TY - JOUR
T1 - Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis
AU - Flynn, Michelle C.
AU - Kraakman, Michael J.
AU - Tikellis, Christos
AU - Lee, Man K. S.
AU - Hanssen, Nordin M. J.
AU - Kammoun, Helene L.
AU - Pickering, Raelene J.
AU - Dragoljevic, Dragana
AU - Al-Sharea, Annas
AU - Barrett, Tessa J.
AU - Hortle, Fiona
AU - Byrne, Frances L.
AU - Olzomer, Ellen
AU - McCarthy, Domenica A.
AU - Schalkwijk, Casper G.
AU - Forbes, Josephine M.
AU - Hoehn, Kyle
AU - Makowski, Liza
AU - Lancaster, Graeme I.
AU - El-Osta, Assam
AU - Fisher, Edward A.
AU - Goldberg, Ira J.
AU - Cooper, Mark E.
AU - Nagareddy, Prabhakara R.
AU - Thomas, Merlin C.
AU - Murphy, Andrew J.
N1 - Funding Information:
This work was supported by an National Health and Medical Research Council (NHMRC) grant (APP1106154) to A.J. Murphy and M.C. Thomas. M.J. Kraak-man is a Russell Berrie Foundation Scholar in Diabetes Research from the Naomi Berrie Diabetes Centre. N.M.J. Hanssen is supported by the Dutch Heart Foundation (2017T039), Dutch Diabetes Foundation (2017.85.005), and the European Foundation for the Study of Diabetes (EFSD). T.J. Barrett is supported by an American Heart Association (AHA) Career Development Award (18CDA34110203AHA). L. Makowski was funded by American Heart Association 13BGIA17070106 and University of Tennessee Health Science Center (UTHSC) Methodist Mission Support Fund. J.M. Forbes is supported by an NHM-RC fellowship (APP1102935) and the Mater Foundation. E.A. Fisher was funded by the NIH P01 HL131481. I.J. Goldberg is supported by grants HL45095 and HL73029 and American Heart Association Strategically Focused Research Network (35210245) in Cardiometabolic Health. A. El-Osta is an NHMRC Senior Research Fellow (APP1154650). P.R. Nagareddy is supported by grants from the NIH (R01HL137799 and R00HL122505). A.J. Murphy is supported by Career Development Fellowship from the NHMRC (APP1085752), a Future Leader Fellowship from the National Heart Foundation (100440), a Viertel Award from Diabetes Australia Research Trust, and a Centenary Award from Commonwealth Serum Laboratories (CSL).
Publisher Copyright:
© 2020 Lippincott Williams and Wilkins. All rights reserved.
PY - 2020/9/11
Y1 - 2020/9/11
N2 - 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.
AB - 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.
KW - atherosclerosis
KW - diabetes mellitus
KW - inflammation
KW - metabolism
KW - stem cells
KW - INSULIN-INDUCED HYPOGLYCEMIA
KW - HEMATOPOIETIC STEM
KW - DIABETES-MELLITUS
KW - EATING PATTERNS
KW - GLUCOSE
KW - DISEASE
KW - BINDING
KW - MONOCYTOSIS
KW - MACROPHAGES
KW - RECEPTOR
U2 - 10.1161/CIRCRESAHA.120.316653
DO - 10.1161/CIRCRESAHA.120.316653
M3 - Article
C2 - 32564710
SN - 0009-7330
VL - 127
SP - 877
EP - 892
JO - Circulation Research
JF - Circulation Research
IS - 7
ER -