Resveratrol attenuates dapagliflozin-induced renal gluconeogenesis <i>via</i> activating the PI3K/Akt pathway and suppressing the FoxO1 pathway in type 2 diabetes

Sun, Xiaoya; Cao, Ziqiang; Ma, Yuanyuan; Shao, Yimin; Zhang, Junqing; Yuan, Geheng; X, Guo

doi:10.1039/d0fo02387f

Cited by 30 publications

(21 citation statements)

References 43 publications

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“…The potential molecular mechanisms underlying these effects of dapagliflozin are still under investigation, but the pathways at play most likely involve the transcription factors CREB and FOXO1 (forkhead box protein O1). Dapagliflozin has been reported to inhibit the activities of both CREB [ 66 ] and FOXO1 [ 67 , 68 ] in vitro and in vivo, although there are a couple of studies arguing for dapagliflozin activating (rather than blocking) FOXO1 [ 69 , 70 ]. These discrepancies in the reported literature are probably the result of the well-known tissue/cell type specific SGLT2 inhibitor’s actions, i.e., as gliflozins can have different effects on the same molecules depending on the cell/tissue type studied.…”

Section: Research Hypothesis: Dapagliflozin Attenuates Adrenal Catecholamine Productionmentioning

confidence: 99%

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Lymperopoulos

Borges

Cora

et al. 2021

IJMS

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Heart failure (HF) remains the leading cause of morbidity and death in the western world, and new therapeutic modalities are urgently needed to improve the lifespan and quality of life of HF patients. The sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed and mainly indicated for diabetes mellitus treatment, have been increasingly shown to ameliorate heart disease, and specifically HF, in humans, regardless of diabetes co-existence. Indeed, dapagliflozin has been reported to reduce cardiovascular mortality and hospitalizations in patients with HF and reduced ejection fraction (HFrEF). This SGLT2 inhibitor demonstrates these benefits also in non-diabetic subjects, indicating that dapagliflozin’s efficacy in HF is independent of blood glucose control. Evidence for the effectiveness of various SGLT2 inhibitors in providing cardiovascular benefits irrespective of their effects on blood glucose regulation have spurred the use of these agents in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious question arising from all these studies is, of course, which molecular/pharmacological mechanisms underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed over the past few years and tested in cell and animal models and prominent among those is the potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is known to be high in HF patients, contributing significantly to the morbidity and mortality of the disease. The present minireview first summarizes the current evidence in the literature supporting the notion that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, exert sympatholysis, and also outlines the main putative underlying mechanisms for these sympatholytic effects. Then, we propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire amount of circulating epinephrine and of a significant percentage of circulating norepinephrine in the human body. If proven true experimentally, this hypothesis, along with other emerging experimental evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood glucose-lowering effects.

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Section: Research Hypothesis: Dapagliflozin Attenuates Adrenal Catecholamine Productionmentioning

confidence: 99%

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Lymperopoulos

Borges

Cora

et al. 2021

IJMS

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“…A previous study indicated that resveratrol treatment upregulated components in renal insulin signaling at both gene and protein level in diabetic rats [43]. Finally, Sun et al, demonstrated that resveratrol significantly ameliorated dapagliflozin-induced renal gluconeogenesis by promoting the insulin signaling pathway which subsequently inhibits nuclear translocation of FoxO1 [44]. Hyperglycemia, a consequence of diabetes, enhances the formation of advanced glycation end products (AGEs) and senescent protein derivatives that result from the auto-oxidation of glucose and fructose [14].…”

Section: Discussionmentioning

confidence: 96%

Blocking of SGLT2 to Eliminate NADPH-Induced Oxidative Stress in Lenses of Animals with Fructose-Induced Diabetes Mellitus

Chen

et al. 2022

IJMS

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Chronic hyperglycemia triggers an abnormal rise in reactive oxygen species (ROS) that leads to blindness in patients with diabetes mellitus (DM) and cataracts. In this study, the effects of dapagliflozin, metformin and resveratrol on ROS production were investigated in lens epithelial cells (LECs) of animals with fructose-induced DM. LECs were isolated from patients without DM, or with DM devoid of diabetic retinopathy. Animals were treated with 10% fructose for 8 weeks to induce DM, which was verified by monitoring blood pressure and serum parameters. For drug treatments, 1.2 mg/day of dapagliflozin was given for 2 weeks, 500 mg/kg/day of metformin was given, and 10 mg/kg/day of resveratrol was given. Dihydroethidium was used to stain endogenous O2˙− production in vivo of the LECs. Superoxide production was expressed in the cataract of DM, or patients without DM. Sodium–glucose cotransporter 2 (SGLT2), glucose transporter 1 (GLUT1), GLUT5, the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47/p67-phox, NOX4 and RAGE were significantly increased in LECs with DM. In addition, the dapagliflozin treatment reduced GLUT5, p47/p67-phox, NADPH oxidase 4 (NOX4) and receptor for advanced glycation end products (RAGE) expressions. On the contrary, metformin or resveratrol inhibited p47-phox, GLUT5, and SGLT2 expressions, but not nuclear factor erythroid 2–related factor 2 (NRF2). In summary, dapagliflozin, metformin or resveratrol down-regulated p47-phox expression through SGLT2 inactivation and ROS reduction. These important findings imply that SGLT2 can be blocked to ameliorate oxidative stress in the cataracts of DM patients.

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“…The resulting activation of Pi3k subsequently leads to activation of Akt, which facilitates phosphorylation of a variety of substrates to ensure glucose homeostasis (40). Several markers of β‐cell dedifferentiation have been linked with Pi3k/Akt signaling in type 2 diabetes (41,42). On this basis, we speculated that IRS‐1/2/Pi3k/Akt signaling is involved in β‐cell dedifferentiation.…”

Section: Discussionmentioning

confidence: 99%

MiR‐195 promotes pancreatic β‐cell dedifferentiation by targeting Mfn2 and impairing Pi3k/Akt signaling in type 2 diabetes

Tang

Dai

et al. 2022

Obesity

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Type 2 diabetes mellitus (T2DM) has now reached epidemic proportions worldwide. This major chronic metabolic disease is characterized by insulin resistance, progressive β-cell failure, and long-term hyperglycemia (1). Multiple cellular events are involved in β-cell failure including glucolipotoxicity, inflammation, oxidative stress, and endoplasmic reticulum stress (2,3). Pancreatic β-cell dedifferentiation, defined as the regression of mature β-cells (expressing transcription factor MafA, insulin, and pancreas/duodenum homeobox protein 1 [Pdx1]) back into progenitor or stem-like cells (expressing neurogenin-3 [Ngn3], octamer-binding protein 4 [Oct4; also known as POU domain, class 5, transcription factor 1, Pou5f1],and aldehyde dehydrogenase family 1 member A3 [ALDH1A3]) (4), has been implicated as the main mechanism for progressive diabetic β-cell failure (5). In addition, mitochondrial dysfunction, which is

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Resveratrol attenuates dapagliflozin-induced renal gluconeogenesis via activating the PI3K/Akt pathway and suppressing the FoxO1 pathway in type 2 diabetes

Abstract: Resveratrol ameliorated dapagliflozin-induced renal gluconeogenesis by activating the PI3K/Akt pathway and suppressing the FoxO1 signaling pathway.

Cited by 30 publications

References 43 publications

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Blocking of SGLT2 to Eliminate NADPH-Induced Oxidative Stress in Lenses of Animals with Fructose-Induced Diabetes Mellitus

MiR‐195 promotes pancreatic β‐cell dedifferentiation by targeting Mfn2 and impairing Pi3k/Akt signaling in type 2 diabetes

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