Journal ArticleDOI
SGLT-2 Inhibition with Dapagliflozin Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Cardiomyopathy in Mice with Type 2 Diabetes. Further Augmentation of the Effects with Saxagliptin, a DPP4 Inhibitor
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TLDR
Dapa attenuated the activation of the inflammasome, fibrosis, and deterioration of LVEF in BTBR mice and the anti-inflammatory, anti-fibrotic effects are likely SGLT2- and glucose-lowering-independent, as they were replicated in the in vitro model.Abstract:
We assessed whether (1) dapagliflozin (Dapa, an SGLT2-inhibitor) attenuates the deterioration of heart function Nlrp3 and inflammasome activation in diabetic mice. (2) The effects can be augmented with saxagliptin (Saxa), a DDP4-inhibitor. (3) Dapa effect is possibly SGLT2-independent on cardiofibroblasts in vitro. Type 2 diabetic (BTBR ob/ob) and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Glucose tolerance test and echocardiogram were performed. Cardiofibroblasts from WT and BTBR hearts were incubated with Dapa and exposed to LPS. Left ventricular ejection fraction (LVEF) was 81 ± 1% in the WT and 53 ± 1% in the T2D-cont mice. Dapa and Dapa+Saxa improved LVEF to 68 ± 1 and 74.6 ± 1% in the BTBR mice (p < 0.001). The mRNA levels of NALP3, ASC, IL-1β, IL-6, caspase-1, and TNFα were significantly higher in the BTBR compared to the WT hearts; and Dapa and Dapa+Saxa significantly attenuated these levels. Likewise, protein levels of NLRP3, TNFα, and caspase-1 were higher in the BTBR compared to the WT hearts and Dapa, and to a greater extent Dapa+Saxa, attenuated the increase in the BTBR mice. Collagen-1 and collagen-3 mRNA levels significantly increased in the BTBR mice and these increases were attenuated by Dapa and Dapa+Saxa. P-AMPK/total-AMPK ratio was significantly lower in the BTBR mice than in the WT mice. Dapa and Dapa+Saxa equally increased the ratio in the BTBR mice. This in vitro study showed that NALP3, ASC, IL-1β, and caspase-1 mRNA levels were higher in the BTBR cardiofibroblasts and attenuated with Dapa. The effect was AMPK-dependent and SGLT1-independent. Dapa attenuated the activation of the inflammasome, fibrosis, and deterioration of LVEF in BTBR mice. The anti-inflammatory, anti-fibrotic effects are likely SGLT2- and glucose-lowering-independent, as they were replicated in the in vitro model. The effects on remodeling were augmented when Saxa was added to Dapa. Yet, adding Saxa to Dapa did not result in a greater effect on myocardial fibrosis and collagen levels.read more
Citations
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Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review
TL;DR: It is critical for cardiologists, diabetologists, nephrologists, and primary care physicians to be familiar with SGLT2i, as their use is now being studied in the treatment of heart failure and chronic kidney disease, even in patients without diabetes.
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Renoprotective effects of sodium-glucose cotransporter-2 inhibitors.
TL;DR: The aim is to review the rationale for renal protection with SGLT2 inhibitors, and their current place in the clinical management of patients with kidney disease.
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Metformin Inhibits the NLRP3 Inflammasome via AMPK/mTOR-dependent Effects in Diabetic Cardiomyopathy.
Fan Yang,Ying Qin,Yueqiu Wang,Songyan Meng,Huimin Xian,Hui Che,Hui Che,Jie Lv,Yang Li,Yahan Yu,Yunlong Bai,Yunlong Bai,Lihong Wang,Lihong Wang +13 more
TL;DR: Investigating whether metformin can inhibit the NLRP3 inflammasome by activating the AMPK/mTOR pathway in diabetic cardiomyopathy found that it can activate AMPK, thus improving autophagy via inhibiting the mTOR pathway and alleviating pyroptosis in DCM.
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Obesity, Hypertension, and Cardiac Dysfunction: Novel Roles of Immunometabolism in Macrophage Activation and Inflammation.
TL;DR: It is proposed that obesity and hypertension induce M1 macrophages polarization via mechanisms that directly target macrophage metabolism, including changes in circulating glucose and fatty acid substrates, lipotoxicity, and tissue hypoxia.
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Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: The potential contribution to diabetes complications and cardiovascular disease.
Fernand Bonnet,André Scheen +1 more
TL;DR: Experimental findings suggest that part of the renoprotective effects of SGLT2 inhibition may be related to anti-inflammatory actions at the kidney level and may involve weight loss, and reduction in adipose tissue inflammation, slight increase in ketone bodies and diminution of uric acid levels.
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