Islet Amyloid in Patients With Diabetes Due to Exocrine Pancreatic Disorders, Type 2 Diabetes, and Nondiabetic Patients

2020 ◽  
Vol 105 (8) ◽  
pp. 2595-2605
Author(s):  
Sandra Ueberberg ◽  
Michael A Nauck ◽  
Waldemar Uhl ◽  
Chiara Montemurro ◽  
Andrea Tannapfel ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Tissue ◽  
Amyloid Formation ◽  
Β Cell ◽  
Islet Amyloid ◽  
Amyloid Deposits ◽  
Typical Finding ◽  
Patients With Diabetes ◽  
Pancreatic Disorders

Abstract Background Amyloid deposits are a typical finding in pancreatic islets from patients with type 2 diabetes. Whether this is linked to the pathogenesis of type 2 diabetes is currently unknown. Therefore, we compared the occurrence of islet amyloid in patients with type 2 diabetes, diabetes secondary to pancreatic disorders, and nondiabetic individuals. Patients and methods Pancreatic tissue from 15 nondiabetic patients, 22 patients with type 2 diabetes, and 11 patients with diabetes due to exocrine pancreatic disorders (chronic pancreatitis, pancreatic carcinoma) were stained for insulin, amyloid, and apoptosis. β-cell area, amyloid deposits, and β-cell apoptosis were quantified by morphometric analysis. Results The proportion of islets containing amyloid deposits was significantly higher in both type 2 diabetes and diabetes due to exocrine pancreatic disorders than in healthy subjects. Islets with both amyloid and apoptosis were observed more frequently in type 2 diabetes and significantly more so in diabetes due to exocrine pancreatic disorders. In both diabetic groups, apoptotic ß-cells were found significantly more frequently in islets with more prominent amyloid deposits. Conclusions The occurrence of amyloid deposits in both type 2 diabetes and diabetes secondary to exocrine pancreatic disorders suggests that islet amyloid formation is a common feature of diabetes mellitus of different etiologies and may be associated with a loss of pancreatic ß-cells.

scholarly journals Loss of β-Cell Identity Occurs in Type 2 Diabetes and Is Associated With Islet Amyloid Deposits

Diabetes ◽  
2015 ◽  
Vol 64 (8) ◽  
pp. 2928-2938 ◽  
Author(s):  
H. Siebe Spijker ◽  
Heein Song ◽  
Johanne H. Ellenbroek ◽  
Maaike M. Roefs ◽  
Marten A. Engelse ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Β Cell ◽  
Islet Amyloid ◽  
Cell Identity ◽  
Amyloid Deposits

Up-Regulated Pancreatic Tissue MicroRNA-375 Associates With Human Type 2 Diabetes Through β-Cell Deficit and Islet Amyloid Deposition

Pancreas ◽  
2010 ◽  
Vol 39 (6) ◽  
pp. 843-846 ◽  
Author(s):  
Hailu Zhao ◽  
Jing Guan ◽  
Heung-Man Lee ◽  
Yi Sui ◽  
Lan He ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Tissue ◽  
Amyloid Deposition ◽  
Β Cell ◽  
Islet Amyloid ◽  
Human Type

scholarly journals Molecular Structure, Membrane Interactions, and Toxicity of the Islet Amyloid Polypeptide in Type 2 Diabetes Mellitus

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Lucie Caillon ◽  
Anais R. F. Hoffmann ◽  
Alexandra Botz ◽  
Lucie Khemtemourian
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Membrane Damage ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Formation ◽  
Membrane Interactions ◽  
Islet Amyloid ◽  
Amyloid Deposits

Human islet amyloid polypeptide (hIAPP) is the major component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus (T2DM). Mature hIAPP, a 37-aa peptide, is natively unfolded in its monomeric state but forms islet amyloid in T2DM. In common with other misfolded and aggregated proteins, amyloid formation involves aggregation of monomers of hIAPP into oligomers, fibrils, and ultimately mature amyloid deposits. hIAPP is coproduced and stored with insulin by the pancreatic isletβ-cells and is released in response to the stimuli that lead to insulin secretion. Accumulating evidence suggests that hIAPP amyloid deposits that accompany T2DM are not just an insignificant phenomenon derived from the disease progression but that hIAPP aggregation induces processes that impair the functionality and the viability ofβ-cells. In this review, we particularly focus on hIAPP structure, hIAPP aggregation, and hIAPP-membrane interactions. We will also discuss recent findings on the mechanism of hIAPP-membrane damage and on hIAPP-induced cell death. Finally, the development of successful antiamyloidogenic agents that prevent hIAPP fibril formation will be examined.

scholarly journals Islet amyloid deposits preferentially in the highly functional and most blood-perfused islets

2017 ◽  
Vol 6 (7) ◽  
pp. 458-468 ◽  
Author(s):  
Sara Ullsten ◽  
Sara Bohman ◽  
Marie E Oskarsson ◽  
K Peter R Nilsson ◽  
Gunilla T Westermark ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
High Fat Diet ◽  
Islet Amyloid Polypeptide ◽  
Prohormone Convertase ◽  
Amyloid Formation ◽  
High Fat ◽  
Islet Amyloid ◽  
Amyloid Deposits ◽  
Release Capacity

Islet amyloid and beta cell death in type 2 diabetes are heterogeneous events, where some islets are affected early in the disease process, whereas others remain visibly unaffected. This study investigated the possibility that inter-islet functional and vascular differences may explain the propensity for amyloid accumulation in certain islets. Highly blood-perfused islets were identified by microspheres in human islet amyloid polypeptide expressing mice fed a high-fat diet for three or 10 months. These highly blood-perfused islets had better glucose-stimulated insulin secretion capacity than other islets and developed more amyloid deposits after 10 months of high-fat diet. Similarly, human islets with a superior release capacity formed more amyloid in high glucose culture than islets with a lower release capacity. The amyloid formation in mouse islets was associated with a higher amount of prohormone convertase 1/3 and with a decreased expression of its inhibitor proSAAS when compared to islets with less amyloid. In contrast, levels of prohormone convertase 2 and expression of its inhibitor neuroendocrine protein 7B2 were unaltered. A misbalance in prohormone convertase levels may interrupt the normal processing of islet amyloid polypeptide and induce amyloid formation. Preferential amyloid load in the most blood-perfused and functional islets may accelerate the progression of type 2 diabetes.

Dual role of interleukin-1β in islet amyloid formation and its β-cell toxicity: Implications for type 2 diabetes and islet transplantation

2017 ◽  
Vol 19 (5) ◽  
pp. 682-694 ◽  
Author(s):  
Yoo Jin Park ◽  
Garth L. Warnock ◽  
Ziliang Ao ◽  
Nooshin Safikhan ◽  
Mark Meloche ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Islet Transplantation ◽  
Dual Role ◽  
Interleukin 1Β ◽  
Amyloid Formation ◽  
Cell Toxicity ◽  
Β Cell ◽  
Islet Amyloid

scholarly journals Islet Inflammation Impairs the Pancreatic β-Cell in Type 2 Diabetes

Physiology ◽  
2009 ◽  
Vol 24 (6) ◽  
pp. 325-331 ◽  
Author(s):  
Marc Y. Donath ◽  
Marianne Böni-Schnetzler ◽  
Helga Ellingsgaard ◽  
Jan A. Ehses
Keyword(s):  
Type 2 Diabetes ◽  
Cell Mass ◽  
Metabolic Stress ◽  
Innate Immune ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Amyloid Deposits ◽  
Impaired Insulin ◽  
Islet Inflammation

Onset of Type 2 diabetes occurs when the pancreatic β-cell fails to adapt to the increased insulin demand caused by insulin resistance. Morphological and therapeutic intervention studies have uncovered an inflammatory process in islets of patients with Type 2 diabetes characterized by the presence of cytokines, immune cells, β-cell apoptosis, amyloid deposits, and fibrosis. This insulitis is due to a pathological activation of the innate immune system by metabolic stress and governed by IL-1 signaling. We propose that this insulitis contributes to the decrease in β-cell mass and the impaired insulin secretion observed in patients with Type 2 diabetes.

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

scholarly journals β-Cell Loss and β-Cell Apoptosis in Human Type 2 Diabetes Are Related to Islet Amyloid Deposition

2011 ◽  
Vol 178 (6) ◽  
pp. 2632-2640 ◽  
Author(s):  
Catherine A. Jurgens ◽  
Mirna N. Toukatly ◽  
Corinne L. Fligner ◽  
Jayalakshmi Udayasankar ◽  
Shoba L. Subramanian ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Apoptosis ◽  
Cell Loss ◽  
Amyloid Deposition ◽  
Β Cell ◽  
Islet Amyloid ◽  
Human Type

scholarly journals Amyloid damage to islet β-cells in type 2 diabetes: hypoxia or pseudo-hypoxia?

2019 ◽  
Author(s):  
Vittorio Bellotti ◽  
Alessandra Corazza ◽  
Beatrice Foglia ◽  
Erica Novo ◽  
J. Paul Simons ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amyloid Deposition ◽  
Β Cells ◽  
Islet Amyloid ◽  
Good Tool ◽  
Amyloid Deposits ◽  
Oxygen Perfusion

ABSTRACTAggregation of islet amyloid polypeptide (IAPP) and amyloid deposition in the islets of Langerhans may significantly contribute to the multifactorial pathogenic mechanisms leading to type 2 diabetes. A direct toxic effect on β-cells of oligomeric IAAP has been demonstrated in in vitro models, but the mechanism operating in vivo is still unclear. Mice models presenting amyloid deposition and glucose intolerance represent a good tool for exploring in vivo a putative mechanism of toxicity directly related to the physical expansion of the extracellular matrix by the amyloid fibrillar aggregates. Based on our hypothesis that deposition of amyloid may influence the oxygen perfusion, we have calculated that the mean distribution of oxygen partial pressure would drop by more than 50 % in the presence of amyloid deposits in the islet. This condition of hypoxia caused by the remodelling of the extracellular space may explain the metabolic abnormalities in the Langerhans islets, otherwise interpreted as pseudo-hypoxic response to IAPP oligomers.

scholarly journals Vaccination Against Amyloidogenic Aggregates in Pancreatic Islets Prevents Development of Type 2 Diabetes Mellitus

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 116 ◽  
Author(s):  
Elisa S. Roesti ◽  
Christina N. Boyle ◽  
Daniel T. Zeman ◽  
Marcos Sande-Melon ◽  
Federico Storni ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Pancreatic Islets ◽  
Hormone Secretion ◽  
Β Cell ◽  
Islet Amyloid ◽  
Disease Modifying

Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by insulin resistance and insufficient insulin secretion to maintain normoglycemia. The majority of T2DM patients bear amyloid deposits mainly composed of islet amyloid polypeptide (IAPP) in their pancreatic islets. These—originally β-cell secretory products—extracellular aggregates are cytotoxic for insulin-producing β-cells and are associated with β-cell loss and inflammation in T2DM advanced stages. Due to the absence of T2DM preventive medicaments and the presence of only symptomatic drugs acting towards increasing hormone secretion and action, we aimed at establishing a novel disease-modifying therapy targeting the cytotoxic IAPP deposits in order to prevent the development of T2DM. We generated a vaccine based on virus-like particles (VLPs), devoid of genomic material, coupled to IAPP peptides inducing specific antibodies against aggregated, but not monomeric IAPP. Using a mouse model of islet amyloidosis, we demonstrate in vivo that our vaccine induced a potent antibody response against aggregated, but not soluble IAPP, strikingly preventing IAPP depositions, delaying onset of hyperglycemia and the induction of the associated pro-inflammatory cytokine Interleukin 1β (IL-1β). We offer the first cost-effective and safe disease-modifying approach targeting islet dysfunction in T2DM, preventing pathogenic aggregates without disturbing physiological IAPP function.

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