scholarly journals Measurement of Pro-Islet Amyloid Polypeptide (1–48) in Diabetes and Islet Transplants

2017 ◽  
Vol 102 (7) ◽  
pp. 2595-2603 ◽  
Author(s):  
Jaques A. Courtade ◽  
Agnieszka M. Klimek-Abercrombie ◽  
Yi-Chun Chen ◽  
Nirja Patel ◽  
Phoebe Y. T. Lu ◽  
...  
Keyword(s):  
Limit Of Detection ◽  
Plasma Concentrations ◽  
Islet Amyloid Polypeptide ◽  
Cross Reactivity ◽  
Intermediate Form ◽  
Β Cells ◽  
Β Cell ◽  
Islet Amyloid ◽  
Prohormone Processing ◽  
Islet Transplants

Abstract Context: Islet amyloid is a feature of β-cell failure in type 2 diabetes (T2D) and type 1 diabetes (T1D) recipients of islet transplants. Islet amyloid contains islet amyloid polypeptide (IAPP; amylin), a circulating peptide that is produced in β cells by processing of its precursor, proIAPP1-67, via an intermediate form, proIAPP1-48. Elevated proinsulin to C-peptide ratios in the plasma of persons with diabetes suggest defects in β-cell prohormone processing. Objective: Determine whether plasma levels of precursor forms of IAPP are elevated in diabetes. Design, Setting, and Patients: We developed an immunoassay to detect proIAPP1-48 in human plasma, and we determined the ratio of proIAPP1-48 to mature IAPP in subjects with T1D, T2D, recipients of islet transplants, and healthy controls. Results: The proIAPP1-48 immunoassay had a limit of detection of 0.18 ± 0.06 pM and cross-reactivity with intact proIAPP1-67 <15%. Healthy individuals had plasma concentrations of proIAPP1-48 immunoreactivity of 1.5 ± 0.2 pM and a proIAPP1-48 to total IAPP ratio of 0.28 ± 0.03. Plasma concentrations of proIAPP1-48 immunoreactivity were not significantly different in subjects with T2D but were markedly increased in T1D recipients of islet transplants. Children and adults with T1D had reduced mature IAPP levels relative to age-matched controls but an elevated ratio of proIAPP1-48 to total IAPP. Conclusion: The β cells in T1D and islet transplants have impaired processing of the proIAPP1-48 intermediate. The ratio of proIAPP1-48-to-IAPP immunoreactivity may have value as a biomarker of β-cell stress and dysfunction.

scholarly journals An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jinyoung Kim ◽  
Kihyoun Park ◽  
Min Jung Kim ◽  
Hyejin Lim ◽  
Kook Hwan Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Therapeutic Modality ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Islet Amyloid ◽  
Amyloid Accumulation ◽  
Human Diabetes

AbstractWe have reported that autophagy is crucial for clearance of amyloidogenic human IAPP (hIAPP) oligomer, suggesting that an autophagy enhancer could be a therapeutic modality against human diabetes with amyloid accumulation. Here, we show that a recently identified autophagy enhancer (MSL-7) reduces hIAPP oligomer accumulation in human induced pluripotent stem cell-derived β-cells (hiPSC-β-cells) and diminishes oligomer-mediated apoptosis of β-cells. Protective effects of MSL-7 against hIAPP oligomer accumulation and hIAPP oligomer-mediated β-cell death are significantly reduced in cells with knockout of MiTF/TFE family members such as Tfeb or Tfe3. MSL-7 improves glucose tolerance and β-cell function of hIAPP+ mice on high-fat diet, accompanied by reduced hIAPP oligomer/amyloid accumulation and β-cell apoptosis. Protective effects of MSL-7 against hIAPP oligomer-mediated β-cell death and the development of diabetes are also significantly reduced by β-cell-specific knockout of Tfeb. These results suggest that an autophagy enhancer could have therapeutic potential against human diabetes characterized by islet amyloid accumulation.

scholarly journals Graphene quantum dots rescue protein dysregulation of pancreatic β-cells exposed to human islet amyloid polypeptide

Nano Research ◽  
2019 ◽  
Vol 12 (11) ◽  
pp. 2827-2834 ◽  
Author(s):  
Ava Faridi ◽  
Yunxiang Sun ◽  
Monika Mortimer ◽  
Ritchlynn R. Aranha ◽  
Aparna Nandakumar ◽  
...  
Keyword(s):  
Quantum Dots ◽  
Islet Amyloid Polypeptide ◽  
Graphene Quantum Dots ◽  
Human Islet ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

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.

scholarly journals Lipid Modulation in the Formation of β-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on β-Cell Homeostasis

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1201 ◽  
Author(s):  
Israel Martínez-Navarro ◽  
Raúl Díaz-Molina ◽  
Angel Pulido-Capiz ◽  
Jaime Mas-Oliva ◽  
Ismael Luna-Reyes ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Membrane Lipids ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Β Cells ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Insulin Granules ◽  
The Impact ◽  
Β Sheet

Human islet amyloid polypeptide (hIAPP) corresponds to a 37-residue hormone present in insulin granules that maintains a high propensity to form β-sheet structures during co-secretion with insulin. Previously, employing a biomimetic approach, we proposed a panel of optimized IAPP sequences with only one residue substitution that shows the capability to reduce amyloidogenesis. Taking into account that specific membrane lipids have been considered as a key factor in the induction of cytotoxicity, in this study, following the same design strategy, we characterize the effect of a series of lipids upon several polypeptide domains that show the highest aggregation propensity. The characterization of the C-native segment of hIAPP (residues F23-Y37), together with novel variants F23R and I26A allowed us to demonstrate an effect upon the formation of β-sheet structures. Our results suggest that zwitterionic phospholipids promote adsorption of the C-native segments at the lipid-interface and β-sheet formation with the exception of the F23R variant. Moreover, the presence of cholesterol did not modify this behavior, and the β-sheet structural transitions were not registered when the N-terminal domain of hIAPP (K1-S20) was characterized. Considering that insulin granules are enriched in phosphatidylserine (PS), the property of lipid vesicles containing negatively charged lipids was also evaluated. We found that these types of lipids promote β-sheet conformational transitions in both the C-native segment and the new variants. Furthermore, these PS/peptides arrangements are internalized in Langerhans islet β-cells, localized in the endoplasmic reticulum, and trigger critical pathways such as unfolded protein response (UPR), affecting insulin secretion. Since this phenomenon was associated with the presence of cytotoxicity on Langerhans islet β-cells, it can be concluded that the anionic lipid environment and degree of solvation are critical conditions for the stability of segments with the propensity to form β-sheet structures, a situation that will eventually affect the structural characteristics and stability of IAPP within insulin granules, thus modifying the insulin secretion.

scholarly journals β-Cell Dysfunctional ERAD/Ubiquitin/Proteasome System in Type 2 Diabetes Mediated by Islet Amyloid Polypeptide–Induced UCH-L1 Deficiency

Diabetes ◽  
2010 ◽  
Vol 60 (1) ◽  
pp. 227-238 ◽  
Author(s):  
Safia Costes ◽  
Chang-jiang Huang ◽  
Tatyana Gurlo ◽  
Marie Daval ◽  
Aleksey V. Matveyenko ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Islet Amyloid Polypeptide ◽  
Ubiquitin Proteasome System ◽  
Β Cell ◽  
Islet Amyloid ◽  
Ubiquitin Proteasome

Relationship between islet amyloid polypeptide (IAPP) deposition and insulin response and β-cell volume in diabetes mellitus

1992 ◽  
Vol 15 (1) ◽  
pp. 15-16 ◽  
Author(s):  
Tetsuro Kobayashi ◽  
Yuriko Ito ◽  
Koji Nakanish ◽  
Kazuhiko Sugawara ◽  
Minoru Okubo ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cell Volume ◽  
Islet Amyloid Polypeptide ◽  
Insulin Response ◽  
Β Cell ◽  
Islet Amyloid

scholarly journals Pancreatic β-Cell Membrane Fluidity and Toxicity Induced by Human Islet Amyloid Polypeptide Species

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Emily H. Pilkington ◽  
Esteban N. Gurzov ◽  
Aleksandr Kakinen ◽  
Sara A. Litwak ◽  
William J. Stanley ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Membrane Fluidity ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Cell Membrane Fluidity

scholarly journals Translational Control of Glucose-Induced Islet Amyloid Polypeptide Production in Pancreatic Islets

Endocrinology ◽  
2012 ◽  
Vol 153 (5) ◽  
pp. 2082-2087 ◽  
Author(s):  
Cristina Alarcon ◽  
C. Bruce Verchere ◽  
Christopher J. Rhodes
Keyword(s):  
Translational Control ◽  
Islet Amyloid Polypeptide ◽  
Glucose Regulation ◽  
Mrna Levels ◽  
Β Cells ◽  
Islet Amyloid ◽  
Isolated Rat Islets ◽  
Proprotein Processing ◽  
Isolated Rat

Dysfunctional islet amyloid polypeptide (IAPP) biosynthesis and/or processing are thought contribute to formation of islet amyloid in type 2 diabetes. However, it is unclear how normal pro-IAPP biosynthesis and processing are regulated to be able to define such dysfunction. Here, it was found that acute exposure to high glucose concentrations coordinately regulated the biosynthesis of pro-IAPP, proinsulin, and its proprotein convertase PC1/3 in normal isolated rat islets, without affecting their respective mRNA levels. Pro-7B2 biosynthesis, like that of pro-PC2, did not appreciably change, but this was likely due to a much higher expression in pancreatic α-cells masking glucose regulation of their biosynthesis in β-cells. Biosynthesis of pro-SAAS, the putative PC1/3 chaperone, was unaffected by glucose, consistent with its scarce expression in β-cells. We conclude that translational control of pro-IAPP biosynthesis, in parallel to the pro-PC1/3, pro-PC2, and pro-7B2 proprotein-processing endopeptidases/chaperones, is the predominate mechanism to produce IAPP in islet β-cells.

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