1. The major component ofislet amyloid is a 37-aminoacidpeptide, islet amyloidpolypeptide (IAPP;amy-lin) (4-6),whichis anormalsecretoryproductofthe pancre-atic f3 cell (7, 8). Islet amyloid has been shown to lead to a progressive loss of β-cell mass and function ( 8 – 11 ), and thus it has … The transplants were fixed and embedded for light microscopy. Amyloid is deposited initially adjacent to capillaries but progressively replaces islet cells. In Alzheimer’s the unique peptide is the beta-amyloid protein (Abeta) and in type 2 diabetes it is the islet amyloid polypeptide (IAPP) also known as amylin[4]. It is the most abundant component of pancreatic amyloid [1, 2]. Heparin enhances amyloid deposition in cultured human islets. Islets from patients with type 2 diabetes exhibit b cell dysfunction, amyloid deposition, macrophage infiltration, and increased expression of proinflammatory cytokines and chemokines. 2007, Stull et al. Figure 2. Objective: Hyperamylinemia, a common pancreatic disorder in obese and insulin-resistant patients, is known to cause amylin oligomerization and cytotoxicity in pancreatic islets, leading to β-cell mass depletion and development of type 2 diabetes. Formation of islet amyloid deposits from restores glucose homeostasis and prevents islet amyloid deposition in mice overexpressing hIAPP in pancreatic islets. Amyloid deposits and apoptosis in endocrine pancreatic islets. It is poorly understood how the building block of amyloid, islet amyloid polypeptide (IAPP), misfolds and accumulates within the islet to contribute to cellular dysfunction. Islets were immunostained for insulin (red) and stained for amyloid with Thioflavin S (ThioS; green). Pancreatic islets were isolated from C57BL/6 and transgenic mice using modifications of prior methods (Szot et al. 4. Localized amyloid deposition in the islets of Langerhans is more frequent in the pancreas in patients with diabetes mellitus. AMYLOID DEPOSITS IN TRANSPLANTED PANCREATIC ISLETS INFLUENCE OF IMPLANTATION SITE, FUNCTIONAL ACTIVITY, AND MICROENCAPSULATION. N Engl J Med 2008;359(9):977–9. Consistent with MMP-9 cleavage resulting in largely non-amyloidogenic degradation products, adenoviral overexpression of MMP-9 in amyloid-prone islets reduced amyloid deposition and β-cell apoptosis. Amyloid Deposition in Transplanted Human Pancreatic Islets: A Conceivable Cause of Their Long-Term Failure By Arne Andersson, Sara Bohman, L. A. Håkan Borg, Johan F. Paulsson, Sebastian W. Schultz, Gunilla T. Westermark and Per Westermark Human IAPP is a 37-amino acid residue peptide, expressed as a prepromolecule. In order to study the possible progression of islet amyloid deposition, four nude mice received human islets from two different donors under the renal capsule. amyloid, first from a human insulinoma [9, 10] and later from islets of Langerhans [11, 12].Thesamepeptidewas found to form amyloid in apes [13, 14] and cats [11, 15]. Amyloid deposition in pancreatic islets, islet amyloid, is one of the most common pathologic features of T2DM, being found in more than 90% of patients at autopsy 5. The deposition of the islet amyloid polypeptide (IAPP) as insoluble amyloid fibrils in the pancreatic islets is associated with type II diabetes. 3. Even in mildly involved islets amyloid was found not as a small focal area but more as a more diffuse deposit along the capillaries. Amyloid deposition consisted of islet amyloid polypeptide (IAPP) can be observed in pancreatic biopsy of patient with T2DM. IAPP is a 37-amino acid peptide of the calcitonin gene family. Representative pancreatic tissue sections (formalin fixation) were stained generating fluorescence signals using thioflavin S (for amyloid deposits, green), TUNEL (for apoptosis, red), immune fluorescence (for insulin, cyan) and 4′,6-diamidino-2-phenylindole (for deoxyribonucleic acid /nuclei, blue) are shown (quadruple staining). 1999; 48: 448. After removal of the signal peptide, the 67-amino acid propeptide is further processed at two In our first report on the rapid deposition of amyloid in human islets transplanted into nude mice, our primary aim was to study the occurrence of IAPP-positive cells in the grafts . extracellular space where amyloid has been shown to occur (14). Progressive amyloidosis results in loss of insulin-producing cells and increased severity of disease. In addition to the β-cell secretory defect, islet amyloid deposition occurs in the pancreatic islets of the vast majority of subjects with type 2 diabetes (6,7). Westermark GT, Davalli AM, Secchi A, et al. Amyloid deposits are found in the pancreatic islets of most individuals with non-insulin-dependent diabetes mellitus (NIDDM)(1-3). Recent data has revealed that hyperamylinemia also affects the vascular system, heart, and kidneys. The amount of amyloid deposition in each single islet based on the deposition in islets of transgenic mice expressing human islet amyloid viewing of one or several Congo red-stained sections was estimated on a polypeptide versus human islets implanted into nude mice. Amyloid deposition in pancreas is rare. As controls, we also treated islets from WT mice, which do not express hIAPP, with 100 nM aggregated IAPP; no significant accumulation of IAPP amyloid was observed in that experiment , suggesting that IAPP accumulation in Tg islets was composed of new deposition of endogenous IAPP nucleated by the exogenously added synthetic aggregates. They all had access to normal diet and water ad libitum and were killed after 26 weeks. Amyloid deposition, macrophage infiltration, and upregulation of pro-inflammatory cytokines are common pathological features of both type 2 diabetic and transplanted islets. Amyloid has been fluorescently leballed with thioflavin S (green). EXPERIMENTALPROCEDURES Islet Isolation and Culture—Pancreatic islets were isolated from 10-week-old male and female hemizygous hIAPP trans- the islets. Westermark GT, Westermark P, Berne C, Korsgren O. 2012) The pancreas was first perfused by cannulating the bile duct with a combination of 1 mg/mL collagenase and thermolysin (products C9407 and P1512, Sigma Aldrich) in a sterile HBSS solution. Presence of enhancing mural nodule in a cyst on imaging is a worrisome feature for malignancy, and warrants surgical resection in a surgically fit candidate, as per Fukuoka guidelines for management of cystic lesions in pancreas. 2. Amyloid deposition in transplanted human pancreatic islets: a conceivable cause of their long-term failure Andersson, Arne Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. A confocal micrograph of a pancreatic islet from a patient with Type II diabetes. e only pancreatic tumor associated with amyloidosis is Insulin expressing pan-creatic neuroendocrine tumor, which is rarely associated Thus, in the current study we sought to determine whetherMMP-2andMMP-9playaroleinreducingorlimiting islet amyloid deposition. These aggregates could stimulate amyloid formation and deposition by cross-seeding in pancreatic cells and neurons. Widespread Amyloid Deposition in Transplanted Human Pancreatic Islets. Further Evidence for Amyloid Deposition in Clinical Pancreatic Islet Grafts. Amyloid deposition is a common pathological feature in insulinoma and in the islets of the pancreas in type-2 diabetic patients. Amyloid-negative islets in which the section happened to lie more or less centrally never showed amyloid deposition in any other section. IAPP amyloid deposition has been correlated with disease severity, reduced β ‐cell mass, and the development of hyperglycemia. Islet amyloid contributes to loss of β-cell mass and function in type 2 diabetes. The present immunohisto-chemical study revealed that normal B-cells, insulinoma, and amyloid deposits in insulinoma and diabetic pancreatic islets were commonly immunoreactive with antiserum to C-terminal synthetic tetradecapeptide of human islet amyloid … Pancreatic islets in type 2 diabetes show characteristic deposition of the amyloid polypeptide IAPP. Transplantation 2012;93(2):219–23. Lactoferrin amyloid deposition has not been reported in pancreas, till date. To the Editor: We report on a patient with type 1 diabetes mellitus, diagnosed at 16 years of age, in whom widespread amyloid deposits developed many years later in transplanted human islets. Recent studies have revealed that pre-fibrillar proteospecies and/or the amyloidogenic process mediate β-cell degeneration whereas amyloid fibrils are poorly cytotoxic. Representative sections of human islets cultured in the (A) absence or presence of (B) 41 IU/mL or (C) 410 IU/mL heparin for 14 days. In addition, we found that PBA prevents and re-verses islet amyloid aggregation when islets are exposed to high glucose levels. It is cosecreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Metabolism 5-graded scale (0 to 4⫹). T Towards understanding and treating Alzheimer’s disease Although more than 90% Type 2 diabetic patients have at least one islet with amyloid, not all islets are affected in all subjects. amyloid, first from a human insulinoma [9, 10] and later from islets of Langerhans [11, 12].Thesamepeptidewas found to form amyloid in apes [13, 14] and cats [11, 15]. In order for fibrils to form in neurons and in pancreatic islets, in Alzheimer’s and DM2 respectively, the unique peptides must be present. The salient features were marked atrophy of the pancreatic parenchyma, ductal obstruction or dilatation with epithelial hyperplasia and dysplasia, interstitial fibrosis, fat infiltration, reduction of V β and M β, and marked amyloid deposition in the islets. After removal of the signal peptide, the 67-amino acid propeptide is further processed at two e type of amyloid bril in this setting is islet amyloid polypeptide (IAPP). Amyloid deposition in islets composed primarily of islet amyloid polypeptide (IAPP or amylin) is a common feature in T2D and has been implicated in pancreatic β‐cell death and islet inflammation . Islet amyloid is comprised primarily of aggregates of islet amyloid polypeptide (IAPP), a peptide that is … Although amyloid deposition in the islets was de tected in three of these (patients 14, 17 and 19), the percentage of islets with deposition (0.54-2.9%) was markedly lower than that in patients with diabetic pancreata, as will be dis cussed later. Deposition of amyloid in pancreatic islets is a feature of type 2 diabetes in man but the causal factors are unknown. Schematic representation of the correlations between islet amyloid polypeptide of diabetes and amyloid- peptide from Alzheimer’s disease; conditions characterized by cell loss and abnormal of A , tau, and amylin deposition. Human IAPP is a 37-amino acid residue peptide, expressed as a prepromolecule. Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. To the Editor: We report on a patient with type 1 diabetes mellitus, diagnosed at 16 years of age, in whom widespread amyloid deposits developed many years later in transplanted human islets.
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