Michelle C Flynn1,2, Michael J Kraakman1,3, Christos Tikellis4, Man K S Lee1,2, Nordin M J Hanssen5, Helene L Kammoun1,2, Raelene J Pickering4, Dragana Dragoljevic1, Annas Al-Sharea1, Tessa J Barrett6, Fiona Hortle1, Frances L Byrne7, Ellen Olzomer7, Domenica A McCarthy8, Casper G Schalkwijk5, Josephine M Forbes8, Kyle Hoehn7, Liza Makowski9, Graeme I Lancaster1,2, Assam El-Osta4,10,11,12,13, Edward A Fisher6, Ira J Goldberg6, Mark E Cooper4, Prabhakara R Nagareddy14, Merlin C Thomas4, Andrew J Murphy15. 1. From the Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia (M.C.F., M.J.K., M.K.S.L., H.L.K., D.D., A.A.-S., F.H., G.I.L., A.J.M.), Monash University, Melbourne, Australia. 2. Department of Immunology (M.C.F., M.K.S.L., H.L.K., G.I.L., A.J.M.), Monash University, Melbourne, Australia. 3. Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York (M.J.K.). 4. Diabetes (C.T., R.J.P., A.E.-O., M.E.C., M.C.T.), Monash University, Melbourne, Australia. 5. Department of Internal Medicine, CARIM, School of Cardiovascular Diseases, Maastricht University, the Netherlands (N.M.J.H., C.G.S.). 6. Division of Cardiology (T.J.B., E.A.F., I.J.G.), New York University School of Medicine. 7. Division of Endocrinology, Diabetes and Metabolism (F.L.B., E.O., K.H.), New York University School of Medicine. 8. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia (D.A.M., J.M.F.). 9. Glycation and Diabetes Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia (L.M.). 10. Division of Hematology and Oncology, Department of Medicine, University of Tennessee Health Science Center, Memphis (A.E.-O.). 11. Department of Medicine and Therapeutics (A.E.-O.), The Chinese University of Hong Kong. 12. Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital (A.E.-O.), The Chinese University of Hong Kong. 13. Li Ka Shing Institute of Health Sciences (A.E.-O.), The Chinese University of Hong Kong. 14. Cardiac Surgery, Department of Surgery, Ohio State University, Columbus (P.R.N.). 15. Department of Physiology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Australia (A.J.M.).
Abstract
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-Chi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9, S100a8, or its cognate receptor Rage prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-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 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. Graphic Abstract: A graphic abstract is available for this article.
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-Chi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9, S100a8, or its cognate receptor Rage prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-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 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. Graphic Abstract: A graphic abstract is available for this article.
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