SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms

Osataphan, Soravis; Macchi, Chiara; Singhal, Garima; Chimene-Weiss, Jeremy; Sales, Vicência; Kozuka, Chisayo; Dreyfuss, Jonathan M.; Hui, Pei; Tangcharoenpaisan, Yanin; Morningstar, Jordan; Gerszten, Robert E.; Patti, Mary‐Elizabeth

doi:10.1172/jci.insight.123130

Cited by 148 publications

(133 citation statements)

References 51 publications

(51 reference statements)

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“…Empagliflozin also is associated with decreased hypertension, reduced arterial stiffness, and decreased vascular resistance (594,595). In both rodents and humans with non-alcoholic fatty liver disease, SGLT-2 inhibitors have been shown to reduce ectopic liver fat by blunting de novo hepatic lipogenesis (596)(597)(598)(599), with reduced alanine transaminase (ALT) and aspartate transaminase (AST) levels (600), two markers of hepatic metabolic stress. Furthermore, empagliflozin is associated with weight loss in humans when administered in combination with other therapeutics, such as metformin, thiazolidinediones, and sulfonylureas (601)(602)(603).…”

Section: Sglt-2 Inhibitorsmentioning

confidence: 99%

Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease

Chait¹,

Hartigh²

2020

Front. Cardiovasc. Med.

715

658

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Adipose tissue plays essential roles in maintaining lipid and glucose homeostasis. To date several types of adipose tissue have been identified, namely white, brown, and beige, that reside in various specific anatomical locations throughout the body. The cellular composition, secretome, and location of these adipose depots define their function in health and metabolic disease. In obesity, adipose tissue becomes dysfunctional, promoting a pro-inflammatory, hyperlipidemic and insulin resistant environment that contributes to type 2 diabetes mellitus (T2DM). Concurrently, similar features that result from adipose tissue dysfunction also promote cardiovascular disease (CVD) by mechanisms that can be augmented by T2DM. The mechanisms by which dysfunctional adipose tissue simultaneously promote T2DM and CVD, focusing on adipose tissue depot-specific adipokines, inflammatory profiles, and metabolism, will be the focus of this review. The impact that various T2DM and CVD treatment strategies have on adipose tissue function and body weight also will be discussed.

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Section: Sglt-2 Inhibitorsmentioning

confidence: 99%

Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease

Chait¹,

Hartigh²

2020

Front. Cardiovasc. Med.

715

658

View full text Add to dashboard Cite

show abstract

“…It is therefore noteworthy that SGLT2 inhibitors induce a transcriptional paradigm that closely mimics the cellular response to starvation (Fig. 1) (27). These drugs activate SIRT1/AMPK and suppress Akt/mTOR signaling and, consequently, they can promote autophagy, independent of their effects on glucose or insulin (28)(29)(30)(31).…”

Section: Sglt2 Inhibitors Produce Cardioprotective and Renoprotectivementioning

confidence: 99%

“…First, SGLT2 inhibitors induce a loss of calories in the urine, and glycosuria is accompanied by a decrease of glucagon synthesis (often with the promotion of glycolysis), increased fatty acid oxidation, and the shrinkage of adipose tissue depots, including the alleviation of organ steatosis (27). Viewed from this perspective, the ketonemia seen with these drugs is not the source of an efficient fuel but instead is a biomarker of a fasting-like transcriptional state.…”

Section: Clinical Evidence Supporting the Proposed Conceptual Frameworkmentioning

confidence: 99%

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

2020

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“…SGLT2 inhibitors induce a loss of calories in the urine and promote ketogenesis, and thus these drugs induce a biological state that mimics starvation. The resulting shift in the transcriptional paradigm includes activation of AMPK and SIRT1. SGLT2 inhibitors lead to the phosphorylation of AMPK and/or upregulation of SIRT1 and induce biomarkers of autophagy in the kidney, and experimental knockout of SGLT2 in the renal proximal tubule may promote autophagic flux .…”

Section: Are Sglt2 Inhibitors Renoprotective Through An Action To Stimentioning

confidence: 99%

“…Stimulation of HIF‐2α (which transactivates the gene for erythropoietin) may explain why SGLT2 inhibitors cause erythrocytosis in clinical trials . The enhanced interplay of AMPK, SIRT1 and HIF‐2α may underlie the action of SGLT2 inhibitors to ameliorate oxidative and endoplasmic reticular stress, and thereby minimize glomerular and tubular injury and inflammation, and attenuate the development of nephropathy . An increase in AMPK and SIRT1 may also directly enhance tubuloglomerular feedback, thereby linking changes in the activity of these energy sensors to the action of SGLT2 inhibitors to ameliorate glomerular hyperfiltration.…”

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

show abstract

SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms

Cited by 148 publications

References 51 publications

Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease

Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease

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

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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