Diabetes-Induced Changes in Macrophage Biology Might Lead to Reduced Risk for Abdominal Aortic Aneurysm Development

Abstract

Type 2 diabetes patients are less likely to develop an abdominal aortic aneurysm (AAA). Since macrophages play a crucial role in AAA development, we hypothesized that this decrease in AAA risk in diabetic patients might be due to diabetes-induced changes in macrophage biology. To test this hypothesis, we treated primary macrophages obtained from healthy human volunteers with serum from non-diabetic vs. diabetic AAA patients and observed differences in extracellular acidification and the expression of genes involved in glycolysis and lipid oxidation. These results suggest an increase in metabolism in macrophages treated with serum from diabetic AAA patients. Since serum samples used did not differ in glucose content, these changes are not likely to be caused by differences in glycemia. Macrophage functions have been shown to be linked to their metabolism. In line with this, our data suggest that this increase in macrophage metabolism is accompanied by a shift towards an anti-inflammatory state. Together, these results support a model where diabetes-induced changes in metabolism in macrophages might lead to a reduced risk for AAA development.

Differences between inflammatory cells infiltrated into tunica intima, media, and adventitia of ascending aortic aneurysms within diabetic and hypertensive patients

“…The inflammatory state was tested and found no differences in pro-fibrotic and anti-inflammatory cytokine TGFβ, a slight increase in the marker for M2 cells, a slight increase in cytokine with pro-inflammatory properties IL1β, an increase in anti-inflammatory cytokine IL10, and decrease in pro-inflammatory cytokine TNFα. They suggested that changes in macrophage metabolism caused by diabetic serum lead to reduced risk for the development of aortic aneurysm [ 38 ]. The finding that the metabolism of inflammatory cells is changed could be the reason that in our study, the amount of collagen and elastic fibers of VSMC and ground substance in the AH and DM groups is the same.…”

“…AH increases the risk of thoracic aortic aneurysm formation [ 39 ], while diabetes decreases it [ 40 ]. Glycation changes the metabolism of macrophages in the direction of anti-inflammatory state (M2), which stimulates the formation of collagen fibers, strengthens the vascular wall, and reduces the risk of abdominal aneurysm formation [ 38 , 41 , 42 ]. In our study, we had a group of patients who had diabetes and an aneurysm but did not have hypertension.…”

Diabetes and Abdominal Aortic Aneurysm: Is the Protective Effect on AAA Due to Antidiabetic Medications Alone, Due to the Disease Alone, or Both?

“…Similarly, it has also been postulated that hyperglycemia forms advanced glycation end products (AGE) which eventually crosslinks, forming a stable aortic wall [ 48 ]. On the other hand, other studies hypothesized that chronic hyperglycemia resulting from diabetes may allow for an increase in macrophage metabolism, causing it to have an anti-inflammatory effect, therefore protecting the walls of abdominal aorta [ 34 , 35 ]. While these studies demonstrate the direct protective effect of hyperglycemia on AAA, other studies question if the concurrent use of hypoglycemic agents may be the real reason for protection.…”

“…One of the proposed reasoning behind the way in which diabetes protects from AAA formation is that the concurrent use of antidiabetic medications aids in modifying the pathophysiological process of AAA development which helps curtail its formation [ 31 , 32 , 33 ]. Another proposed idea is that diabetes could potentially change the macrophage metabolism, therefore protecting against AAA development [ 34 , 35 ]. Additionally, it has also been suggested that the presence of cell division autoantigen 1 (CDA 1) protects against severe aneurysm [ 36 ].…”

Protection of diabetes in aortic abdominal aneurysm: Are antidiabetics the real effectors?

“…Studies in endothelial cells suggest that downregulation of insulin receptor may contribute to vascular remodeling in an insulin resistant environment ( 91 , 92 ). A recent study focused on macrophages as potential responsible of the potential protective effect of DM on AAA showed that stimulation of macrophages with serum from patients with DM and AAA increase macrophage metabolism (based on differences in extracellular acidification and the expression of genes involved in glycolysis and lipid oxidation), which is accompanied by a shift towards an anti-inflammatory state ( 93 ). IR is accompanied by hyperinsulinemia and literature suggests that insulin modulates the inflammatory response in macrophages.…”