Pancreatic islet amyloidosis, β-cell apoptosis, and α-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons
Rodolfo Guardado-Mendoza,Alberto M. Davalli,Alberto O. Chavez,Gene B. Hubbard,Edward J. Dick,Abraham Majluf-Cruz,Carlos Enrique Tene-Pérez,Lukasz Goldschmidt,John Hart,Carla Perego,Anthony G. Comuzzie,Maria Elizabeth Tejero,Giovanna Finzi,Claudia Placidi,Stefano La Rosa,Carlo Capella,Glenn A. Halff,Amalia Gastaldelli,Ralph A. DeFronzo,Franco Folli +19 more
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TLDR
The results strongly support the concept that IA and β-cell apoptosis in concert with α-cell proliferation and hypertrophy are key determinants of islets of Langerhans “dysfunctional remodeling” and hyperglycemia in the baboon, a nonhuman primate model of type-2 diabetes mellitus.Abstract:
beta-Cell dysfunction is an important factor in the development of hyperglycemia of type-2 diabetes mellitus, and pancreatic islet amyloidosis (IA) has been postulated to be one of the main contributors to impaired insulin secretion. The aim of this study was to evaluate the correlation of IA with metabolic parameters and its effect on islets of Langerhans remodeling and relative endocrine-cell volume in baboons. We sequenced the amylin peptide, determined the fibrillogenic propensities, and evaluated pancreatic histology, clinical and biochemical characteristics, and endocrine cell proliferation and apoptosis in 150 baboons with different metabolic status. Amylin sequence in the baboon was 92% similar to humans and showed superimposable fibrillogenic propensities. IA severity correlated with fasting plasma glucose (FPG) (r = 0.662, P < 0.001) and HbA1c (r = 0.726, P < 0.001), as well as with free fatty acid, glucagon values, decreased homeostasis model assessment (HOMA) insulin resistance, and HOMA-B. IA severity was associated with a decreased relative beta-cell volume, and increased relative alpha-cell volume and hyperglucagonemia. These results strongly support the concept that IA and beta-cell apoptosis in concert with alpha-cell proliferation and hypertrophy are key determinants of islets of Langerhans "dysfunctional remodeling" and hyperglycemia in the baboon, a nonhuman primate model of type-2 diabetes mellitus. The most important determinants of IA were age and FPG (R(2) = 0.519, P < 0.0001), and different FPG levels were sensitive and specific to predict IA severity. Finally, a predictive model for islet amyloid severity was generated with age and FPG as required variables.read more
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Journal ArticleDOI
Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus
TL;DR: This review deals both with physiological aspects of IAPP and with the pathophysiological role of aggregated forms of I APP, including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.
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Pancreatic islet plasticity: Interspecies comparison of islet architecture and composition
TL;DR: It is proposed that this plasticity of islet architecture and cellular composition among various species including changes in response to metabolic states within a single species reflects evolutionary acquired adaptation induced by altered physiological conditions, rather than inherent disparities between species.
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Islet Inflammation Impairs the Pancreatic β-Cell in Type 2 Diabetes
TL;DR: This insulitis is due to a pathological activation of the innate immune system by metabolic stress and governed by IL-1 signaling and contributes to the decrease in beta-cell mass and the impaired insulin secretion observed in patients with Type 2 diabetes.
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β-Cell Loss and β-Cell Apoptosis in Human Type 2 Diabetes Are Related to Islet Amyloid Deposition
Catherine A. Jurgens,Mirna N. Toukatly,Corinne L. Fligner,Jayalakshmi Udayasankar,Shoba L. Subramanian,Sakeneh Zraika,Kathryn Aston-Mourney,Darcy B. Carr,Per Westermark,Gunilla T. Westermark,Steven E. Kahn,Rebecca L. Hull +11 more
TL;DR: Islet amyloid is associated with decreasedβ-cell area and increased β-cell apoptosis, suggesting that islet ameloid deposition contributes to the decreased β- cell mass that characterizes type 2 diabetes.
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Type 2 diabetes as a protein misfolding disease
TL;DR: The current understanding of the mechanisms implicated in the formation of protein aggregates in the endocrine pancreas and associated toxicity in the light of the long-standing knowledge from neurodegenerative disorders associated with protein misfolding is discussed.
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