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.

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.

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 Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Diana C Rodriguez Camargo ◽  
Kyle J Korshavn ◽  
Alexander Jussupow ◽  
Kolio Raltchev ◽  
David Goricanec ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Death ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Β ◽  
Md Simulations ◽  
Human Islet ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Induce Cell Death

Membrane-assisted amyloid formation is implicated in human diseases, and many of the aggregating species accelerate amyloid formation and induce cell death. While structures of membrane-associated intermediates would provide tremendous insights into the pathology and aid in the design of compounds to potentially treat the diseases, it has not been feasible to overcome the challenges posed by the cell membrane. Here, we use NMR experimental constraints to solve the structure of a type-2 diabetes related human islet amyloid polypeptide intermediate stabilized in nanodiscs. ROSETTA and MD simulations resulted in a unique β-strand structure distinct from the conventional amyloid β-hairpin and revealed that the nucleating NFGAIL region remains flexible and accessible within this isolated intermediate, suggesting a mechanism by which membrane-associated aggregation may be propagated. The ability of nanodiscs to trap amyloid intermediates as demonstrated could become one of the most powerful approaches to dissect the complicated misfolding pathways of protein aggregation.

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.

Photodegradation of porphyrin-bound hIAPP(1–37) fibrils

2020 ◽  
Vol 44 (22) ◽  
pp. 9438-9443
Author(s):  
Yongxiu Song ◽  
Ping Li ◽  
Zhiming Zhang ◽  
Yin Wang ◽  
Zhefei Zhang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Pancreatic Islets ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Preventive Strategy ◽  
Islet Amyloid ◽  
Amyloid Deposits

Amyloid deposits in pancreatic islets of type 2 diabetes mellitus (T2DM) are mainly comprised of human islet amyloid polypeptide (hIAPP), the degradation of hIAPP fibrils by photoactive porphyrin could be a preventive strategy against T2DM.

Sign in / Sign up

Export Citation Format

Share Document