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Islet amyloid with macrophage migration correlates with augmented ?-cell deficits in type 2 diabetic patients.

ABSTRACT: AIMS:Islet amyloid is a hallmark in type 2 diabetic subjects, but its implication in clinical features and development of islet pathology is still unclear. METHODS:From 118 autopsy cases with type 2 diabetes, 26 cases with islet amyloid deposition (DA+) were selected. Twenty diabetic subjects without obvious amyloid deposition (DA-) matched for the age and diabetes duration and 20 non-diabetic subjects (ND) served for comparison. We examined the severity of amyloid deposition and its relationships with population of endocrine cells, expression of cell damage markers or macrophage infiltration. Correlation of clinical profile with islet pathology was also sought on the subset of the investigated patients. RESULTS:?-Cell volume density was nearly 40% less in DA+ and 20% less in DA- when compared to ND. Severity of amyloid deposition correlated with reduced volume densities of ?-cell and ?-cell, and increased body mass index (BMI), but not with duration of diabetes, age or HbA1c. Amyloid-rich islets contained an increased number of macrophages mixed with ?-cells with oxidative stress-related DNA damage, characterized by ?H2AX expression, and suppressed (pro)insulin mRNA expression. CONCLUSIONS:In Japanese type 2 diabetic patients, islet amyloid was more common with severe ?-cell loss and high BMI, associated with macrophage infiltration.

SUBMITTER: Kamata K

PROVIDER: S-EPMC4196506 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Islet amyloid with macrophage migration correlates with augmented β-cell deficits in type 2 diabetic patients.

Kamata Kosuke K Mizukami Hiroki H Inaba Wataru W Tsuboi Kentaro K Tateishi Yoshinori Y Yoshida Taro T Yagihashi Soroku S

Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 20140709 3

<h4>Aims</h4>Islet amyloid is a hallmark in type 2 diabetic subjects, but its implication in clinical features and development of islet pathology is still unclear.<h4>Methods</h4>From 118 autopsy cases with type 2 diabetes, 26 cases with islet amyloid deposition (DA+) were selected. Twenty diabetic subjects without obvious amyloid deposition (DA-) matched for the age and diabetes duration and 20 non-diabetic subjects (ND) served for comparison. We examined the severity of amyloid deposition and ...[more]

PMID: 25007035

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Project description:Complement inhibitor C4b-binding protein (C4BP) is synthesized in liver and pancreas and composed of 7 identical alpha chains and one unique beta chain. We showed previously that C4BP binds islet amyloid polypeptide (IAPP) and affects fibril formation in vitro. Now we found that polymeric C4BP inhibited lysis of human erythrocytes incubated with monomeric IAPP while no erythrocyte lysis was observed after incubation with preformed IAPP fibrils. In contrast, monomeric alpha chain of C4BP had significantly reduced activity. Further, addition of monomeric IAPP to a rat insulinoma cell line (INS-1) resulted in decreased cell viability, which was restored in the presence of physiological concentrations of C4BP. Accordingly, addition of C4BP rescued the ability of INS-1 cells and isolated rat islets to respond to glucose stimulation with insulin secretion, which was impaired in the presence of IAPP alone. C4BP was internalized together with IAPP into INS-1 cells and therefore we aimed to study its effect on gene expression. Pathway analyses of mRNA expression microarray data indicated that cells exposed to C4BP and IAPP in comparison to IAPP alone increased expression of genes involved in cholesterol synthesis. Depletion of cholesterol through methyl-Î²-cyclodextrin or cholesterol oxidase abolished the protective effect of C4BP on IAPP cytotoxicity of INS-1 cells. Also, inhibition of phosphoinositide 3-kinase but not NF-ÎºB had a similar effect. Taken together, one of the mechanisms by which C4BP protects beta-cells from IAPP cytotoxicity is by enhancing cholesterol synthesis. The INS-1 cells were grown as 5 separate clones for 10 passages before plating in a 12-well plate (Nunc) at 100.000 cells per well and grown in complete RPMI 1640 medium to 70% confluency for approximately 48 h. The cells were then challenged by adding 77 Î¼M monomeric IAPP alone or together with C4BP (0.6 Î¼M). DMSO (1%) used as solvent for IAPP as well as C4BP (0.6 Î¼M) alone were used as controls. RNA was extracted after 10h incubation and analysis carried out using Rat Gene 2.0 array chip (Affymetrix).

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Islet amyloid with macrophage migration correlates with augmented ?-cell deficits in type 2 diabetic patients.

Publications

Islet amyloid with macrophage migration correlates with augmented β-cell deficits in type 2 diabetic patients.

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