Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome

Abstract

BackgroundThe potential benefit of SGLT2 inhibitors in metabolic syndrome is with prediabetic stage unclear. This work was undertaken to investigate the non-glycemic effect of empagliflozin on metabolic syndrome rats with prediabetes.MethodsSHR/NDmcr-cp(+/+) rats (SHRcp), a model of metabolic syndrome with prediabetes, were given empagliflozin for 10 weeks to examine the effects on urinary sodium and water balance, visceral and subcutaneous adipocyte, and cardiac injury. Further, the effect of empagliflozin on blood pressure and autonomic nervous system was continuously investigated by using radiotelemetry system.ResultsEmpagliflozin significantly reduced urinary sodium and water balance of SHRcp only within 1 week of the treatment, but later than 1 week did not alter them throughout the treatment. Empagliflozin significantly reduced body weight of SHRcp, which was mainly attributed to the significant reduction of subcutaneous fat mass. Empagliflozin significantly reduced the size of visceral adipocytes and increased the number of smaller size of adipocytes, which was associated with the attenuation of oxidative stress. Empagliflozin ameliorated cardiac hypertrophy and fibrosis of SHRcp, in association with the attenuation of cardiac oxidative stress and inflammation. However, empagliflozin did not significantly change blood pressure, heart rate, sympathetic activity, or baroreceptor function, as evidenced by radiotelemetry analysis.ConclusionsOur present work provided the evidence that SGLT2 inhibition reduced visceral adipocytes hypertrophy and ameliorated cardiac injury in prediabetic metabolic syndrome rat, independently of diuretic effect or blood pressure lowering effect. Thus, SGLT2 inhibition seems to be a promising therapeutic strategy for prediabetic metabolic syndrome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0473-7) contains supplementary material, which is available to authorized users.

Hypoxia‐inducible factor 1‐alpha (HIF‐1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction

“…SGLT2 inhibitors have previously demonstrated a broad range of effects . Empagliflozin reduced cardiac hypertrophy and fibrosis in the prediabetic MS rat . Empagliflozin significantly reduced cardiac myocyte hypertrophy, inflammation, cardiac oxidative stress, and interstitial fibrosis in Male SHR/NDmcr‐cp(+/+) rats (SHRcp), a rat model of MetS characterized by obesity, insulin resistance, impaired glucose tolerance with normal fasting blood glucose, hypertension, and hyperlipidaemia .…”

Long-Term Effects of Ipragliflozin on Adipose Tissue in Japanese Patients with Obese Type 2 Diabetes

“…Body weight decrease may be attributed to visceral fat tissue lipolysis due to SGLT2 inhibitor induced enhancement in lipid metabolism [8]. Longterm empagliflozin treatment significantly reduced weight of subcutaneous but not visceral fat in rats [15]. They concluded that the decrease in body weight of rats treated with SGLT2 inhibitor was due to a decrease in subcutaneous rather than visceral fat, and suggested that body weight decrease may be due to visceral fat adipocyte hypertrophy and reduction of oxidative stress.…”

“…Canagliflozin improved liver dysfunction in patients with T2D, assessed by monitoring serum AST, ALT, and γ-GTP levels [15]. Ogawa et al reported that ipragliflozin improved liver function in clinical and basic research [19].…”

“…Visceral fat area was significantly reduced in 6-month observation of 64 diabetic patients [2]. However, obesity is difficult to treat as many subjects regain weight after temporary weight loss [11][12][13][14][15]. Any study on body weights, the longer, the better.…”

Role of the sodium‐hydrogen exchanger in mediating the renal effects of drugs commonly used in the treatment of type 2 diabetes

“…Furthermore, although SGLT2 is not expressed in the heart, SGLT2 inhibitors can inhibit cardiac NHE1, possibly through a binding site for SGLT2 on NHE1 . Such an action may underlie the observation that SGLT2 inhibitors have favourable structural and functional effects on the heart, which are independent of their effects on sodium reabsorption or blood pressure . These NHE‐dependent effects on both the kidney and the heart, working in concert, may explain why this class of drugs reduces the risks of cardiovascular death, of heart failure and of diabetic chronic kidney disease …”