title: Amelioration of Hyperglycemia with a Sodium-Glucose Cotransporter 2 Inhibitor Prevents Macrophage-Driven Atherosclerosis through Macrophage Foam Cell Formation Suppression in Type 1 and Type 2 Diabetic Mice.
abstract: Direct associations between hyperglycemia and atherosclerosis remain unclear. We investigated the association between the amelioration of glycemia by sodium-glucose cotransporter 2 inhibitors (SGLT2is) and macrophage-driven atherosclerosis in diabetic mice. We administered dapagliflozin or ipragliflozin (1.0 mg/kg/day) for 4-weeks to apolipoprotein E-null (Apoe-/-) mice, streptozotocin-induced diabetic Apoe-/- mice, and diabetic db/db mice. We then determined aortic atherosclerosis, oxidized low-density lipoprotein (LDL)-induced foam cell formation, and related gene expression in exudate peritoneal macrophages. Dapagliflozin substantially decreased glycated hemoglobin (HbA1c) and glucose tolerance without affecting body weight, blood pressure, plasma insulin, and lipids in diabetic Apoe-/- mice. Aortic atherosclerotic lesions, atheromatous plaque size, and macrophage infiltration in the aortic root increased in diabetic Apoe-/- mice; dapagliflozin attenuated these changes by 33%, 27%, and 20%, respectively. Atherosclerotic lesions or foam cell formation highly correlated with HbA1c. Dapagliflozin did not affect atherosclerosis or plasma parameters in non-diabetic Apoe-/- mice. In db/db mice, foam cell formation increased by 4-fold compared with C57/BL6 mice, whereas ipragliflozin decreased it by 31%. Foam cell formation exhibited a strong correlation with HbA1c. Gene expression of lectin-like ox-LDL receptor-1 and acyl-coenzyme A:cholesterol acyltransferase 1 was upregulated, whereas that of ATP-binding cassette transporter A1 was downregulated in the peritoneal macrophages of both types of diabetic mice. SGLT2i normalized these gene expressions. Our study is the first to demonstrate that SGLT2i exerts anti-atherogenic effects by pure glucose lowering independent of insulin action in diabetic mice through suppressing macrophage foam cell formation, suggesting that foam cell formation is highly sensitive to glycemia ex vivo.
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan.
authors.forename: Michishige
authors.initials: M
authors.lastname: Terasaki
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan.
authors.forename: Munenori
authors.initials: M
authors.lastname: Hiromura
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kohashi
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nagashima
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kushima
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Horinouchi, Hachioji-City, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hirano
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005487:Foam Cells / Q000378:metabolism*; D015870:Gene Expression; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000008:administration & dosage / Q000494:pharmacology; D006943:Hyperglycemia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C529054:dapagliflozin