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Published on: January 7, 2018
Glycemic Control with Ipragliflozin, a Novel Selective SGLT2 Inhibitor, Ameliorated Endothelial Dysfunction in
Hotimah Masdan Salim1, Daiju Fukuda1, Shusuke Yagi1
1Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School , Tokushima , Japan.
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 administered via gavage for 3 weeks. Vascular function was assessed by isometric tension recording. Human umbilical vein endothelial cells (HUVEC) were used for in vitro experiments. 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 eNOSSer1177 in 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). In in vitro studies, 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.
Conclusion:
Ipragliflozin improved hyperglycemia and prevented the development of endothelial dysfunction under a hyperglycemic state, at least partially by attenuation of oxidative stress.
Insights
Ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, improved blood glucose and prevented endothelial dysfunction in diabetic mice. This occurred through reducing oxidative stress and inflammation, offering a potential treatment for diabetic vascular complications.
Area of Science:
- Endocrinology
- Cardiovascular Biology
- Pharmacology
Background:
- Endothelial dysfunction in diabetes is linked to oxidative stress and vascular disease.
- Ipragliflozin, an SGLT2 inhibitor, enhances glucose excretion and is a potential diabetes treatment.
- This study investigated ipragliflozin's effect on endothelial dysfunction in diabetic mice.
Purpose of the Study:
- To determine if ipragliflozin can attenuate endothelial dysfunction in a mouse model of diabetes.
- To explore the mechanisms underlying ipragliflozin's effects on oxidative stress and inflammation in diabetic vasculature.
Main Methods:
- Diabetes was induced in C57BL/6 mice using streptozotocin.
- Mice received ipragliflozin (3 mg/kg/day) or vehicle for 3 weeks.
- Vascular function, oxidative stress markers (8-OHdG), and inflammatory gene/protein expression (MCP-1, VCAM-1, ICAM-1) were assessed.
Main Results:
- Ipragliflozin significantly reduced blood glucose and improved acetylcholine-dependent vasodilation in diabetic mice.
- The treatment ameliorated impaired Akt/eNOS phosphorylation and reduced oxidative stress (urinary 8-OHdG).
- Ipragliflozin decreased aortic expression of inflammatory molecules (MCP-1, VCAM-1, ICAM-1).
Conclusions:
- Ipragliflozin effectively improves hyperglycemia and prevents endothelial dysfunction in diabetic mice.
- The protective effects are partly mediated by the attenuation of oxidative stress and inflammation.
- Ipragliflozin shows promise for managing diabetic vascular complications.
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