Hyperglycemia limits experimental aortic aneurysm progression

Abstract

Objective Diabetes mellitus (DM) is associated with reduced progression of abdominal aortic aneurysm (AAA) disease. Mechanisms responsible for this negative association remain unknown. We created AAAs in hyperglycemic mice to examine the influence of serum glucose concentration on experimental aneurysm progression. Methods Aortic aneurysms were induced in hyperglycemic (DM) and normoglycemic models by using intra-aortic porcine pancreatic elastase (PPE) infusion in C57BL/6 mice or by systemic infusion of angiotensin II (ANG) in apolipoprotein E-deficient (ApoE−/−) mice, respectively. In an additional DM cohort, insulin therapy was initiated after aneurysm induction. Aneurysmal aortic enlargement progression was monitored with serial transabdominal ultrasound measurements. At sacrifice, AAA cellularity and proteolytic activity were evaluated by immunohistochemistry and substrate zymography, respectively. Influences of serum glucose levels on macrophage migration were examined in separate models of thioglycollate-induced murine peritonitis. Results At 14 days after PPE infusion, AAA enlargement in hyperglycemic mice (serum glucose ≥ 300 mg/dL) was less than that in euglycemic mice (PPE-DM: 54% ± 19% vs PPE: 84% ± 24%, P < .0001). PPE-DM mice also demonstrated reduced aortic mural macrophage infiltration (145 ± 87 vs 253 ±119 cells/cross-sectional area, P = .0325), elastolysis (% residual elastin: 20% ± 7% vs 12% ± 6%, P = .0209), and neovascularization (12 ± 8 vs 20 ± 6 vessels/high powered field, P = .0229) compared with PPE mice. Hyperglycemia limited AAA enlargement after ANG infusion in ApoE−/− mice (ANG-DM: 38% ± 12% vs ANG: 61% ± 37% at day 28). Peritoneal macrophage production was reduced in response to thioglycollate stimulation in hyperglycemic mice, with limited augmentation noted in response to vascular endothelial growth factor administration. Insulin therapy reduced serum glucose levels and was associated with AAA enlargement rates intermediate between euglycemic and hyperglycemic mice (PPE: 1.21 ± 0.14 mm vs PPE-DM: 1.00 ± 0.04 mm vs PPE-DM + insulin: 1.14 ± 0.05 mm). Conclusions Hyperglycemia reduces progression of experimental AAA disease; lowering of serum glucose levels with insulin treatment diminishes this protective effect. Identifying mechanisms of hyperglycemic aneurysm inhibition may accelerate development of novel clinical therapies for AAA disease. Clinical Relevance This report provides mechanistic insight into prior population-based clinical studies identifying a negative association between diabetes mellitus and abdominal aortic aneurysm (AAA). The inhibitory effects of hyperglycemia on aneurysm development are examined independent of other AAA risk factors. Further investigations into these or related mechanisms may accelerate the development of effective medical strategies to suppress progression of AAA disease.

Parametric study of effects of collagen turnover on the natural history of abdominal aortic aneurysms

“…Future material testing of AAAs should seek to correlate overall changes in anisotropy and stiffness with mass fractions as well as collagen fibre diameter, undulation, orientation and cross-linking. Indeed, evidence suggests that diabetes tends to reduce the occurrence, expansion rate and rupture risk of AAAs [48,49], possibly through increased non-enzymatic cross-linking of collagen and/or other effects of hyperglycaemia, while overexpression of the cross-linking enzyme lysyl oxidase has been shown to protect mice from AAA development [50].…”

Relation of diabetes to coronary artery ectasia: A meta-analysis study

“…By intracoronary ultrasound, researchers found that diabetics with atherosclerosis have less compensatory coronary artery enlargement than non-diabetics and the researchers considered it can explain the diffuse and accelerated course of coronary artery disease in these patients (38). Patients with a longer duration of diabetes who were treated with insulin had (paradoxically) less reference segment and stenosis plaque accumulation and hyperglycemia increases plasminogen activator inhibitor 1 expression and attenuates AAA diameter had been demonstrated by animal experimental studies (39,40), lowering of serum glucose levels with insulin treatment diminishes this protective effect (41). Other researchers argued that diabetes promotes negative arterial wall remodeling or at least impairs compensatory arterial enlargement during the course of the atherosclerotic process (10).…”

Diabetes Mellitus: Is It Protective against Aneurysm? A Narrative Review

“…A statistically significant reduction in aortic diameter was seen in DM-AAA mice compared to controls ( p = 0.047). Aortic medial neovascularity has been shown to play a role in aneurysm pathogenesis via its close involvement with MMP activation in the proteolytic degradation of the aortic wall [50, 51]. This study showed a decrease in neovessel density, macrophage infiltration and MMP-9 levels, demonstrating hyperglycemia to be protective against the formation of an aneurysm.…”

“…Miyama et al [50] investigated the role of hyperglycemia on aortic diameter, medial neovascularity and MMP-9 level. A statistically significant reduction in aortic diameter was seen in DM-AAA mice compared to controls ( p = 0.047).…”