Islet-associated macrophages in type 2 diabetes
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KeywordsCD68+ cells Enteroviral capsid protein vp1 Inflammation Protein kinase R Type 2 diabetes
To the Editor: Recently evidence has emerged that supports a role for islet inflammation in the development of type 2 diabetes in man, suggesting that there may be certain common features underlying the pathology of beta cell loss in both type 1 and type 2 diabetes. In particular, data have recently been presented revealing an increased number of macrophages infiltrating the islets of nine type 2 diabetic patients, as well as in several animal models of type 2 diabetes (including high-fat-fed C57BL6/6J mice, GK rats and the db/db mouse) when compared with relevant controls . Those authors argued that this evidence implies that macrophage infiltration could be involved in mediating beta cell dysfunction and loss in type 2 diabetes. In view of these conclusions, we considered it important to verify whether increased macrophage infiltration is also observed in a different and larger cohort of human patients with type 2 diabetes and to assess the magnitude of this response.
A critical issue arising from these observations is the biological relevance of this relatively modest rise in macrophage number within the islet milieu. In order to evaluate this, the proportion of islets having more than three CD68+ cells per islet section was previously examined  on the basis that this might provide a more robust index of islet inflammation. Using a similar criterion, we observed that 20.6 ± 4.1% of the islets examined in patients with type 2 diabetes were inflamed. This compared with 4.6 ± 1.4% of islets in non-diabetic individuals (Fig. 1b; p = 0.007). Moreover, we noted that CD68+ macrophages were frequently located among the endocrine cells within the islets of the type 2 diabetic cases, whereas they were usually distributed more peripherally in the islets of non-diabetic controls.
During a parallel analysis of islet inflammation in human type 1 diabetes, we considered it important to define a still more stringent threshold for insulitis and a minimum of five immune cells per islet was selected . If this criterion is employed in the present analysis, the proportion of islets considered to be inflamed is inevitably lower but a significant difference is still noted between the number of CD68+ cells seen within the islets in type 2 diabetes vs controls (5.6 ± 1.4% vs 0.6 ± 0.3%, respectively; p = 0.001). Thus, these findings support the evidence in the previous report  that an increased proportion of islets are infiltrated by macrophages in patients with type 2 diabetes.
The mechanism(s) by which CD68+ cells are recruited to the islets in type 2 diabetes are unknown but it was reported that medium recovered after in vitro culture of islets from patients with type 2 diabetes was chemotactic to monocytes and neutrophils . This implies that such islets may be induced to secrete chemokines which promote macrophage recruitment. Of interest in this respect is our recent finding  that the enteroviral capsid protein vp1, is produced in the islets of patients with type 2 diabetes at a higher frequency than in controls (40% vs 13%; p < 0.01). We suggest, therefore, that consideration should be given to the possibility that a persistent, low-grade enteroviral infection of islet endocrine cells may induce functional changes that contribute to the recruitment of macrophages in some patients with type 2 diabetes. In support of this, during a more detailed analysis of 351 islets in ten patients with type 2 diabetes, we noted a significant correlation between islet inflammation (defined as islets containing more than five CD68+ cells per section) and the production of both vp1 (detected in 34.6% [nine of 26] of inflamed islets vs 11.1% [36 of 325] of non-inflamed islets [χ2p < 0.01]) and the double-stranded RNA-activated kinase, protein kinase R (present in 50% [13 of 26] of inflamed islets vs 16.9% (55 of 325) of non-inflamed islets [χ2p < 0.001]).
We thank Diabetes UK, the Juvenile Diabetes Research Foundation (JDRF), the European Foundation for the Study of Diabetes (EFSD) and the Coordinated Action of the European Union (Type ONE Coordinated Action [TONECA]) for financial support.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
- 3.Richardson SJ, Willcox A, Bone AJ, Foulis AK, Morgan NG (2009) The prevalence of enteroviral vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia doi:10.1007/s00125-009-1276-0