Abstract 399: Apolipoprotein AI Suppresses Diabetes-Associated Leukocytosis

Abstract

Objective: Diabetes-associated hyperglycemia increases circulating neutrophil and monocyte counts in mice via the proliferation and expansion of bone marrow myeloid progenitors. Clinically, diabetic patients also have elevated leukocyte counts, with the differing subsets (inc. neutrophils and monocytes) phenotypically more inflammatory when compared to leukocytes from non-diabetics. An emerging concept is that there is a positive association of leukocyte counts with the increased risk of cardiovascular disease (CVD) in diabetics. Various reports have shown that apolipoprotein AI (apoA1) and high density lipoprotein (HDL) can suppress both myeloproliferation and reduce the inflammatory state of neutrophils and monocytes. Given that low apoA1/HDL is a typical feature of diabetic dyslipidemia this study aimed to establish whether raising apoA1/HDL levels could reduce hyperglycemia-driven leukocytosis in a model of diabetes. Methods and Results: C57Bl6 (WT) and hApoA1 (overexpressing) transgenic (TG) mice were given daily i.p. injections of STZ for 5 d to induce diabetes. The TG mice had circulating [hApoa1] of 400 mg/dL (vs. 120 mg/dL mApoA1 in WT) and [HDL-C] levels of 150mg/dL (vs 50 mg/dL in WT). Hyperglycemia induced leukocytosis in WT mice (total WBC 18.6 k/uL), however elevated hApoA1 attenuated this to 13.8 k/uL. This decrease included a significant reduction in the circulating neutrophil (3.5 vs 2.5 k/uL) and monocyte counts (1.3 vs 0.9 k/uL) in the diabetic hApoA1 TG mice. Attenuation of leukocytosis was explained by a reduction in the proliferation and expansion of the neutrophil and monocyte myeloid progenitors in the bone marrow of the diabetic hApoA1 TG mice. Furthermore, s.c. injections of hApoA1 into diabetic WT mice attenuated hyperglycemia-driven myeloid proliferation. Conclusion: This study provides the first evidence that apoA1, the major protein component of HDL, can potently suppress diabetes-associated leukocytosis by overcoming the myeloid proliferation observed in diabetes.