Glycemic Control with Ipragliflozin, a Novel Selective SGLT2 Inhibitor, Ameliorated Endothelial Dysfunction in Streptozotocin-Induced Diabetic Mouse.
BACKGROUND
Endothelial dysfunction caused by increased oxidative stress is a critical initiator of macro- and micro-vascular disease development in diabetic patients. Ipragliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, offers a novel approach for the treatment of diabetes by enhancing urinary glucose excretion. The aim of this study was to examine whether ipragliflozin attenuates endothelial dysfunction in diabetic mice.


METHODS
Eight-week-old male C57BL/6 mice were treated with streptozotocin (150 mg/kg) by a single intraperitoneal injection to induce diabetes mellitus. At 3 days of injection, ipragliflozin (3 mg/kg/day) was administeredviagavage for 3 weeks. Vascular function was assessed by isometric tension recording. Human umbilical vein endothelial cells (HUVEC) were used forin vitroexperiments. RNA and protein expression were examined by quantitative RT-PCR (qPCR) and western blot, respectively. Oxidative stress was determined by measuring urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) level.


RESULTS
Ipragliflozin administration significantly reduced blood glucose level (P< 0.001) and attenuated the impairment of endothelial function in diabetic mice, as determined by acetylcholine-dependent vasodilation (P< 0.001). Ipragliflozin did not alter metabolic parameters, such as body weight and food intake. Ipragliflozin administration ameliorated impaired phosphorylation of Akt and eNOSSer1177in the abdominal aorta and reduced reactive oxygen species generation as determined by urinary excretion of 8-OHdG in diabetic mice. Furthermore, qPCR analyses demonstrated that ipragliflozin decreased the expression of inflammatory molecules [e.g., monocyte chemoattractant protein-1 (MCP-1) vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule (ICAM)-1] in the abdominal aorta (P< 0.05). Inin vitrostudies, incubation with methylglyoxal, one of the advanced glycation end products, significantly impaired phosphorylation of Akt and eNOSSer1177(P< 0.01) and increased the expression of MCP-1, VCAM-1, and ICAM-1 in HUVEC.


CONCLUSIONS
Ipragliflozin improved hyperglycemia and prevented the development of endothelial dysfunction under a hyperglycemic state, at least partially by attenuation of oxidative stress.
Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima , Japan.
Hotimah Masdan
HM
Salim
Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima , Japan.
Daiju
D
Fukuda
Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima , Japan.
Shusuke
S
Yagi
Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima , Japan.
Takeshi
T
Soeki
Department of Cardio-Diabetes Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima , Japan.
Michio
M
Shimabukuro
Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima , Japan.
Masataka
M
Sata
SGLT2 inhibitor; endothelial function; hyperglycemia; inflammation; oxidative stress