Central administration of sodium-glucose cotransporter-2 inhibitors increases food intake involving adenosine monophosphate-activated protein kinase phosphorylation in the lateral hypothalamus in healthy rats

IntroductionSodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake.Research design and methodsWe administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Intraperitoneal administration of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin.ResultsBolus ICV injection of tofogliflozin induced a robust increase in food intake starting at 1.5 hours postinjection, and lasting for 5 days. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. ICV dapagliflozin and empagliflozin significantly enhanced food intake, although the strength of these effects varied among drugs. Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. ICV tofogliflozin increased phosphorylation of AMPK and c-fos expression in the lateral hypothalamus.ConclusionsSGLT2 inhibitors in the CNS increase food intake. SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area.

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1153-P: Sodium-Glucose Cotransporter-2 Inhibitors Increase Food Intake via a Mechanism That Acts on the Central Nervous System Involving Phosphorylation of Adenosine Monophosphate-Activated Protein Kinase in the Lateral Hypothalamus

Diabetes ◽

10.2337/db21-1153-p ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 1153-P

Author(s):

KENJI TAKEDA ◽

HIRAKU ONO ◽

TOMOHIRO OHNO ◽

KOUTARO YOKOTE

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Protein Kinase ◽

Food Intake ◽

Lateral Hypothalamus ◽

Adenosine Monophosphate ◽

Sodium Glucose Cotransporter ◽

Increase Food Intake ◽

The Central Nervous System

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Mitigation of the Adverse Consequences of Nutrient Excess on the Kidney: A Unified Hypothesis to Explain the Renoprotective Effects of Sodium-Glucose Cotransporter 2 Inhibitors

American Journal of Nephrology ◽

10.1159/000506534 ◽

2020 ◽

Vol 51 (4) ◽

pp. 289-293 ◽

Cited By ~ 2

Author(s):

Milton Packer

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Renin Angiotensin System ◽

Tissue Expansion ◽

Adenosine Monophosphate ◽

Sglt2 Inhibitors ◽

Sirtuin 1 ◽

Glomerular Hyperfiltration ◽

Sodium Glucose Cotransporter

The 2 most common causes of chronic kidney disease worldwide (type 2 diabetes and obesity) are states of nutrient excess, suggesting that fuel overabundance leads to deleterious effects on the structure and function of the kidneys. Three pathophysiological pathways may potentially explain this linkage. First, both obesity and type 2 diabetes are characterized by glomerular hyperfiltration, which may result from increased proximal tubular reabsorption of sodium (due to enhanced glucose and sodium transport) coupled with activation of the renin-angiotensin system. Second, both obesity and type 2 diabetes are characterized by adipose tissue expansion and inflammation, followed by the augmented synthesis and release of lipid intermediates and proinflammatory adipocytokines that can have deleterious effects on the kidney. Third, states of nutrient excess cause a diminution in the activation of the energy sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). The result is a suppression of autophagy, a lysosomal degradative pathway that is responsible for the clearance of damaged organelles that are an important source of oxidative and endoplasmic reticulum stress and inflammation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors induces a transcriptional paradigm that mimics fasting, which leads to the amelioration of glomerular hyperfiltration and adipose tissue inflammation as well as augmentation of AMPK/SIRT1 signaling and autophagy, thereby acting to mute organellar and cellular stress in the kidney. Therefore, SGLT2 inhibitors are positioned to antagonize all 3 pathways by which nutrient excess can lead to nephropathy.

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Effects of SGLT2 Inhibitors on Atherosclerosis: Lessons from Cardiovascular Clinical Outcomes in Type 2 Diabetic Patients and Basic Researches

Journal of Clinical Medicine ◽

10.3390/jcm11010137 ◽

2021 ◽

Vol 11 (1) ◽

pp. 137

Author(s):

Jing Xu ◽

Taro Hirai ◽

Daisuke Koya ◽

Munehiro Kitada

Keyword(s):

Molecular Mechanisms ◽

Vascular Endothelial Cells ◽

Sglt2 Inhibitors ◽

Major Adverse Cardiovascular Events ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Cardiovascular Outcome Trials ◽

Sodium Glucose Cotransporter ◽

Reduce Blood Glucose

Atherosclerosis-caused cardiovascular diseases (CVD) are the leading cause of mortality in type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective oral drugs for the treatment of T2DM patients. Multiple pre-clinical and clinical studies have indicated that SGLT2 inhibitors not only reduce blood glucose but also confer benefits with regard to body weight, insulin resistance, lipid profiles and blood pressure. Recently, some cardiovascular outcome trials have demonstrated the safety and cardiovascular benefits of SGLT2 inhibitors beyond glycemic control. The SGLT2 inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin reduce the rates of major adverse cardiovascular events and of hospitalization for heart failure in T2DM patients regardless of CVD. The potential mechanisms of SGLT2 inhibitors on cardioprotection may be involved in improving the function of vascular endothelial cells, suppressing oxidative stress, inhibiting inflammation and regulating autophagy, which further protect from the progression of atherosclerosis. Here, we summarized the pre-clinical and clinical evidence of SGLT2 inhibitors on cardioprotection and discussed the potential molecular mechanisms of SGLT2 inhibitors in preventing the pathogenesis of atherosclerosis and CVD.

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Cardioprotection conferred by sodium-glucose cotransporter 2 inhibitors: a renal proximal tubule perspective

AJP Cell Physiology ◽

10.1152/ajpcell.00275.2019 ◽

2020 ◽

Vol 318 (2) ◽

pp. C328-C336 ◽

Cited By ~ 7

Author(s):

Danúbia Silva dos Santos ◽

Juliano Z. Polidoro ◽

Flávio A. Borges-Júnior ◽

Adriana C. C. Girardi

Keyword(s):

Proximal Tubule ◽

Molecular Mechanisms ◽

Extracellular Volume ◽

Renal Proximal Tubule ◽

Sglt2 Inhibitors ◽

Tubular Dysfunction ◽

Cardiovascular Outcome Trials ◽

Sodium Glucose Cotransporter ◽

Multiple Processes ◽

Proximal Tubular

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, also known as gliflozins, improve glycemia by suppressing glucose reuptake in the renal proximal tubule. Currently, SGLT2 inhibitors are primarily indicated as antidiabetic agents; however, their benefits extend far beyond glucose control. Cardiovascular outcome trials indicated that all studied SGLT2 inhibitors remarkably and consistently reduce cardiovascular mortality and hospitalization for heart failure (HF) in type 2 diabetes (T2D) patients. Nevertheless, the mechanisms underlying the unprecedented cardiovascular benefits of gliflozins remain elusive. Multiple processes that directly or indirectly improve myocardial performance may be involved, including the amelioration of proximal tubular dysfunction. Therefore, this paper provides a perspective on the potential cellular and molecular mechanisms of the proximal tubule that may, at least in part, mediate the cardioprotection conferred by SGLT2 inhibitors. Specifically, we focus on the effects of SGLT2 on extracellular volume homeostasis, including its plausible functional and physical association with the apical Na+/H+ exchanger isoform 3 as well as its complex and its possible bidirectional interactions with the intrarenal angiotensin system and renal sympathetic nervous system. We also discuss evidence supporting a potential benefit of gliflozins in reducing cardiovascular risk, attributable to their effect on proximal tubule handling of uric acid and albumin as well as in erythropoietin production. Unraveling the mechanisms behind the beneficial actions of SGLT2 inhibitors may not only contribute to a better understanding of the pathophysiology of cardiovascular diseases but also enable repurposing of gliflozins to improve the routine management of HF patients with or without T2D.

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Safety of Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors Among Patients With Type 2 Diabetes

Case Medical Research ◽

10.31525/ct1-nct04017221 ◽

2019 ◽

Author(s):

Keyword(s):

Type 2 Diabetes ◽

Sglt2 Inhibitors ◽

Sodium Glucose Cotransporter

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Mechanisms of Protective Effects of SGLT2 Inhibitors in Cardiovascular Disease and Renal Dysfunction

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190828161409 ◽

2019 ◽

Vol 19 (20) ◽

pp. 1818-1849 ◽

Cited By ~ 4

Author(s):

Ban Liu ◽

Yuliang Wang ◽

Yangyang Zhang ◽

Biao Yan

Keyword(s):

Diabetes Mellitus ◽

Heart Failure ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Renal Dysfunction ◽

Sglt2 Inhibitors ◽

Sodium Glucose Cotransporter ◽

Glucose Reabsorption ◽

Renal Glucose Reabsorption

: Type 2 diabetes mellitus is one of the most common forms of the disease worldwide. Hyperglycemia and insulin resistance play key roles in type 2 diabetes mellitus. Renal glucose reabsorption is an essential feature in glycaemic control. Kidneys filter 160 g of glucose daily in healthy subjects under euglycaemic conditions. The expanding epidemic of diabetes leads to a prevalence of diabetes-related cardiovascular disorders, in particular, heart failure and renal dysfunction. Cellular glucose uptake is a fundamental process for homeostasis, growth, and metabolism. In humans, three families of glucose transporters have been identified, including the glucose facilitators GLUTs, the sodium-glucose cotransporter SGLTs, and the recently identified SWEETs. Structures of the major isoforms of all three families were studied. Sodium-glucose cotransporter (SGLT2) provides most of the capacity for renal glucose reabsorption in the early proximal tubule. A number of cardiovascular outcome trials in patients with type 2 diabetes have been studied with SGLT2 inhibitors reducing cardiovascular morbidity and mortality. : The current review article summarises these aspects and discusses possible mechanisms with SGLT2 inhibitors in protecting heart failure and renal dysfunction in diabetic patients. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed down the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.

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Efficacy and cardiovascular safety of SGLT2 Inhibitors

Current Drug Safety ◽

10.2174/1574886315666201002154640 ◽

2020 ◽

Vol 15 ◽

Author(s):

Cornelius James Fernandez ◽

Abisha Graciano Nevins ◽

Shasta Nawaz ◽

Tahir Nazir ◽

Fahmy W F Hanna

Keyword(s):

Decision Process ◽

Cardiovascular Events ◽

Unmet Need ◽

Clinical Decision ◽

Sglt2 Inhibitors ◽

Renal Protection ◽

Sodium Glucose Cotransporter ◽

Patients With Diabetes ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

: Patients with diabetes continued to exhibit a high risk for cardiovascular and renal events despite achieving satisfactory glycemic, blood pressure and lipid targets. Studies evaluating new diabetes medications focused on cardiovascular events, largely overlooking heart failure (HF). The latter has recently been recognised as a major cause of morbidity and mortality in patients with diabetes mellitus. There had been an unmet need for drugs with cardiovascular (including HF) and renal protection, with an expectation that an ideal diabetic drug should improve these end points. Moreover, an ideal drug should have weight lowering benefits. Recently published outcome trials have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) can reduce cardiovascular and renal events, together with statistically significant weight reduction. As a result, many recently published international guidelines have recommended SGLT2 inhibitors and GLP-1RAs in patients with diabetes and pre-existing cardiovascular disease (CVD). In this review we will critically analyse the efficacy and cardiovascular (CV) safety of SGLT2 inhibitors, based on the available literature to help position them in the clinical decision process.

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Role of Long Non-Coding RNAs and the Molecular Mechanisms Involved in Insulin Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms22147256 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7256

Author(s):

Vianet Argelia Tello-Flores ◽

Fredy Omar Beltrán-Anaya ◽

Marco Antonio Ramírez-Vargas ◽

Brenda Ely Esteban-Casales ◽

Napoleón Navarro-Tito ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Kinase ◽

Molecular Mechanisms ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Biological Species ◽

Necrosis Factor Alpha ◽

Polypyrimidine Tract Binding Protein ◽

Non Coding Rnas

Long non-coding RNAs (lncRNAs) are single-stranded RNA biomolecules with a length of >200 nt, and they are currently considered to be master regulators of many pathological processes. Recent publications have shown that lncRNAs play important roles in the pathogenesis and progression of insulin resistance (IR) and glucose homeostasis by regulating inflammatory and lipogenic processes. lncRNAs regulate gene expression by binding to other non-coding RNAs, mRNAs, proteins, and DNA. In recent years, several mechanisms have been reported to explain the key roles of lncRNAs in the development of IR, including metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), imprinted maternal-ly expressed transcript (H19), maternally expressed gene 3 (MEG3), myocardial infarction-associated transcript (MIAT), and steroid receptor RNA activator (SRA), HOX transcript antisense RNA (HOTAIR), and downregulated Expression-Related Hexose/Glucose Transport Enhancer (DREH). LncRNAs participate in the regulation of lipid and carbohydrate metabolism, the inflammatory process, and oxidative stress through different pathways, such as cyclic adenosine monophosphate/protein kinase A (cAMP/PKA), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), polypyrimidine tract-binding protein 1/element-binding transcription factor 1c (PTBP1/SREBP-1c), AKT/nitric oxide synthase (eNOS), AKT/forkhead box O1 (FoxO1), and tumor necrosis factor-alpha (TNF-α)/c-Jun-N-terminal kinases (JNK). On the other hand, the mechanisms linked to the molecular, cellular, and biochemical actions of lncRNAs vary according to the tissue, biological species, and the severity of IR. Therefore, it is essential to elucidate the role of lncRNAs in the insulin signaling pathway and glucose and lipid metabolism. This review analyzes the function and molecular mechanisms of lncRNAs involved in the development of IR.

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