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

Abstract

AimsIslet amyloid is a hallmark in type 2 diabetic subjects, but its implication in clinical features and development of islet pathology is still unclear.MethodsFrom 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.Resultsβ-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 β-cell and α-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 β-cells with oxidative stress-related DNA damage, characterized by γH2AX expression, and suppressed (pro)insulin mRNA expression.ConclusionsIn Japanese type 2 diabetic patients, islet amyloid was more common with severe β-cell loss and high BMI, associated with macrophage infiltration.

Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet β-Cell Endoplasmic Reticulum Stress and Proliferation

“…A pancreatic morphometric analysis was performed as described (20,21). Pancreas tissue was dissected, weighed, and embedded into two paraffin blocks.…”

Islet inflammation in type 2 diabetes

“…There have also been conflicting results regarding the possible deleterious actions of islet-infiltrating macrophages. In fact, it has been reported that islets with invading macrophages are characterised by decreased insulin immunoreactivity, increased amyloid deposits, beta cells with oxidative stress-related DNA damage and reduced expression of the gene encoding proinsulin [8,24]. However, type 2 diabetic islets with increased CD68 + cells did not display an increased number of TUNEL + cells, and macrophages were not observed in the vicinity of apoptotic beta cells [8].…”

“…By using antibodies against CD68 (a likely marker of M1 macrophages) and CD163 (a likely marker of M2 macrophages), one study reported that intraislet-infiltrating macrophages were both CD68 + and CD163 + [8]; however, in a different article it was shown that whereas the number of islet-associated CD68 + macrophages in type 2 diabetic Martino et al (2015) Increased infiltration and invasiveness Macrophage infiltration also in the non-endocrine pancreas [10] amyloid-positive islets was increased, that of CD163 + cells was not [24]. There have also been conflicting results regarding the possible deleterious actions of islet-infiltrating macrophages.…”

“…The analysis of 545 diabetic and 564 control islets revealed a significantly higher percentage of islets with more than three CD68 + cells per islet in diabetic vs control cases (20.6 ± 4.1% vs 4.6 ± 1.4%), and demonstrated that the number of CD68 + cells found in diabetic islets was more than twofold higher compared with that in non-diabetic islets (1.34 ± 0.18 vs 0.52 ± 0.08 cells per islet). Additional information comes from a study performed with autopsy samples from Japanese individuals with type 2 diabetes [24]. The authors identified cases with (n = 20) or without (n = 20) islet amyloid deposition, and demonstrated a significantly greater (approximately threefold) CD68 + cell infiltration in amyloidladen islets, which correlated with the severity of amyloid deposition.…”

IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants

“…In contrast, de Koning and colleagues found that macrophage density was not different between islets with and without amyloid in diabetic humans and Macaca mulatta monkeys, nor between hIAPP transgenic and control mice (de Koning et al 1998). In a more recent study, amyloid-positive islets in T2D were found to have significantly more macrophages (CD68+ cells) accumulating within or near amyloid plaques and around microvessels relative to matched T2D subjects without amyloid and to non-diabetic controls (Kamata et al 2014). The majority of CD68+ cells in this study co-expressed nitric oxide synthase 2 (NOS2), whereas the number of …”