Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2

Matthews, Vance B.; Elliot, Rosemary H.; Rudnicka, Caroline; Hricova, Jana; Herat, Lakshini Y.; Schlaich, Markus P.

doi:10.1097/hjh.0000000000001434

Cited by 163 publications

(143 citation statements)

References 39 publications

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“…Conversely, we found no signi cant difference in LP as an indicator of depolarization or TWA as an indicator of repolarization abnormality. Although experimental data and clinical case reports have suggested that SGLT2 inhibitors improved cardiac sympathetic hyperactivity [16,17], the present study, to the best of our knowledge, is the rst trial to provide randomized clinical data demonstrating that empagli ozin improved both the cardiac sympathetic and parasympathetic activities in humans. The evidence connecting the autonomic nervous system to life-threatening arrhythmias and cardiovascular mortality is well established [18][19][20].…”

Section: Discussionmentioning

confidence: 76%

Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial

Shimizu

Kubota

Hoshika

et al. 2020

Preprint

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Background: Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium–glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity.Methods: This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency–to–high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT.Results: Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were +11.6 and +9.1 msec in the empagliflozin (P=0.02) and placebo groups (P=0.06), respectively. Change in LF/HF ratio was –0.57 and –0.17 in the empagliflozin (P=0.01) and placebo groups (P=0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P=0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed.Conclusions: This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events. Trial Registration: The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442

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Section: Discussionmentioning

confidence: 76%

Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial

Shimizu

Kubota

Hoshika

et al. 2020

Preprint

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“…Adipokines such as tumour necrosis factor-α and interleukin 6 (IL-6) were found to upregulate SGLT2 in vitro 41 , and increased adiponectin was shown to cause activation of PPARδ in the adipose tissue and reduce renal SGLT2 35 . Recent evidence showed potential cross-talk between the sympathetic nervous system and SGLT2 regulation 42 while sex and species differences appeared to be influencing SGLT2 expression in rodents 43 . At the transcriptional level, hepatocyte nuclear factor 1 alpha (HNF1α) is known to bind to the SGLT2 promoter in the kidney, and had been considered a vital transcription factor for SGLT2 expression since HNF1α -null mice have reduced SGLT2 transcript levels in tubular cells 37 .…”

Section: Discussionmentioning

confidence: 99%

Vertical sleeve gastrectomy lowers kidney SGLT2 expression in the mouse

Akalestou

López-Noriega

Leclerc

et al. 2019

Preprint

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Background: Bariatric surgery has been established to improve insulin sensitivity and glucose clearance, but also increases insulin and glucagon secretion. Each of the above effects have also been observed following treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors. Aim: To determine whether there is an effect of bariatric surgery (Vertical Sleeve Gastrectomy; VSG) on renal SGLT2 expression in mice. Methods: Eighteen lean mice underwent VSG (n=8) or sham (n=9) surgery. Glucose tolerance tests with or without treatment with the SGLT2 inhibitor dapagliflozin were performed four weeks post operatively, in order to assess if pharmacological SGLT2 inhibition has the same euglycemic effects after bariatric surgery. Kidneys were harvested from fed mice and SGLT2 expression was analysed using Quantitative reverse-transcription PCR and immunofluorescence.Results: VSG mice displayed significantly improved glucose tolerance (AUC=103±6.8; AUC=66.6±2.9 in control and VSG mice, respectively; p<0.001), despite an absence of significant weight loss when compared to sham operated mice (p=0.37, Mann-Whitney test). Treatment of sham-operated mice with dapagliflozin (10 mg/kg) improved glucose tolerance. In contrast, dapagliflozin did not further improve glucose tolerance in VSG-operated mice. Moreover, qRT-PCR and immunofluorescence analysis on mouse kidneys demonstrated a significant lowering of SGLT2 expression at both the mRNA (n=7, p<0.0001) and protein (n=5, p=0.0007) levels four weeks after VSG. Conclusions: Vertical sleeve gastrectomy in lean animals causes a significant inhibition of SGLT2 expression in the kidney cortex. These findings are in line with our previous results on the effects of Duodenal Jejunal Bypass in lean rats, and point towards a physiologically-relevant gut-kidney axis. SGLT2 inhibition may thus be an important mechanism through which bariatric surgery improves glucose tolerance in man.

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“…Leptin can promote sodium retention by increasing sympathetic nerve traffic to the kidneys, but SGLT2 inhibitors decrease this traffic to the periphery, explaining the lack of a reflex sympathetic nerve response to their natriuretic effects . Furthermore, leptin‐mediated neurohormonal activation causes upregulation of SGLT2 in the renal tubules, potentially explaining why the renal response to inhibitors of the renin‐angiotensin system parallels that seen with SGLT2 inhibitors in individual patients . In addition, SGLT2 suppression leads to decreases in serum aldosterone (thus opposing the actions of leptin), despite the decrease in plasma volume.…”

Section: Potential Role Of Sglt2 Antagonists As Antagonists Of Leptinmentioning

confidence: 99%

“…Leptin decreases the expression of SGLT1 in the intestinal epithelium, thus adaptively attenuating the absorption of glucose into the bloodstream . In contrast, leptin‐mediated activation of the sympathetic nerve system and renin‐angiotensin system causes upregulation of SGLT2 in the renal tubules, thus enhancing the clearance of glucose from the bloodstream.…”

Section: Is the Relationship Between Sglt2 Inhibitors And Leptin A Comentioning

confidence: 99%

Do sodium‐glucose co‐transporter‐2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis

Packer

2018

Diabetes Obesity Metabolism

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Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of serious heart failure events in patients with type 2 diabetes, but little is known about mechanisms that might mediate this benefit. The most common heart failure phenotype in type 2 diabetes is obesity-related heart failure with a preserved ejection fraction (HFpEF). It has been hypothesized that the synthesis of leptin in this disorder leads to sodium retention and plasma volume expansion as well as to cardiac and renal inflammation and fibrosis. Interestingly, leptin-mediated neurohormonal activation appears to enhance the expression of SGLT2 in the renal tubules, and SGLT2 inhibitors exert natriuretic actions at multiple renal tubular sites in a manner that can oppose the sodium retention produced by leptin. In addition, SGLT2 inhibitors reduce the accumulation and inflammation of perivisceral adipose tissue, thus minimizing the secretion of leptin and its paracrine actions on the heart and kidneys to promote fibrosis. Such fibrosis probably contributes to the impairment of cardiac distensibility and glomerular function that characterizes obesity-related HFpEF. Ongoing clinical trials with SGLT2 inhibitors in heart failure are positioned to confirm or refute the hypothesis that these drugs may favourably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin. K E Y W O R D S antidiabetic drug, cardiovascular disease, SGLT2 inhibitor 1 | INTRODUCTION Sodium-glucose co-transporter-2 (SGLT2) inhibitors have reduced the risk of important heart failure events in patients with type 2 diabetes. In large-scale trials, the risk of heart failure hospitalization was reduced by 35% with empagliflozin and by 33% with canagliflozin. 1,2 2 | POTENTIAL MECHANISMS OF SGLT2 INHIBITORS IN HEART FAILURE Several mechanisms have been proposed to explain the beneficial effects of SGLT2 inhibitors on heart failure. SGLT2 antagonists block sodium reabsorption in the proximal renal tubule, not only by inhibiting SGLT2 but also sodium-hydrogen exchanger (NHE) isoform 3 (NHE3), which is the primary mechanism of sodium reuptake in the kidneys. 3-5 Because of the intimate relationship between SGLT2 and NHE3 in the early segment of the proximal renal tubule, inhibition of one component attenuates the actions of the complex on ion transport. 5 This natriuretic effect accounts for the haemoconcentration seen in clinical trials. 1In addition, the benefit of SGLT2 inhibitors may be related to effects on the heart. First, their antihyperglycaemic effect might reduce cardiac glucotoxicity, 6 although the magnitude of glucoselowering is modest when compared with other antidiabetic agents that do not reduce heart failure events. 7 Second, the mild hyperketonaemia produced by SGLT2 inhibition can shift the fuel supply in the heart from fatty acids to ketones, which may enhance energy efficiency. 8 However, the failing heart already relies on ketone bodies for its metabolism, and this fuel shift may not be adaptive. 9 Third,...

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Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2

Cited by 163 publications

References 39 publications

Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial

Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial

Vertical sleeve gastrectomy lowers kidney SGLT2 expression in the mouse

Do sodium‐glucose co‐transporter‐2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis

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