SGLT2 Inhibitors Produce Cardiorenal Benefits by Promoting Adaptive Cellular Reprogramming to Induce a State of Fasting Mimicry: A Paradigm Shift in Understanding Their Mechanism of Action

Packer, Milton

doi:10.2337/dci19-0074

Cited by 174 publications

(162 citation statements)

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“…Glucose leaves the basolateral membrane through GLUT1 and GLUT2 [105]. Although the AMPK regulation of SGLT2 has not been clearly addressed, the use of SGLT2 inhibitors mimics the cellular response to starvation and indirectly activates AMPK, leading to the improvement of nephropathy development [106]. However, it has been demonstrated that AMPK activates SGLT1-dependent glucose transport in colorectal cells and cardiomyocytes that needs to be confirmed in the renal tissue [107,108].…”

Section: Ampk and Renal Glucose Metabolismmentioning

confidence: 99%

Critical Role for AMPK in Metabolic Disease-Induced Chronic Kidney Disease

Juszczak

Caron

Mathew

et al. 2020

IJMS

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Chronic kidney disease (CKD) is prevalent in 9.1% of the global population and is a significant public health problem associated with increased morbidity and mortality. CKD is associated with highly prevalent physiological and metabolic disturbances such as hypertension, obesity, insulin resistance, cardiovascular disease, and aging, which are also risk factors for CKD pathogenesis and progression. Podocytes and proximal tubular cells of the kidney strongly express AMP-activated protein kinase (AMPK). AMPK plays essential roles in glucose and lipid metabolism, cell survival, growth, and inflammation. Thus, metabolic disease-induced renal diseases like obesity-related and diabetic chronic kidney disease demonstrate dysregulated AMPK in the kidney. Activating AMPK ameliorates the pathological and phenotypical features of both diseases. As a metabolic sensor, AMPK regulates active tubular transport and helps renal cells to survive low energy states. AMPK also exerts a key role in mitochondrial homeostasis and is known to regulate autophagy in mammalian cells. While the nutrient-sensing role of AMPK is critical in determining the fate of renal cells, the role of AMPK in kidney autophagy and mitochondrial quality control leading to pathology in metabolic disease-related CKD is not very clear and needs further investigation. This review highlights the crucial role of AMPK in renal cell dysfunction associated with metabolic diseases and aims to expand therapeutic strategies by understanding the molecular and cellular processes underlying CKD.

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Section: Ampk and Renal Glucose Metabolismmentioning

confidence: 99%

Critical Role for AMPK in Metabolic Disease-Induced Chronic Kidney Disease

Juszczak

Caron

Mathew

et al. 2020

IJMS

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“…Recent cardiovascular outcome trials in patients with type 2 diabetes mellitus (T2DM) [1][2][3], and dedicated heart failure (HF) trials in patients with HF and reduced ejection fraction (HFrEF) with or without T2DM [4][5][6] have demonstrated a consistently significant reduction in hospitalization for HF with SGLT2 inhibitor treatment versus placebo. Therefore, it has been postulated that SGLT2 inhibition in the kidney does not serve as full explanation for the marked clinical benefits associated with SGLT2 inhibitor treatment [7][8][9][10][11], suggesting direct cardiovascular mechanisms, which are currently incompletely understood given that SGLT2 is not expressed in the normal or diseased heart [9,[12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Characterization of left ventricular myocardial sodium-glucose cotransporter 1 expression in patients with end-stage heart failure

Sayour

Oláh

Ruppert

et al. 2020

Cardiovasc Diabetol

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Background Whereas selective sodium-glucose cotransporter 2 (SGLT2) inhibitors consistently showed cardiovascular protective effects in large outcome trials independent of the presence of type 2 diabetes mellitus (T2DM), the cardiovascular effects of dual SGLT1/2 inhibitors remain to be elucidated. Despite its clinical relevance, data are scarce regarding left ventricular (LV) SGLT1 expression in distinct heart failure (HF) pathologies. We aimed to characterize LV SGLT1 expression in human patients with end-stage HF, in context of the other two major glucose transporters: GLUT1 and GLUT4. Methods Control LV samples (Control, n = 9) were harvested from patients with preserved LV systolic function who went through mitral valve replacement. LV samples from HF patients undergoing heart transplantation (n = 71) were obtained according to the following etiological subgroups: hypertrophic cardiomyopathy (HCM, n = 7); idiopathic dilated cardiomyopathy (DCM, n = 12); ischemic heart disease without T2DM (IHD, n = 14), IHD with T2DM (IHD + T2DM, n = 11); and HF patients with cardiac resynchronization therapy (DCM:CRT, n = 9, IHD:CRT, n = 9 and IHD-T2DM:CRT, n = 9). We measured LV SGLT1, GLUT1 and GLUT4 gene expressions with qRT-PCR. The protein expression of SGLT1, and activating phosphorylation of AMP-activated protein kinase (AMPKα) and extracellular signal-regulated kinase 1/2 (ERK1/2) were quantified by western blotting. Immunohistochemical staining of SGLT1 was performed. Results Compared with controls, LV SGLT1 mRNA and protein expressions were significantly and comparably upregulated in HF patients with DCM, IHD and IHD + T2DM (all P < 0.05), but not in HCM. LV SGLT1 mRNA and protein expressions positively correlated with LVEDD and negatively correlated with EF (all P < 0.01). Whereas AMPKα phosphorylation was positively associated with SGLT1 protein expression, ERK1/2 phosphorylation showed a negative correlation (both P < 0.01). Immunohistochemical staining revealed that SGLT1 expression was predominantly confined to cardiomyocytes, and not fibrotic tissue. Overall, CRT was associated with reduction of LV SGLT1 expression, especially in patients with DCM. Conclusions Myocardial LV SGLT1 is upregulated in patients with HF (except in those with HCM), correlates significantly with parameters of cardiac remodeling (LVEDD) and systolic function (EF), and is downregulated in DCM patients with CRT. The possible role of SGLT1 in LV remodeling needs to be elucidated.

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“…Some reports showed that SGLT2 inhibitors induced a fasting-like state. 21 During fasting, lipogenesisrelated genes decreased and increased after refeeding, 22 and such phenomena may occur during SGLT2 inhibitor treatment. As the half-life of canagliflozin was relatively short (2-4 h) in mice, 23 continuous administration could maintain blood canagliflozin levels and the Food group could therefore have higher renal glucose excretion rates compared with untreated controls for a longer duration than the Gav group.…”

Section: Discussionmentioning

confidence: 99%