scholarly journals Novel Human Insulin Isoforms and Cα-peptide Product in Islets of Langerhans and Choroid Plexus

2021 ◽  
Author(s):  
Qing-Rong Liu ◽  
Min Zhu ◽  
Pingbo Zhang ◽  
Caio H. Mazucanti ◽  
Nicholas S. Huang ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Islets Of Langerhans ◽  
Human Insulin ◽  
Mammalian Species ◽  
Peptide Sequence ◽  
Upstream Open Reading Frame ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
C Peptide

<a>Human insulin (<i>INS</i>) gene diverged from the ancestral genes of invertebrate and mammalian species millions of years ago. We previously found that mouse insulin gene (<i>Ins2</i>) isoforms are expressed in brain choroid plexus (ChP) epithelium cells where insulin secretion is regulated by serotonin and not by glucose. We further compared human <i>INS</i> isoform expression in postmortem <u>ChP</u> and islets of Langerhans. We uncovered novel <i>INS</i> upstream open reading frame (uORF) isoforms and their protein products. In addition, we found a novel alternatively spliced isoform that translates to a 74-amino acid (AA) proinsulin containing a shorter 19-AA C-peptide sequence, herein designated C</a>a-peptide. The middle portion of the conventional C-peptide contains b-sheet (GQVEL) and hairpin (GGGPG) motifs that are not present in Ca-peptide. Islet amyloid polypeptide (<i>IAPP</i>) is not expressed in ChP and its amyloid formation was inhibited <i>in vitro</i> by Ca-peptide more efficiently than by C-peptide. Of clinical relevance, the ratio of the 74-AA proinsulin to proconvertase processed Ca-peptide was significantly increased in islets from type 2 diabetes mellitus (T2DM) autopsy donors. Intriguingly, 100 years after the discovery of insulin we found that <i>INS</i> isoforms are present in ChP <a>from insulin-deficient autopsy donors.</a> <p> </p>

scholarly journals Novel Human Insulin Isoforms and Cα-peptide Product in Islets of Langerhans and Choroid Plexus

2021 ◽  
Author(s):  
Qing-Rong Liu ◽  
Min Zhu ◽  
Pingbo Zhang ◽  
Caio H. Mazucanti ◽  
Nicholas S. Huang ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Islets Of Langerhans ◽  
Human Insulin ◽  
Mammalian Species ◽  
Peptide Sequence ◽  
Upstream Open Reading Frame ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
C Peptide

<a>Human insulin (<i>INS</i>) gene diverged from the ancestral genes of invertebrate and mammalian species millions of years ago. We previously found that mouse insulin gene (<i>Ins2</i>) isoforms are expressed in brain choroid plexus (ChP) epithelium cells where insulin secretion is regulated by serotonin and not by glucose. We further compared human <i>INS</i> isoform expression in postmortem <u>ChP</u> and islets of Langerhans. We uncovered novel <i>INS</i> upstream open reading frame (uORF) isoforms and their protein products. In addition, we found a novel alternatively spliced isoform that translates to a 74-amino acid (AA) proinsulin containing a shorter 19-AA C-peptide sequence, herein designated C</a>a-peptide. The middle portion of the conventional C-peptide contains b-sheet (GQVEL) and hairpin (GGGPG) motifs that are not present in Ca-peptide. Islet amyloid polypeptide (<i>IAPP</i>) is not expressed in ChP and its amyloid formation was inhibited <i>in vitro</i> by Ca-peptide more efficiently than by C-peptide. Of clinical relevance, the ratio of the 74-AA proinsulin to proconvertase processed Ca-peptide was significantly increased in islets from type 2 diabetes mellitus (T2DM) autopsy donors. Intriguingly, 100 years after the discovery of insulin we found that <i>INS</i> isoforms are present in ChP <a>from insulin-deficient autopsy donors.</a> <p> </p>

scholarly journals Low concentration IL-1β promotes islet amyloid formation by increasing hIAPP release from humanised mouse islets in vitro

Diabetologia ◽  
2020 ◽  
Vol 63 (11) ◽  
pp. 2385-2395
Author(s):  
Andrew T. Templin ◽  
Mahnaz Mellati ◽  
Daniel T. Meier ◽  
Nathalie Esser ◽  
Meghan F. Hogan ◽  
...  
Keyword(s):  
Amyloid Formation ◽  
Islet Amyloid ◽  
Low Concentration ◽  
Mouse Islets

Tissue Plasminogen Activator (tPA) Expression Is Increased by Islet Amyloid Formation In Vitro

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 2107-P
Author(s):  
NATHALIE ESSER ◽  
MEGHAN F. HOGAN ◽  
ANDREW T. TEMPLIN ◽  
MARK ZIEMANN ◽  
ASSAM EL-OSTA ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Tissue Plasminogen

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 Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity

Biomolecules ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 134 ◽  
Author(s):  
Anna L. Gharibyan ◽  
Tohidul Islam ◽  
Nina Pettersson ◽  
Solmaz A. Golchin ◽  
Johanna Lundgren ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Formation ◽  
Loss Of Function ◽  
Islet Amyloid ◽  
Amyloid Deposits ◽  
Primary Focus ◽  
The Impact

Apolipoprotein E (ApoE) has become a primary focus of research after the discovery of its strong linkage to Alzheimer’s disease (AD), where the ApoE4 variant is the highest genetic risk factor for this disease. ApoE is commonly found in amyloid deposits of different origins, and its interaction with amyloid-β peptide (Aβ), the hallmark of AD, is well known. However, studies on the interaction of ApoEs with other amyloid-forming proteins are limited. Islet amyloid polypeptide (IAPP) is an amyloid-forming peptide linked to the development of type-2 diabetes and has also been shown to be involved in AD pathology and vascular dementia. Here we studied the impact of ApoE on IAPP aggregation and IAPP-induced toxicity on blood vessel pericytes. Using both in vitro and cell-based assays, we show that ApoE efficiently inhibits the amyloid formation of IAPP at highly substoichiometric ratios and that it interferes with both nucleation and elongation. We also show that ApoE protects the pericytes against IAPP-induced toxicity, however, the ApoE4 variant displays the weakest protective potential. Taken together, our results suggest that ApoE has a generic amyloid-interfering property and can be protective against amyloid-induced cytotoxicity, but there is a loss of function for the ApoE4 variant.

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 Glucose- and time-dependence of islet amyloid formation in vitro

2007 ◽  
Vol 354 (1) ◽  
pp. 234-239 ◽  
Author(s):  
Sakeneh Zraika ◽  
Rebecca L. Hull ◽  
Jayalakshmi Udayasankar ◽  
Kristina M. Utzschneider ◽  
Jenny Tong ◽  
...  
Keyword(s):  
Time Dependence ◽  
Amyloid Formation ◽  
Islet Amyloid

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.

scholarly journals A novel assay in vitro of human islet amyloid polypeptide amyloidogenesis and effects of insulin secretory vesicle peptides on amyloid formation

1998 ◽  
Vol 331 (3) ◽  
pp. 809-813 ◽  
Author(s):  
Yogish C. KUDVA ◽  
Cheryl MUESKE ◽  
Peter C. BUTLER ◽  
Norman L. EBERHARDT
Keyword(s):  
Diabetes Mellitus ◽  
Islet Amyloid Polypeptide ◽  
Insulin Dependent Diabetes Mellitus ◽  
Human Islet ◽  
Dependent Diabetes Mellitus ◽  
Amyloid Formation ◽  
Β Cell ◽  
Islet Amyloid ◽  
C Peptide ◽  
Insulin Dependent

Human islet amyloid polypeptide (IAPP) is a 37-residue peptide that is co-secreted with insulin by the β-cell and might be involved in the pathogenesis of non-insulin-dependent diabetes mellitus. We developed an improved assay in vitrobased on the fluorescence of bound thioflavin T to study factors affecting amyloidogenesis. Monomeric IAPP formed amyloid fibrils, as detected by increased fluorescence and by electron microscopy. Fluorimetric analysis revealed that the initial rate of amyloid formation was: (1) proportional to the peptide monomer concentration, (2) maximal at pH 9.5, (3) maximal at 200 mM KCl, and (4) proportional to temperature from 4 to 37 °C. We found that 5-fold and 10-fold molar excesses of proinsulin inhibited fibril formation by 39% and 59% respectively. Insulin was somewhat more potent with 5-fold and 10-fold molar excesses inhibiting fibril formation by 69% and 73% respectively, whereas C-peptide had no effect at these concentrations. Thus at physiological ratios of IAPP to insulin, insulin and proinsulin, but not C-peptide, can retard amyloidogenesis. Because insulin resistance or hyperglycaemia increase the IAPP-to-insulin ratio, increased intracellular IAPP compared with insulin expression in genetically predisposed individuals might contribute to intracellular amyloid formation, β-cell death and the genesis of non-insulin-dependent diabetes mellitus.

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