Crosstalk between Sodium–Glucose Cotransporter Inhibitors and Sodium–Hydrogen Exchanger 1 and 3 in Cardiometabolic Diseases

Al-Shamasi, Al-Anood; Elkaffash, Rozina; Mohamed, Meram; Rayan, Menatallah; Al-Khater, Dhabya; Gadeau, Alain‐Pierre; Ahmed, Rashid; Hasan, Anwarul; Eldassouki, Hussein; Yalcin, Huseyin C.; Abdul‐Ghani, Muhammad; Mraiche, Fatima

doi:10.3390/ijms222312677

Cited by 7 publications

(6 citation statements)

References 161 publications

(201 reference statements)

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“…Further studies should be conducted to investigate the off-target effect of DAPA in the downregulation of the Na+/H+ exchanger-1 (NHE1) during endotoxemia. NHE1 inhibition by DAPA mitigates cardiovascular injuries independent of glycemia as reported recently [ 48 , 49 ].…”

Section: Discussionsupporting

confidence: 62%

Dapagliflozin Mitigates Hypotension in Lipopolysaccharide-Induced Acute Inflammation Independent of Glycemia Level

et al. 2023

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Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been suggested to have anti-inflammatory properties in diabetes. The goal of this study was to evaluate the role of the SGLT2 inhibitor dapagliflozin (DAPA) in the attenuation of lipopolysaccharide (LPS)-induced hypotension. Male Wistar albino rats were divided into normal and diabetic groups and received DAPA (1 mg/kg/day) for two weeks followed by a single dose of 10 mg/kg LPS. Blood pressure was recorded throughout the study and the circulatory levels of cytokines were assessed using a multiplex array, while the aortas were harvested for analysis. DAPA attenuated the vasodilation and hypotension caused by LPS. Mean arterial pressure (MAP) was preserved in the normal and diabetic DAPA-treated septic groups (MAP = 83.17 ± 5.27, 98.43 ± 5.57 mmHg) compared to the vehicle-treated septic groups (MAP = 65.60 ± 3.31, 68.21 ± 5.88 mmHg). Most of the cytokines induced by LPS were decreased in the DAPA-treated septic groups. In the aorta, the inducible nitric oxide synthase-derived nitric oxide had lower expression in the DAPA-treated rats. In contrast, the expression of α-smooth muscle actin, a marker of the vessel’s contractile state, was higher in the DAPA-treated rats in comparison with non-treated septic rats. These findings revealed that the protective role of DAPA against LPS-induced hypotension is likely to be glucose-lowering independent, as was observed in the non-diabetic septic group. Taken together, the results show that DAPA has a potential effect in the prevention of the hemodynamic disturbances of sepsis regardless of glycemia levels.

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Section: Discussionsupporting

confidence: 62%

Dapagliflozin Mitigates Hypotension in Lipopolysaccharide-Induced Acute Inflammation Independent of Glycemia Level

et al. 2023

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“…In patients with T2D, increased levels of insulin and glucose stimulate the activity of NHE-3. Enhanced sodium influx causes a rise in peripheral vascular resistance, which increases cardiac output [ 104 ]. Due to the similar localisation of NHE-3 and SGLT-2 in the kidney, it seems possible that SGLT-2is trigger diuresis via NHE-3 inhibition [ 105 ].…”

Section: Novel Antihypertensive Drugsmentioning

confidence: 99%

Hypertension and Type 2 Diabetes—The Novel Treatment Possibilities

Przezak

Bielka

Pawlik

2022

IJMS

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Elevated blood pressure and hyperglycaemia frequently coexist and are both components of metabolic syndrome. Enhanced cardiovascular risk is strongly associated with diabetes and the occurrence of hypertension. Both hypertension and type 2 diabetes, if treated inappropriately, lead to serious complications, increasing the mortality of patients and generating much higher costs of health systems. This is why it is of great importance to find the missing link between hypertension and diabetes development and to simultaneously search for drugs influencing these two disorders or even drugs aimed at their pathological bases. Standard antihypertensive therapy mainly focuses on blood pressure reduction, while novel drugs also possess a wide range of pleiotropic modes of actions, such as cardio- and nephroprotective properties or body weight reduction. These properties are especially desirable in a situation when type 2 diabetes coexists with hypertension. This review describes the connections between diabetes and hypertension development and briefly summarises the current knowledge regarding attempts to define targets for the treatment of high blood pressure in diabetic patients. It also describes the standard hypotensive drugs preferred in patients with type 2 diabetes, as well as novel drugs, such as finerenone, esaxerenone, sodium–glucose co-transporter-2 inhibitors, glucagon-like peptide-1 analogues and sacubitril/valsartan.

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Section: Pathophysiology Of Sglt2i‐induced Acidosismentioning

confidence: 99%

“…SGLT2 inhibitors induce this pathway and increase lipid peroxidation 64 . They facilitate overt urinary glucose excretion and reduce available substrate for the Krebs cycle and, therefore, induce acetoacetyl‐CoA synthesis which, in turn, is converted to ketone bodies 64,83 . A recent study demonstrated that dapagliflozin therapy mobilizes FFAs from adipose tissue and increases hepatic FFA oxidation in diabetic animals 83 .…”

Section: Pathophysiology Of Sglt2i‐induced Acidosismentioning

confidence: 99%

New insights into cellular links between sodium–glucose cotransporter‐2 inhibitors and ketogenesis

Yaribeygi

Maleki

Butler

et al. 2022

J of Cellular Biochemistry

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Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a newly developed class of highly effective antidiabetic therapies that normalize hyperglycemia via urinary glucose excretion. However, they may be accompanied by certain side effects that negatively impact their therapeutic benefits. SGLT2is induce a metabolic shift from glucose to fatty acids and thus increase lipolysis which, in turn, induces ketogenesis. The complete pathways linking SGLT2is to ketoacidosis have not yet been fully elucidated, though much is now known.Therefore, in this mechanistic study, we present the current knowledge and shed light upon the possible cellular pathways involved. A deeper understanding of the possible links between SGLT2is and ketogenesis could help to prevent adverse side effects in diabetic patients treated with these drugs.

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Crosstalk between Sodium–Glucose Cotransporter Inhibitors and Sodium–Hydrogen Exchanger 1 and 3 in Cardiometabolic Diseases

Cited by 7 publications

References 161 publications

Dapagliflozin Mitigates Hypotension in Lipopolysaccharide-Induced Acute Inflammation Independent of Glycemia Level

Dapagliflozin Mitigates Hypotension in Lipopolysaccharide-Induced Acute Inflammation Independent of Glycemia Level

Hypertension and Type 2 Diabetes—The Novel Treatment Possibilities

New insights into cellular links between sodium–glucose cotransporter‐2 inhibitors and ketogenesis

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