◽  
Membrane Spanning ◽  
New Strategies

A validated imaging marker for beta-cell mass would improve understanding of diabetes etiology and enable new strategies in therapy development. We previously identified the membrane-spanning protein GPR44 as highly expressed and specific to the beta cells of the pancreas. The selective GPR44 antagonist MK-7246 was radiolabeled with carbon-11 and the resulting positron-emission tomography (PET) tracer [11C]MK-7246 was evaluated in a pig model and in vitro cell lines. The [11C]MK-7246 compound demonstrated mainly hepatobiliary excretion with a clearly defined pancreas, no spillover from adjacent tissues, and pancreatic binding similar in magnitude to the previously evaluated GPR44 radioligand [11C]AZ12204657. The binding could be blocked by preadministration of nonradioactive MK-7246, indicating a receptor-binding mechanism. [11C]MK-7246 showed strong potential as a PET ligand candidate for visualization of beta-cell mass (BCM) and clinical translation of this methodology is ongoing.

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.

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