Effect of sodium‐glucose cotransporter 2 inhibitor, empagliflozin, and α‐glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes

Kim, Ji Won; Lee, Ye Jee; You, Young Hye; Moon, Min Kyong; Yoon, Kun Ho; Ahn, Yu‐Bae; Ko, Seung‐Hyun

doi:10.1002/jcb.28141

Cited by 43 publications

(38 citation statements)

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“…Because SIRT1 is an energy-sensing molecule responsible for the promotion of healthy longevity mediated by caloric restriction[ 14 ], it is possible that temporary calorie loss due to the urinary glucose excretion caused by ipragliflozin may stimulate hepatic SIRT1. Similar conclusions were reached by Kim et al[ 31 ]. In addition, AMPK enhances SIRT1 activity by increasing cellular NAD+ levels[ 32 ], and the interplay between SIRT1 and AMPK is suggested to be reciprocal[ 33 ].…”

Section: Discussionsupporting

confidence: 92%

Ipragliflozin-induced improvement of liver steatosis in obese mice may involve sirtuin signaling

Suga

Sato

Ohyama

et al. 2020

WJH

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BACKGROUND Sodium glucose cotransporter 2 (SGLT2) inhibitors are newly developed oral antidiabetic drugs. SGLT2 is primarily expressed in the kidneys and reabsorbs approximately 90% of the glucose filtered by the renal glomeruli. SGLT2 inhibitors lower glucose levels independently of insulin action by facilitating urinary glucose excretion. The SGLT2 inhibitor ipragliflozin has reportedly improved liver steatosis in animal models and clinical studies. However, the mechanisms by which SGLT2 inhibitors improve liver steatosis are not fully understood. AIM To investigate the ameliorative effects of ipragliflozin on liver steatosis and the mechanisms of these effects in obese mice. METHODS We analyzed 8-wk-old male obese ( ob/ob ) mice that were randomly divided into a group receiving a normal chow diet and a group receiving a normal chow diet supplemented with ipragliflozin (3 mg/kg or 10 mg/kg) for 4 wk. We also analyzed their lean sex-matched littermates receiving a normal chow diet as another control group. Body weight and liver weight were evaluated, and liver histology, immunoblotting, and reverse transcription-polymerase chain reaction analyses were performed. RESULTS Hepatic lipid accumulation was significantly ameliorated in ob/ob mice treated with 10 mg/kg ipragliflozin compared to untreated ob/ob mice irrespective of body weight changes. Ipragliflozin had no appreciable effects on hepatic oxidative stress-related gene expression levels or macrophage infiltration, but significantly reduced hepatic interleukin-1β (IL-1β) mRNA expression levels. Ipragliflozin increased both the mRNA and protein expression levels of sirtuin 1 (SIRT1) in the liver. The hepatic mRNA levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα), and fibroblast growth factor-21 (FGF21) were also significantly higher in ipragliflozin-treated ob/ob mice than in untreated ob/ob mice. CONCLUSION Our study suggests that the liver steatosis-ameliorating effects of ipragliflozin in ob/ob mice may be mediated partly by hepatic SIRT1 signaling, possibly through the PGC-1α/PPARα-FGF21 pathway.

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Section: Discussionsupporting

confidence: 92%

Ipragliflozin-induced improvement of liver steatosis in obese mice may involve sirtuin signaling

Suga

Sato

Ohyama

et al. 2020

WJH

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“…Experimental studies indicates that SGLT2 inhibitors can activate AMPK, SIRT1 and HIF‐1α in the myocardium, thereby potentially contributing to their actions to reduce heart failure and adverse renal events ( Figure ). Canagliflozin increases the expression, phosphorylation and activation of AMPK; although similar effects have been reported for empagliflozin and dapagliflozin, the evidence is less certain . Both canagliflozin and empagliflozin have been shown to upregulate SIRT1, and both empagliflozin and dapagliflozin induce the expression of HIF‐1α .…”

Section: Novel Mechanisms By Which Sglt2 Inhibitors May Promote Cardimentioning

confidence: 73%

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

Packer

2020

European J of Heart Fail

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In five large-scale trials involving >40 000 patients, sodium-glucose cotransporter 2 (SGLT2) inhibitors decreased the risk of serious heart failure events by 25-40%. This effect cannot be explained by control of hyperglycaemia, since it is not observed with antidiabetic drugs with greater glucose-lowering effects. It cannot be attributed to ketogenesis, since it is not causally linked to ketone body production, and the benefit is not enhanced in patients with diabetes. The effect cannot be ascribed to a natriuretic action, since SGLT2 inhibitors decrease natriuretic peptides only modestly, and they reduce cardiovascular death, a benefit that diuretics do not possess. Although SGLT2 inhibitors increase red blood cell mass, enhanced erythropoiesis does not favourably influence the course of heart failure. By contrast, experimental studies suggest that SGLT2 inhibitors may reduce intracellular sodium, thereby preventing oxidative stress and cardiomyocyte death. Additionally, SGLT2 inhibitors induce a transcriptional paradigm that mimics nutrient and oxygen deprivation, which includes activation of adenosine monophosphate-activated protein kinase, sirtuin-1, and/or hypoxia-inducible factors-1 /2 . The interplay of these mediators stimulates autophagy, a lysosomally-mediated degradative pathway that maintains cellular homeostasis. Autophagy-mediated clearance of damaged organelles reduces inflammasome activation, thus mitigating cardiomyocyte dysfunction and coronary microvascular injury. Interestingly, the action of hypoxia-inducible factors-1 /2 to both stimulate erythropoietin and induce autophagy may explain why erythrocytosis is strongly correlated with the reduction in heart failure events. Therefore, the benefits of SGLT2 inhibitors on heart failure may be mediated by a direct cardioprotective action related to modulation of pathways responsible for cardiomyocyte homeostasis.In four large-scale clinical trials in patients with type 2 diabetes followed for 2-5 years who largely did not have a diagnosis of heart failure at the time of study entry, patients assigned to treatment

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“…The major distinction between metformin and SGLT2 inhibitors may be the effect of the latter to stimulate hypoxia‐inducible factors (thus explaining the erythrocytosis seen with these drugs, but not with metformin). This difference may possibly be explained by postulating that metformin exerts its effects primarily through the activation of AMPK and that SGLT2 inhibitors act principally through enhanced SIRT1 signalling . Further studies are needed to confirm, modify or refute this hypothesis.…”

Section: Are Sglt2 Inhibitors Renoprotective Through An Action To Stimentioning

confidence: 99%

Interplay of adenosine monophosphate‐activated protein kinase/sirtuin‐1 activation and sodium influx inhibition mediates the renal benefits of sodium‐glucose co‐transporter‐2 inhibitors in type 2 diabetes: A novel conceptual framework

Packer

2020

Diabetes Obesity Metabolism

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Long-term treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors slows the deterioration of renal function in patients with diabetes. This benefit cannot be ascribed to an action on blood glucose, ketone utilization, uric acid or systolic blood pressure. SGLT2 inhibitors produce a striking amelioration of glomerular hyperfiltration. Although initially ascribed to an action of these drugs to inhibit proximal tubular glucose reabsorption, SGLT2 inhibitors exert renoprotective effects, even in patients with meaningfully impaired levels of glomerular function that are sufficient to abolish their glycosuric actions. Instead, the reduction in intraglomerular pressures may be related to an action of SGLT2 inhibitors to interfere with the activity of sodium-hydrogen exchanger isoform 3, thereby inhibiting proximal tubular sodium reabsorption and promoting tubuloglomerular feedback. Yet, experimentally, such an effect may not be sufficient to prevent renal injury. It is therefore noteworthy that the diabetic kidney exhibits an important defect in adenosine monophosphateactivated protein kinase (AMPK) and sirtuin-1 (SIRT1) signalling, which may contribute to the development of nephropathy. These transcription factors exert direct effects to mute oxidative stress and inflammation, and they also stimulate autophagy, a lysosomally mediated degradative pathway that maintains cellular homeostasis in the kidney. SGLT2 inhibitors induce both AMPK and SIRT1, and they have been shown to stimulate autophagy, thereby ameliorating cellular stress and glomerular and tubular injury. Enhanced AMPK/SIRT1 signalling may also contribute to the action of SGLT2 inhibitors to interfere with sodium transport mechanisms.The dual effects of SGLT2 inhibitors on AMPK/SIRT1 activation and renal tubular sodium transport may explain the protective effects of these drugs on the kidney in type 2 diabetes. K E Y W O R D Sautophagy, diabetic nephropathy, sirtuin-1, sodium-glucose co-transporter-2 inhibitor

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Effect of sodium‐glucose cotransporter 2 inhibitor, empagliflozin, and α‐glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes

Cited by 43 publications

References 53 publications

Ipragliflozin-induced improvement of liver steatosis in obese mice may involve sirtuin signaling

Ipragliflozin-induced improvement of liver steatosis in obese mice may involve sirtuin signaling

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

Interplay of adenosine monophosphate‐activated protein kinase/sirtuin‐1 activation and sodium influx inhibition mediates the renal benefits of sodium‐glucose co‐transporter‐2 inhibitors in type 2 diabetes: A novel conceptual framework

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