Hyperglycemia limits experimental aortic aneurysm progression.
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.
Miyama
Noriyuki
N
Division of Vascular Surgery, Stanford University School of Medicine, Stanford, Calif, USA.
Dua
Monica M
MM
Yeung
Janice J
JJ
Schultz
Geoffrey M
GM
Asagami
Tomoko
T
Sho
Eiketsu
E
Sho
Mien
M
Dalman
Ronald L
RL
D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D017544:Aortic Aneurysm, Abdominal / Q000097:blood / Q000139:chemically induced / Q000150:complications* / Q000000981:diagnostic imaging; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D004195:Disease Models, Animal; D018450:Disease Progression; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008264:Macrophages / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010196:Pancreatic Elastase / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000150:complications / Q000473:pathology; D013864:Thioglycolates; D013997:Time Factors; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage
D001057:Apolipoproteins E; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D013864:Thioglycolates; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D010196:Pancreatic Elastase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse