Beneficial effects of sodium–glucose cotransporter 2 inhibitors for preservation of pancreatic <b>β</b>‐cell function and reduction of insulin resistance

Kaneto, Hideaki; Obata, Atsushi; Kimura, Tomohiko; Shimoda, Masashi; Okauchi, Seizo; Shimo, Naoki; Matsuoka, Taka‐aki; Kaku, Kohei

doi:10.1111/1753-0407.12494

Cited by 64 publications

(69 citation statements)

References 55 publications

(156 reference statements)

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“…SGLT2 inhibitors are drawing much attention in clinical medicine as well as in basic research . According to the EMPA‐REG OUTCOME and CANVAS studies, an SGLT2 inhibitor prevents the development and progression of, not only macro‐angiopathy, but also heart failure and albuminuria .…”

Section: Discussionmentioning

confidence: 99%

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Protective effects of the SGLT2 inhibitor luseogliflozin on pancreatic β‐cells in db/db mice: The earlier and longer, the better

Kimura

Obata

Shimoda

et al. 2018

Diabetes Obesity Metabolism

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Section: Discussionmentioning

confidence: 99%

“…Recently, SGLT2 inhibitors have been drawing much attention . SGLT2 inhibitors function in an insulin‐independent manner and lower blood glucose levels by enhancing urinary glucose excretion.…”

Section: Introductionmentioning

confidence: 99%

Protective effects of the SGLT2 inhibitor luseogliflozin on pancreatic β‐cells in db/db mice: The earlier and longer, the better

Kimura

Obata

Shimoda

et al. 2018

Diabetes Obesity Metabolism

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“…Given the key role of hyperglycemia in β-cell dedifferentiation and the demonstrated beneficial effects of the glucose lowering strategies in rodents, SGLT2 inhibition by gliflozins merits further attention in humans (AbdulGhani et al 2017). The use of these drugs in combination with other therapies such as incretins may exert beneficial effects on the β-cell phenotype (Busch & Kane 2017, Kaneto et al 2017). The potential combination with antioxidants such as GPX mimetics and/or chemical chaperones such as the recently identified small-molecule azoramide (Fu et al 2015) merits further experimental and clinical testing.…”

Section: Dedifferentiation As a Potential Adaptive Mechanismmentioning

confidence: 99%

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Bensellam

Jonas

Laybutt

2018

Journal of Endocrinology

202

171

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Like all the cells of an organism, pancreatic β-cells originate from embryonic stem cells through a complex cellular process termed differentiation. Differentiation involves the coordinated and tightly controlled activation/repression of specific effectors and gene clusters in a time-dependent fashion thereby giving rise to particular morphological and functional cellular features. Interestingly, cellular differentiation is not a unidirectional process. Indeed, growing evidence suggests that under certain conditions, mature β-cells can lose, to various degrees, their differentiated phenotype and cellular identity and regress to a less differentiated or a precursor-like state. This concept is termed dedifferentiation and has been proposed, besides cell death, as a contributing factor to the loss of functional β-cell mass in diabetes. β-cell dedifferentiation involves: (1) the downregulation of β-cell-enriched genes, including key transcription factors, insulin, glucose metabolism genes, protein processing and secretory pathway genes; (2) the concomitant upregulation of genes suppressed or expressed at very low levels in normal β-cells, the β-cell forbidden genes; and (3) the likely upregulation of progenitor cell genes. These alterations lead to phenotypic reconfiguration of β-cells and ultimately defective insulin secretion. While the major role of glucotoxicity in β-cell dedifferentiation is well established, the precise mechanisms involved are still under investigation. This review highlights the identified molecular mechanisms implicated in β-cell dedifferentiation including oxidative stress, endoplasmic reticulum (ER) stress, inflammation and hypoxia. It discusses the role of Foxo1, Myc and inhibitor of differentiation proteins and underscores the emerging role of non-coding RNAs. Finally, it proposes a novel hypothesis of β-cell dedifferentiation as a potential adaptive mechanism to escape cell death under stress conditions.

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“…In all of these studies, unfortunately, their impact on liver histology is unknown. Although the underlying mechanisms of impact on NAFLD remain unknown, SGLT2 inhibitors appear to have a variety of functions such as amelioration of insulin resistance, anti‐inflammatory effects, and anti‐oxidative effects . According to a recent clinical trial (the EMPA‐REG OUTCOME trial), among T2DM patients who were at high risk for CV events, the use of empagliflozin was associated with lower cardiovascular mortality and lower progression of kidney disease than was placebo when added to standard care .…”

Section: Novel Antidiabetic Drugsmentioning

confidence: 99%

Novel antidiabetic medications for non‐alcoholic fatty liver disease with type 2 diabetes mellitus

Sumida

Seko

Yoneda

2017

Hepatology Research

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Liver-related diseases are the leading causes of death in patients with type 2 diabetes mellitus (T2DM) in Japan. Type 2 diabetes mellitus is closely associated with non-alcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Non-alcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma and hepatic failure. Non-alcoholic steatohepatitis can be called "diabetic hepatopathy". There are no established pharmacotherapies for NAFLD/NASH patients with T2DM. Although metformin is established as the first-line therapy for T2DM, given its relative safety and beneficial effects on glycosylated hemoglobin, weight, and cardiovascular mortality, this agent is not recommended as specific therapy for NASH/NAFLD due to lack of clinical evidence. The effects of pioglitazone on NASH histology with T2DM have been extensively proved, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. In recent years, novel antidiabetic medications have been approved for T2DM, such as glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase 4 inhibitors, and sodium/glucose cotransporter 2 inhibitors. A key clinical question for hepatologists is what kinds of antidiabetic medications are the most appropriate for the treatment of NAFLD accompanied by T2DM, to prevent progression of hepatic fibrosis resulting in HCC/liver-related mortality without increased risk of cardiovascular events. This review focuses on novel antidiabetic agents and future perspectives on the treatment of NAFLD/NASH with T2DM.

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Beneficial effects of sodium–glucose cotransporter 2 inhibitors for preservation of pancreatic β‐cell function and reduction of insulin resistance

Cited by 64 publications

References 55 publications

Protective effects of the SGLT2 inhibitor luseogliflozin on pancreatic β‐cells in db/db mice: The earlier and longer, the better

Protective effects of the SGLT2 inhibitor luseogliflozin on pancreatic β‐cells in db/db mice: The earlier and longer, the better

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Novel antidiabetic medications for non‐alcoholic fatty liver disease with type 2 diabetes mellitus

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