Sodium–glucose cotransporters: Functional properties and pharmaceutical potential

Sano, Ryuhei; Shinozaki, Yuichi; Ohta, Takeshi

doi:10.1111/jdi.13255

Cited by 70 publications

(54 citation statements)

References 137 publications

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“…Sodium–glucose cotransporter (SGLT) belongs to the solute carrier five gene family, which transports glucose against a concentration gradient in an energy-consuming manner and plays an important role in the active transport of glucose ( Wood and Trayhurn, 2003 ; Sano et al, 2020 ). Sodium–glucose cotransporter 1 (SGLT1) is expressed in various human tissues and organs, including the intestine, lung, heart, skeletal muscle, and kidney ( Gyimesi et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

et al. 2021

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Background: Cardiac fibroblast (CF) activation is a hallmark feature of cardiac fibrosis in diabetic cardiomyopathy (DCM). Inhibition of the sodium-dependent glucose transporter 1 (SGLT1) attenuates cardiomyocyte apoptosis and delays the development of DCM. However, the role of SGLT1 in CF activation remains unclear.Methods: A rat model of DCM was established and treated with si‐SGLT1 to examine cardiac fibrosis. In addition, in vitro experiments were conducted to verify the regulatory role of SGLT1 in proliferation and collagen secretion in high-glucose– (HG–) treated CFs.Results: SGLT1 was found to be upregulated in diabetic cardiac tissues and HG-induced CFs. HG stimulation resulted in increased proliferation and migration, increased the expression of transforming growth factor-β1 and collagen I and collagen III, and increased phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) 1/2. These trends in HG-treated CFs were significantly reversed by si-SGLT1. Moreover, the overexpression of SGLT1 promoted CF proliferation and collagen synthesis and increased phosphorylation of p38 mitogen-activated protein kinase and ERK1/2. SGLT1 silencing significantly alleviated cardiac fibrosis, but had no effect on cardiac hypertrophy in diabetic hearts.Conclusion: These findings provide new information on the role of SGLT1 in CF activation, suggesting a novel therapeutic strategy for the treatment of DCM fibrosis.

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Section: Introductionmentioning

confidence: 99%

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

et al. 2021

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“…Sodium-glucose cotransporters (SGLTs) belong to the solute carrier 5 (SLC5) gene family ( Wood and Trayhurn, 2003 ; Sano et al, 2020 ). The SLC5A family in humans includes 12 genes, six of which are expressed in the heart.…”

Section: Introductionmentioning

confidence: 99%

SGLT1 Inhibition Attenuates Apoptosis in Diabetic Cardiomyopathy via the JNK and p38 Pathway

Lin

Yang

et al. 2021

Front. Pharmacol.

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Background: Recent studies have revealed that a novel selective sodium-glucose cotransporter 1 (SGLT1) inhibiton has shown beneficial effects in cardiovascular diseases. However, the question of whether SGLT1 inhibition influences diabetic cardiomyopathy (DCM) remains unanswered. In this study, we investigated the influence and underlying mechanism of SGLTI inhibition on DCM.Methods: SGLT1 levels were measured in diabetic patients with similar conditions who visited our hospital from January to December 2019. Wistar male rats (n = 50) were divided into five groups: control, diabetes induced by streptozotocin infusion, and diabetes treated with 0.5, 1.0, or 1.5 mg/kg mizagliflozin via stomach gavage for 12 weeks. H9C2 cardiomyocytes were treated with mizagliflozin and then exposed to a high glucose concentration (30 mmol/L). TUNEL assays were performed, and bcl2, bax, p-p38, p-Erk, p-JNK and caspase-3 levels were measured. We used siRNA and an SGLT1 overexpression plasmid to detect the effects of SGLT1.Results: SGLT1 levels were significantly elevated in DCM patients, and receiver operating characteristic (ROC) curve analysis identified SGLT1 as influencing DCM. The area under the curve (AUC) was 0.705 (p < 0.05), with 65.8% sensitivity, and 62.2% specificity. SGLT1 inhibition appeared to attenuate apoptosis in DCM via the JNK and p38 pathway.Conclusion: SGLT1 can be used as a marker for the diagnosis of DCM, and SGLT1 inhibition can attenuate apoptosis, thereby suppressing DCM development via the JNK and p38 pathway.

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“…Based on the data revealing a key role of SGLT1 transporter in increased intestinal glucose absorption and resulting hyperglycemia in diabetes, a new approach to reduce postprandial hyperglycemia using SGLT1 inhibitors seems promising for the treatment of diabetic patients [ 8 , 109 ]. Nevertheless, clinical use of glucose transporter targeting drugs for treatment of diabetes is currently largely limited to SGLT2 inhibitors, for example gliflozins.…”

Section: Adaptive Reactions Of Transporters Sglt1 Glut2 and Paracellular Transport In Metabolic Disease Conditionsmentioning

confidence: 99%

Mechanisms of Glucose Absorption in the Small Intestine in Health and Metabolic Diseases and Their Role in Appetite Regulation

2021

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The worldwide prevalence of metabolic diseases such as obesity, metabolic syndrome and type 2 diabetes shows an upward trend in recent decades. A characteristic feature of these diseases is hyperglycemia which can be associated with hyperphagia. Absorption of glucose in the small intestine physiologically contributes to the regulation of blood glucose levels, and hence, appears as a putative target for treatment of hyperglycemia. In fact, recent progress in understanding the molecular and cellular mechanisms of glucose absorption in the gut and its reabsorption in the kidney helped to develop a new strategy of diabetes treatment. Changes in blood glucose levels are also involved in regulation of appetite, suggesting that glucose absorption may be relevant to hyperphagia in metabolic diseases. In this review we discuss the mechanisms of glucose absorption in the small intestine in physiological conditions and their alterations in metabolic diseases as well as their relevance to the regulation of appetite. The key role of SGLT1 transporter in intestinal glucose absorption in both physiological conditions and in diabetes was clearly established. We conclude that although inhibition of small intestinal glucose absorption represents a valuable target for the treatment of hyperglycemia, it is not always suitable for the treatment of hyperphagia. In fact, independent regulation of glucose absorption and appetite requires a more complex approach for the treatment of metabolic diseases.

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Sodium–glucose cotransporters: Functional properties and pharmaceutical potential

Cited by 70 publications

References 137 publications

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

SGLT1 Inhibition Attenuates Apoptosis in Diabetic Cardiomyopathy via the JNK and p38 Pathway

Mechanisms of Glucose Absorption in the Small Intestine in Health and Metabolic Diseases and Their Role in Appetite Regulation

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