4.7 Article

Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis

Journal

CIRCULATION RESEARCH
Volume 127, Issue 7, Pages 877-892

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.120.316653

Keywords

atherosclerosis; diabetes mellitus; inflammation; metabolism; stem cells

Funding

  1. National Health and Medical Research Council (NHMRC) [APP1106154]
  2. Dutch Heart Foundation [2017T039]
  3. Dutch Diabetes Foundation [2017.85.005]
  4. European Foundation for the Study of Diabetes (EFSD)
  5. American Heart Association (AHA) Career Development Award [18CDA34110203AHA]
  6. American Heart Association [13BGIA17070106]
  7. University of Tennessee Health Science Center (UTHSC) Methodist Mission Support Fund
  8. NHMRC fellowship [APP1102935]
  9. American Heart Association Strategically Focused Research Network in Cardiometabolic Health [35210245, APP1154650]
  10. NIH [R01HL137799, R00HL122505, P01 HL131481]
  11. Career Development Fellowship from the NHMRC [APP1085752]
  12. National Heart Foundation [100440]
  13. Diabetes Australia Research Trust
  14. Commonwealth Serum Laboratories (CSL)
  15. Mater Foundation
  16. [HL45095]
  17. [HL73029]

Ask authors/readers for more resources

Rationale: Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear. Objective: To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis. Methods and Results: To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-C(hi)subset, and neutrophils. Hematopoietic-restricted deletion ofS100a9,S100a8, or its cognate receptorRageprevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion ofSlc2a1(GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis. Conclusions: Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available