Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis

Michelle C. Flynn, Michael J. Kraakman, Christos Tikellis, Man Ks Lee, Nordin Hanssen, Helene L. Kammoun, Raelene Pickering, Dragana Dragoljevic, Annas Al-Sharea, Tessa J. Barrett, Fiona Hortle, Frances L. Byrne, Ellen Olzomer, Domenica A. McCarthy, Casper G. Schalkwijk, Josephine M. Forbes, Kyle Hoehn, Liza Makowski, Graeme I. Lancaster, Assam El-OstaEdward A. Fisher, Ira J. Goldberg, Mark E. Cooper, Prabhakara R. Nagareddy, Merlin C. Thomas, Andrew J. Murphy

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Rationale: Treatment efficacy for diabetes is largely determined by assessment of HbA1c levels, which poorly reflects direct glucose variation. People with pre-diabetes and diabetes 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 (CVD) 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 2hr intervals intraperitoneally once to wild-type (WT) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-Chi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9, S100a8 or its cognate receptor Rage, prevented monocytosis. Mechanistically, glucose uptake via GLUT-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of Slc2a1 (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 CVD. 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 axis could represent a viable approach to protect the vulnerable blood vessels in diabetes.

Original languageEnglish
Number of pages23
JournalCirculation Research
Publication statusAccepted/In press - 22 Jun 2020

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