scholarly journals 4-Phenylbutyrate (PBA) treatment reduces hyperglycemia and islet amyloid in a mouse model of type 2 diabetes and obesity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sara de Pablo ◽  
Júlia Rodríguez-Comas ◽  
Daniela Díaz-Catalán ◽  
Gema Alcarraz-Vizán ◽  
Carlos Castaño ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Metabolism ◽  
Cell Mass ◽  
Amyloid Deposition ◽  
Islet Amyloid ◽  
Chemical Chaperone ◽  
Amyloid Deposits ◽  
And Function ◽  
Diabetes And Obesity

AbstractAmyloid deposits in pancreatic islets, mainly formed by human islet amyloid polypeptide (hIAPP) aggregation, have been associated with loss of β-cell mass and function, and are a pathological hallmark of type 2 diabetes (T2D). Treatment with chaperones has been associated with a decrease in endoplasmic reticulum stress leading to improved glucose metabolism. The aim of this work was to investigate whether the chemical chaperone 4-phenylbutyrate (PBA) prevents glucose metabolism abnormalities and amyloid deposition in obese agouti viable yellow (Avy) mice that overexpress hIAPP in β cells (Avy hIAPP mice), which exhibit overt diabetes. Oral PBA treatment started at 8 weeks of age, when Avy hIAPP mice already presented fasting hyperglycemia, glucose intolerance, and impaired insulin secretion. PBA treatment strongly reduced the severe hyperglycemia observed in obese Avy hIAPP mice in fasting and fed conditions throughout the study. This effect was paralleled by a decrease in hyperinsulinemia. Importantly, PBA treatment reduced the prevalence and the severity of islet amyloid deposition in Avy hIAPP mice. Collectively, these results show that PBA treatment elicits a marked reduction of hyperglycemia and reduces amyloid deposits in obese and diabetic mice, highlighting the potential of chaperones for T2D treatment.

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 Inhibition of Insulin-Degrading Enzyme Does Not Increase Islet Amyloid Deposition in Vitro

Endocrinology ◽  
2016 ◽  
Vol 157 (9) ◽  
pp. 3462-3468 ◽  
Author(s):  
Meghan F. Hogan ◽  
Daniel T. Meier ◽  
Sakeneh Zraika ◽  
Andrew T. Templin ◽  
Mahnaz Mellati ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Metabolism ◽  
Cell Loss ◽  
Amyloid Deposition ◽  
Insulin Degrading Enzyme ◽  
Β Cell ◽  
Islet Amyloid ◽  
Degrading Enzyme ◽  
Human Type

Islet amyloid deposition in human type 2 diabetes results in β-cell loss. These amyloid deposits contain the unique amyloidogenic peptide human islet amyloid polypeptide (hIAPP), which is also a known substrate of the protease insulin-degrading enzyme (IDE). Whereas IDE inhibition has recently been demonstrated to improve glucose metabolism in mice, inhibiting it has also been shown to increase cell death when synthetic hIAPP is applied exogenously to a β-cell line. Thus, we wanted to determine whether a similar deleterious effect is observed when hIAPP is endogenously produced and secreted from islets. To address this issue, we cultured hIAPP transgenic mouse islets that have the propensity to form amyloid for 48 and 144 hours in 16.7 mM glucose in the presence and absence of the IDE inhibitor 1. At neither time interval did IDE inhibition increase amyloid formation or β-cell loss. Thus, the inhibition of IDE may represent an approach to improve glucose metabolism in human type 2 diabetes, without inducing amyloid deposition and its deleterious effects.

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 Deletion of Pten in Pancreatic  -Cells Protects Against Deficient  -Cell Mass and Function in Mouse Models of Type 2 Diabetes

Diabetes ◽  
2010 ◽  
Vol 59 (12) ◽  
pp. 3117-3126 ◽  
Author(s):  
L. Wang ◽  
Y. Liu ◽  
S. Yan Lu ◽  
K.-T. T. Nguyen ◽  
S. A. Schroer ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mouse Models ◽  
Cell Mass ◽  
Pancreatic Cells ◽  
Deficient Cell ◽  
And Function

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

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 Verapamil can be used as a Type 2 Diabetes Mellitus Saviour and Stopping the need for Insulin in Uncontrolled Type 2 Diabetes Mellitus

2021 ◽  
pp. 1-8
Author(s):  
Mahmoud Younis ◽  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Interacting Protein ◽  
Significant Difference ◽  
And Function

Introduction: Diabetes mellitus is not just a disease as it is already known, the matter is more complicated, and it is considered as an assembly of metabolic defects with end result of hyperglycemia.verapamil can decrease the expression of thioredoxin-interacting protein (TXNIP), which is recognized as an important factor in pancreatic beta cells.verapamil could enhance beta cell mass and function. Materials and Methods: 160 type 2 diabetes patients in 2 parallel groups. Results: show statistically significant difference in favour of verapamil in increasing c-peptide levels and decreasing hba1c levels. Conclusion: Verapamil could be used as a type 2 diabetes saviour by increasing beta cell mass and function.

scholarly journals Pancreatic β-Cell Proliferation in Obesity1,2

2014 ◽  
Vol 5 (3) ◽  
pp. 278-288 ◽  
Author(s):  
Amelia K. Linnemann ◽  
Mieke Baan ◽  
Dawn Belt Davis
Keyword(s):  
Type 2 Diabetes ◽  
Cell Proliferation ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Extracellular Signals ◽  
Secreted Factors ◽  
And Function ◽  
Hepatocyte Growth

Abstract Because obesity rates have increased dramatically over the past 3 decades, type 2 diabetes has become increasingly prevalent as well. Type 2 diabetes is associated with decreased pancreatic β-cell mass and function, resulting in inadequate insulin production. Conversely, in nondiabetic obesity, an expansion in β-cell mass occurs to provide sufficient insulin and to prevent hyperglycemia. This expansion is at least in part due to β-cell proliferation. This review focuses on the mechanisms regulating obesity-induced β-cell proliferation in humans and mice. Many factors have potential roles in the regulation of obesity-driven β-cell proliferation, including nutrients, insulin, incretins, hepatocyte growth factor, and recently identified liver-derived secreted factors. Much is still unknown about the regulation of β-cell replication, especially in humans. The extracellular signals that activate proliferative pathways in obesity, the relative importance of each of these pathways, and the extent of cross-talk between these pathways are important areas of future study.

Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes

2009 ◽  
Vol 623 (1-3) ◽  
pp. 148-154 ◽  
Author(s):  
James Mu ◽  
Aleksandr Petrov ◽  
George J. Eiermann ◽  
John Woods ◽  
Yun-Ping Zhou ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glycemic Control ◽  
Islet Cell ◽  
Cell Mass ◽  
Rodent Model ◽  
And Function
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