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1
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Wang D, Miao J, Zhang L, Zhang L. Research advances in the diagnosis and treatment of MASLD/MASH. Ann Med 2025; 57. [DOI: 10.1080/07853890.2024.2445780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/01/2024] [Accepted: 12/02/2024] [Indexed: 01/06/2025] Open
Affiliation(s)
- Dekai Wang
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jinxian Miao
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lihua Zhang
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lin Zhang
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming, China
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Amosova MV, Poluboyarinova IV, Salnikova PV, Zherebchikova KY, Fadeev VV. [Hepatogenic diabetes: three cases report and literature review]. PROBLEMY ENDOKRINOLOGII 2025; 71:66-74. [PMID: 40411331 DOI: 10.14341/probl13443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 05/07/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2025]
Abstract
Hepatogenic diabetes (HepD) is a form of diabetes where the primary pathogenesis is a liver disease, usually cirrhosis, complicated by the development of portal hypertension with the formation of porto-caval shunts. In the development of HepD, in addition to traditional risk factors for carbohydrate metabolism disorders, the pathogenetic features of liver diseases play a significant role. However, the exact mechanism of HepD development remains unclear, and several questions are still open for discussion. Despite having distinct pathophysiological and clinical features, hepatogenic diabetes is currently not considered as an independent disease. This is likely due to the difficulties in differentiating between types of diabetes due to the bidirectional relationship between glucose metabolism disorders and chronic liver diseases. It is known that diabetes negatively affects the development and progression of chronic liver diseases of various etiologies, and their combination is associated with worse clinical outcomes in terms of mortality, the occurrence of liver decompensation, and the development of hepatocellular carcinoma (HCC). Unfortunately, early diagnosis and the selection of optimal therapeutic strategies for diabetes may be challenging due to the lack of established clinical guidelines and the presence of comorbidities in patients with HepD.
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Affiliation(s)
- M V Amosova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - I V Poluboyarinova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - P V Salnikova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - K Y Zherebchikova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - V V Fadeev
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
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Lin Y, Shi J, Yu X, Sun J, Lixia S, Dou J, Zhang M, Li X, Tian Z, Deng H, Feng B, Su Q, Peng Y. Enhancing Diabetes Treatment: Comparing Pioglitazone/Metformin with Dapagliflozin Versus Basal Insulin/Metformin in Type 2 Diabetes. Drug Des Devel Ther 2025; 19:1795-1808. [PMID: 40098912 PMCID: PMC11911819 DOI: 10.2147/dddt.s512872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 03/01/2025] [Indexed: 03/19/2025] Open
Abstract
Aim The aim of this study was to compare the efficacy and safety of fixed-dose combination (FDC) of pioglitazone and metformin supplemented with dapagliflozin (test group) with those of basal insulin supplemented with metformin (control group) in patients with inadequately controlled type 2 diabetes mellitus (T2DM). Methods This 16-week, prospective, randomized, open-label study enrolled patients aged 18-75 years with glycated hemoglobin (HbA1c) levels between ≥ 8% and ≤ 11%. The primary endpoint was the proportion of patients who achieved HbA1c < 7% at week 16 without hypoglycemia or weight gain. The secondary endpoints included blood glucose, lipid profile, body weight, body mass index, inflammatory markers, bone Gla-protein, liver enzymes, and patient satisfaction. Results Among the full analysis set of 147 participants, no significant difference was observed in the primary endpoint between the test group and the control group. However, the test group had a higher percentage of patients who achieved HbA1c <7% at week 16 without hypoglycemia and experienced a weight loss of ≥3% (31.51% vs 13.51%, P=0.009). Patients in the test group whose BMI≥24 kg/m2 also achieved a substantial achievement rate (36.73% vs 15.79%, P=0.014). The test group also exhibited a greater reduction in body weight and improvements in 2-hour postprandial glucose level, systolic blood pressure, and lipid profile. Notably, combination therapy did not increase the risk of hypoglycemia or weight gain. Patients in the test group were more satisfied than those in the control group with continuing to accept pioglitazone/metformin FDC combined with dapagliflozin. Conclusion In the absence of contraindications, pioglitazone/metformin FDC supplemented with dapagliflozin may serve as a safe and effective alternative to basal insulin combined with metformin for rectifying inadequate glucose control, as the former enables metabolic improvements without compromising safety. Chinese Clinical Trial Registry Number CHiCTR2000036076. https://www.chictr.org.cn/showproj.html?proj=58825.
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Affiliation(s)
- Yi Lin
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Jianxia Shi
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Xuemei Yu
- Central Hospital of Fengxian District, Shanghai, People’s Republic of China
| | - Jiao Sun
- Huadong Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China
| | - Suo Lixia
- Shanghai Jiading Central Hospital, Shanghai Jiading Central Hospital, Shanghai, People’s Republic of China
| | - Jiaqing Dou
- Chaohu Hospital of Anhui Medical University, Chaohu, People’s Republic of China
| | - Min Zhang
- Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China
| | - Xiaohua Li
- Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Zhufang Tian
- Xi‘an Central Hospital, Xi’an, Shanxi, People’s Republic of China
| | - Hongyan Deng
- Wuhan Fourth Hospital, Wuhan, People’s Republic of China
| | - Bo Feng
- Dongfang Hospital Affiliated to Tongji University, Shanghai, People’s Republic of China
| | - Qing Su
- Xinhua Hospital Affiliated to Shanghai Jiaotong University, Shanghai, People’s Republic of China
| | - Yongde Peng
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
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Liu W, You D, Lin J, Zou H, Zhang L, Luo S, Yuan Y, Wang Z, Qi J, Wang W, Ye X, Yang X, Deng Y, Teng F, Zheng X, Lin Y, Huang Z, Huang Y, Yang Z, Zhou X, Zhang Y, Chen R, Xu L, Li J, Yang W, Zhang H. SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8 + T cell activation. Cell Metab 2024; 36:2245-2261.e6. [PMID: 39243758 DOI: 10.1016/j.cmet.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/26/2024] [Accepted: 08/09/2024] [Indexed: 09/09/2024]
Abstract
During the progression of metabolic dysfunction-associated steatohepatitis (MASH), the accumulation of auto-aggressive CD8+ T cells significantly contributes to liver injury and inflammation. Empagliflozin (EMPA), a highly selective inhibitor of sodium-glucose co-transporter 2 (SGLT2), exhibits potential therapeutic benefits for liver steatosis; however, the underlying mechanism remains incompletely elucidated. Here, we found that EMPA significantly reduced the hepatic accumulation of auto-aggressive CD8+ T cells and lowered granzyme B levels in mice with MASH. Mechanistically, EMPA increased β-hydroxybutyric acid by promoting the ketogenesis of CD8+ T cells via elevating 3-hydroxybutyrate dehydrogenase 1 (Bdh1) expression. The β-hydroxybutyric acid subsequently inhibited interferon regulatory factor 4 (Irf4), which is crucial for CD8+ T cell activation. Furthermore, the ablation of Bdh1 in T cells aggravated the manifestation of MASH and hindered the therapeutic efficacy of EMPA. Moreover, a case-control study also showed that SGLT2 inhibitor treatment repressed CD8+ T cell infiltration and improved liver injury in patients with MASH. In summary, our study indicates that SGLT2 inhibitors can target CD8+ T cells and may be an effective strategy for treating MASH.
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Affiliation(s)
- Wenhui Liu
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Endocrinology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Danming You
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiayang Lin
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huren Zou
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shenjian Luo
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Youwen Yuan
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhiyi Wang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jingwen Qi
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Weiwei Wang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xueru Ye
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyu Yang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yajuan Deng
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fei Teng
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaojun Zheng
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Yuhao Lin
- Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhiwei Huang
- Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yan Huang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhi Yang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuan Zhou
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanan Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruxin Chen
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lingling Xu
- Department of Endocrinology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Jin Li
- Division of Endocrinology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, China.
| | - Wei Yang
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
| | - Huijie Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China; State Key Laboratory of Organ Failure Research, Guangzhou, China; Guangdong Provincial Key Laboratory of Cell Metabolic Homeostasis and Major Chronic Diseases, Guangzhou, China.
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Suzuki A, Hayashi A, Oda S, Fujishima R, Shimizu N, Matoba K, Taguchi T, Toki T, Miyatsuka T. Prolonged impacts of sodium glucose cotransporter-2 inhibitors on metabolic dysfunction-associated steatotic liver disease in type 2 diabetes: a retrospective analysis through magnetic resonance imaging. Endocr J 2024; 71:767-775. [PMID: 38811192 DOI: 10.1507/endocrj.ej24-0005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/31/2024] Open
Abstract
The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in people with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) have been suggested in several reports based on serological markers, imaging data, and histopathology associated with steatotic liver disease. However, evidence regarding their long-term effects is currently insufficient. In this retrospective observational study, 34 people with T2D and MASLD, treated with SGLT2 inhibitors, were examined by proton density fat fraction derived by magnetic resonance imaging (MRI-PDFF) and other clinical data before, one year after the treatment. Furthermore, 22 of 34 participants underwent MRI-PDFF five years after SGLT2 inhibitors were initiated. HbA1c decreased from 8.9 ± 1.8% to 7.8 ± 1.0% at 1 year (p = 0.006) and 8.0 ± 1.1% at 5 years (p = 0.122). Body weight and fat mass significantly reduced from baseline to 1 and 5 year(s), respectively. MRI-PDFF significantly decreased from 15.3 ± 7.8% at baseline to 11.9 ± 7.6% (p = 0.001) at 1 year and further decreased to 11.3 ± 5.7% (p = 0.013) at 5 years. Thus, a 5-year observation demonstrated that SGLT2 inhibitors have beneficial effects on liver steatosis in people with T2D and MASLD.
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Affiliation(s)
- Agena Suzuki
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Akinori Hayashi
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Satoshi Oda
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Rei Fujishima
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Naoya Shimizu
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Kenta Matoba
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Tomomi Taguchi
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Takuya Toki
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Takeshi Miyatsuka
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
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Hu J, Teng J, Hui S, Liang L. SGLT-2 inhibitors as novel treatments of multiple organ fibrosis. Heliyon 2024; 10:e29486. [PMID: 38644817 PMCID: PMC11031788 DOI: 10.1016/j.heliyon.2024.e29486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 04/08/2024] [Accepted: 04/08/2024] [Indexed: 04/23/2024] Open
Abstract
Fibrosis, a significant health issue linked to chronic inflammatory diseases, affects various organs and can lead to serious damage and loss of function. Despite the availability of some treatments, their limitations necessitate the development of new therapeutic options. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), known for their glucose-lowering ability, have shown promise in offering protective effects against fibrosis in multiple organs through glucose-independent mechanisms. This review explores the anti-fibrotic potential of SGLT2i across different tissues, providing insights into their underlying mechanisms and highlighting recent research advancements. The evidence positions SGLT2i as a potential future treatments for fibrotic diseases.
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Affiliation(s)
- Junpei Hu
- Department of Geriatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, China
| | - Jianhui Teng
- Department of Geriatrics, Hunan Provincial People's Hospital, China
| | - Shan Hui
- Department of Geriatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, China
| | - Lihui Liang
- Department of Geriatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, China
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Shakour N, Karami S, Iranshahi M, Butler AE, Sahebkar A. Antifibrotic effects of sodium-glucose cotransporter-2 inhibitors: A comprehensive review. Diabetes Metab Syndr 2024; 18:102934. [PMID: 38154403 DOI: 10.1016/j.dsx.2023.102934] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/25/2023] [Accepted: 12/20/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND AND AIMS Scar tissue accumulation in organs is the underlying cause of many fibrotic diseases. Due to the extensive array of organs affected, the long-term nature of fibrotic processes and the large number of people who suffer from the negative impact of these diseases, they constitute a serious health problem for modern medicine and a huge economic burden on society. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a relatively new class of anti-diabetic pharmaceuticals that offer additional benefits over and above their glucose-lowering properties; these medications modulate a variety of diseases, including fibrosis. Herein, we have collated and analyzed all available research on SGLT2is and their effects on organ fibrosis, together with providing a proposed explanation as to the underlying mechanisms. METHODS PubMed, ScienceDirect, Google Scholar and Scopus were searched spanning the period from 2012 until April 2023 to find relevant articles describing the antifibrotic effects of SGLT2is. RESULTS The majority of reports have shown that SGLT2is are protective against lung, liver, heart and kidney fibrosis as well as arterial stiffness. According to the results of clinical trials and animal studies, many SGLT2 inhibitors are promising candidates for the treatment of fibrosis. Recent studies have demonstrated that SGLT2is affect an array of cellular processes, including hypoxia, inflammation, oxidative stress, the renin-angiotensin system and metabolic activities, all of which have been linked to fibrosis. CONCLUSION Extensive evidence indicates that SGLT2is are promising treatments for fibrosis, demonstrating protective effects in various organs and influencing key cellular processes linked to fibrosis.
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Affiliation(s)
- Neda Shakour
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shima Karami
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Adliya, Bahrain
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Jin Z, Yuan Y, Zheng C, Liu S, Weng H. Effects of sodium-glucose co-transporter 2 inhibitors on liver fibrosis in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: An updated meta-analysis of randomized controlled trials. J Diabetes Complications 2023; 37:108558. [PMID: 37499274 DOI: 10.1016/j.jdiacomp.2023.108558] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/25/2023] [Accepted: 07/11/2023] [Indexed: 07/29/2023]
Abstract
BACKGROUND AND AIM Sodium-glucose co-transporter 2 inhibitors (SGLT2i) has been verified to improve Non-alcoholic fatty liver disease (NAFLD) in previous clinical practice. We mainly aim to investigate the effects of SGLT2i on liver fibrosis in NAFLD patients with type 2 diabetes mellitus (T2DM). METHODS We conducted a comprehensive literature search utilizing the databases PubMed, Embase, Web of Science, and Cochrane Library, and extracted continuous data in the form of mean and standard deviation of the difference before and after treatment. RevMan 5.3 software was used to chart the pooled forest plot and perform heterogeneity, sensitivity and subgroup analysis. This study is conducted under the protocol registered with the Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY protocol 4946, INPLASY202360058). RESULTS A total of 16 articles involving 699 patients were included. Indicators of liver fibrosis, containing Liver Stiffness Measurement (LSM), Controlled Attenuation Parameter (CAP), Serum ferritin, Serum type 4 collagen 7s, and FIB-4 index, were found to be considerably reduced by SGLT2i medication and subgroup analysis manifested pronounced dose-dependence. Additionally, SGLT2i therapy decreased BMI, lipid buildup and insulin resistance. CONCLUSIONS SGLT2 inhibitors significantly ameliorated liver fibrosis and liver fat content, improved body conditions and insulin resistance, demonstrating that SGLT2i might reduce the risk of the progression of liver fibrosis and have a positive effect on NAFLD patients with T2DM.
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Affiliation(s)
- Zijie Jin
- Fudan University School of Pharmacy, Shanghai 201203, China.
| | - Yan Yuan
- Fudan University School of Pharmacy, Shanghai 201203, China
| | - Chen Zheng
- Fudan University School of Pharmacy, Shanghai 201203, China
| | - Shijian Liu
- Department of Clinical Epidemiology and Biostatistics, Child Health Advocacy Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
| | - Hongbo Weng
- Fudan University School of Pharmacy, Shanghai 201203, China.
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Shen Y, Cheng L, Xu M, Wang W, Wan Z, Xiong H, Guo W, Cai M, Xu F. SGLT2 inhibitor empagliflozin downregulates miRNA-34a-5p and targets GREM2 to inactivate hepatic stellate cells and ameliorate non-alcoholic fatty liver disease-associated fibrosis. Metabolism 2023:155657. [PMID: 37422021 DOI: 10.1016/j.metabol.2023.155657] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/30/2023] [Accepted: 07/05/2023] [Indexed: 07/10/2023]
Abstract
BACKGROUND AND RATIONALE Activation of hepatic stellate cells (HSCs), the central event of fibrosis, indicates the severe stage of non-alcoholic fatty liver disease (NAFLD). MicroRNAs (miRNAs) participate in this process. Treatment with a sodium-glucose cotransporter 2 inhibitor (SGLT2i) alleviates liver fibrosis in patients with type 2 diabetes and NAFLD; however, the role of SGLT2i in ameliorating liver fibrosis in NAFLD by regulating miRNAs remains unclear. APPROACH AND RESULTS We monitored the expression of NAFLD-associated miRNAs in the livers of two NAFLD models and observed high expression of miR-34a-5p. miR-34a-5p was highly expressed in mouse primary liver non-parenchymal cells and LX-2 HSCs, and this miRNA was positively correlated with alanine transaminase levels in NAFLD models. Overexpression of miR-34a-5p enhanced LX-2 activation, whereas its inhibition prevented HSCs activation by regulating the TGFβ signaling pathway. The SGLT2i empagliflozin significantly downregulated miR-34a-5p, inhibited the TGFβ signaling pathway, and ameliorated hepatic fibrosis in NAFLD models. Subsequently, GREM2 was identified as a direct target of miR-34a-5p through database prediction and a dual-luciferase reporter assay. In LX-2 HSCs, the miR-34a-5p mimic and inhibitor directly downregulated and upregulated GREM2, respectively. Overexpressing GREM2 inactivated the TGFβ pathway whereas GREM2 knockdown activated it. Additionally, empagliflozin upregulated Grem2 expression in NAFLD models. In methionine- and choline-deficient diet-fed ob/ob mice, a fibrosis model, empagliflozin downregulated miR-34a-5p and upregulated Grem2 to improve liver fibrosis. CONCLUSIONS Empagliflozin ameliorates NAFLD-associated fibrosis by downregulating miR-34a-5p and targeting GREM2 to inhibit the TGFβ pathway in HSCs.
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Affiliation(s)
- Yunfeng Shen
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Branch of National Clinical Research Center for Metabolic Diseases, Nanchang 330006, China; Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Lidan Cheng
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China; Department of Endocrinology and Metabolism, Jiujiang University Affiliated Hospital, Jiujiang 330300, China
| | - Minxuan Xu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Wei Wang
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China; Department of Gastroenterology, the First Affiliated Hospital of Yangtze University, Jingzhou 434000, China
| | - Zhiping Wan
- Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China; Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Haixia Xiong
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Branch of National Clinical Research Center for Metabolic Diseases, Nanchang 330006, China; Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Wanrong Guo
- Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Mengyin Cai
- Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China.
| | - Fen Xu
- Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China.
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Chen X, Xu C, Hu K, Yang Y, Zhang YJ, Shi HZ, Gu Q, He SM, Zhang C, Wang DD. Quantitative effects of sodium-glucose cotransporter-2 inhibitors on liver functions in patients with nonalcoholic fatty liver disease. Expert Rev Clin Pharmacol 2023; 16:991-998. [PMID: 37669251 DOI: 10.1080/17512433.2023.2256224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 07/25/2023] [Accepted: 08/30/2023] [Indexed: 09/07/2023]
Abstract
BACKGROUND The present study aimed to explore the quantitative effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on liver functions in patients with nonalcoholic fatty liver disease (NAFLD). RESEARCH DESIGN AND METHODS A total of 4771 patients with NAFLD were included for analysis by means of nonlinear mixed effect modeling, where the change rates of liver functions were taken as the evaluation indexes so as to eliminate the potential baseline effects. RESULTS For ALT and AST, the Emax of SGLT-2 inhibitors was -17.8% and -13.9%, respectively, and the ET50 was 6.86 weeks and 10 weeks, respectively. Furthermore, the duration time to achieve 25%, 50%, 75%, and 80% Emax were 2.3 weeks, 6.86 weeks, 20.6 weeks, 27.5 weeks in ALT, 3.4 weeks, 10 weeks, 30 weeks, 40 weeks in AST, respectively. Thus, to realize the plateau period (80% of Emax) of SGLT-2 inhibitors on ALT and AST in patients with NAFLD, 100 mg/day canagliflozin (or 10 mg/day dapagliflozin or 10 mg/day empagliflozin) needs to be taken for 20.6 weeks and 30 weeks, respectively. CONCLUSIONS The present study explored the quantitative effects of SGLT-2 inhibitors on liver functions and recommends a therapeutic regimen in patients with NAFLD.
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Affiliation(s)
- Xiao Chen
- School of Nursing, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Chang Xu
- Department of Pharmacy, The Affiliated Jiangyin Clinical College of Xuzhou Medical University, Wuxi, Jiangsu, China
| | - Ke Hu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yang Yang
- Department of Pharmacy, The Affiliated Changzhou Children's Hospital of Nantong University, Changzhou, Jiangsu, China
| | - Yi-Jia Zhang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hao-Zhe Shi
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Qian Gu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Su-Mei He
- Department of Pharmacy, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, Jiangsu, China
| | - Cun Zhang
- Department of Pharmacy, Xuzhou Oriental Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Dong-Dong Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
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Takeshita Y, Honda M, Harada K, Kita Y, Takata N, Tsujiguchi H, Tanaka T, Goto H, Nakano Y, Iida N, Arai K, Yamashita T, Mizukoshi E, Nakamura H, Kaneko S, Takamura T. Comparison of Tofogliflozin and Glimepiride Effects on Nonalcoholic Fatty Liver Disease in Participants With Type 2 Diabetes: A Randomized, 48-Week, Open-Label, Active-Controlled Trial. Diabetes Care 2022; 45:2064-2075. [PMID: 35894933 PMCID: PMC9472500 DOI: 10.2337/dc21-2049] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 05/21/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) is a liver phenotype of type 2 diabetes and obesity. Currently, the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas in liver pathology and hepatic gene expression profiles for type 2 diabetes with NAFLD are unknown. RESEARCH DESIGN AND METHODS We conducted a 48 week, randomized, open-label, parallel-group trial involving participants with biopsy-confirmed NAFLD. A total of 40 participants were randomly assigned to receive once daily 20 mg tofogliflozin or 0.5 mg glimepiride. The primary outcome was the percentage of participants with at least an improvement in all individual scores for histological categories of steatosis, hepatocellular ballooning, lobular inflammation, and fibrosis by at least 1 point. The secondary end points were the changes in liver enzymes, metabolic markers, and hepatic gene expression profiles. RESULTS Fibrosis scores improved in the tofogliflozin group (60%, P = 0.001), whereas the change from baseline did not differ significantly between the groups (P = 0.172). The histological variables of steatosis (65%, P = 0.001), hepatocellular ballooning (55%, P = 0.002), and lobular inflammation (50%, P = 0.003) were improved in the tofogliflozin group, whereas only hepatocellular ballooning was improved in the glimepiride group (25%, P = 0.025). Hepatic gene expression profiling revealed histology-associated signatures in energy metabolism, inflammation, and fibrosis that were reversed with tofogliflozin. CONCLUSIONS Tofogliflozin and, to a lesser degree, glimepiride led to liver histological and metabolic improvement in participants with type 2 diabetes and NAFLD, with no significant difference between the agents. The hepatic expression of the genes involved in energy metabolism, inflammation, and fibrosis was well correlated with liver histological changes and rescued by tofogliflozin. We need further confirmation through long-term larger-scale clinical trials of SGLT2 inhibitors.
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Affiliation(s)
- Yumie Takeshita
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yuki Kita
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Noboru Takata
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Hiromasa Tsujiguchi
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takeo Tanaka
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hisanori Goto
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yujiro Nakano
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Noriho Iida
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Hiroyuki Nakamura
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
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Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models. Int J Mol Sci 2022; 23:ijms23105634. [PMID: 35628443 PMCID: PMC9144929 DOI: 10.3390/ijms23105634] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/14/2022] [Accepted: 05/16/2022] [Indexed: 12/12/2022] Open
Abstract
Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease. This inflammatory deregulation has been observed in many other diseases, which led the scientific community to have a growing interest in the understanding of the biological processes that lead to or control inflammation deregulation in order to be able to identify potential therapeutic targets that could revert this situation and contribute to the amelioration of the disease. In this line, recent studies showed that gliflozins also act as an anti-inflammatory drug, and have been proposed as a useful strategy to treat other diseases linked to inflammation in addition to cardio-renal diseases, such as diabetes, obesity, atherosclerosis, or non-alcoholic fatty liver disease. In this work, we will review recent studies regarding the role of the main sodium-glucose co-transporter 2 inhibitors in the control of inflammation.
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SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection. Int J Mol Sci 2022; 23:ijms23063107. [PMID: 35328527 PMCID: PMC8953901 DOI: 10.3390/ijms23063107] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/03/2022] [Accepted: 03/09/2022] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an ‘umbrella’ term, comprising a spectrum ranging from benign, liver steatosis to non-alcoholic steatohepatitis, liver fibrosis and eventually cirrhosis and hepatocellular carcinoma. NAFLD has evolved as a major health problem in recent years. Discovering ways to prevent or delay the progression of NAFLD has become a global focus. Lifestyle modifications remain the cornerstone of NAFLD treatment, even though various pharmaceutical interventions are currently under clinical trial. Among them, sodium-glucose co-transporter type-2 inhibitors (SGLT-2i) are emerging as promising agents. Processes regulated by SGLT-2i, such as endoplasmic reticulum (ER) and oxidative stress, low-grade inflammation, autophagy and apoptosis are all implicated in NAFLD pathogenesis. In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD development and progression, providing current evidence from in vitro, animal and human studies. Given this evidence, further mechanistic studies would advance our understanding of the exact mechanisms underlying the pathogenesis of NAFLD and the potential beneficial actions of SGLT-2i in the context of NAFLD treatment.
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14
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Morishita A, Tadokoro T, Fujihara S, Iwama H, Oura K, Fujita K, Tani J, Takuma K, Nakahara M, Shi T, Haba R, Okano K, Nishiyama A, Ono M, Himoto T, Masaki T. Ipragliflozin attenuates non-alcoholic steatohepatitis development in an animal model. PLoS One 2022; 17:e0261310. [PMID: 35192632 PMCID: PMC8863244 DOI: 10.1371/journal.pone.0261310] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/30/2021] [Indexed: 01/02/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease with no decisive treatment. The sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin was developed as a new oral hypoglycemic drug, which can improve NASH via an insulin-independent glucose-lowering effect by inhibiting glucose reabsorption in the renal proximal tubules. However, ipragliflozin appears to modulate steatosis or inflammation via different pathways. To elucidate the new mechanism of ipragliflozin for the treatment of NASH, we evaluated its effects in a NASH mouse model (STAM mice) with beta cell depletion, and compared the expression of microRNAs (miRNAs) in STAM mice treated with or without ipragliflozin (16.7 μg/day for 5 weeks). Ipragliflozin reduced aspartate transaminase and alanine aminotransferase levels, along with reduced hepatic steatosis, hepatocyte ballooning, lobular inflammation, and liver fibrosis. In addition, ipragliflozin upregulated mitochondrial transport-related and antioxidant defensive system-related genes in the liver. Among 2555 mouse miRNA probes, miR-19b-3p was commonly differentially expressed with ipragliflozin treatment for 5 weeks in both the liver and serum but in different directions, with a decrease in the liver and increase in the serum. Therefore, ipragliflozin can improve NASH development likely through the antioxidative stress pathway and by regulating miR-19b-3p.
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Affiliation(s)
- Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa, Japan
- * E-mail:
| | | | | | | | - Kyoko Oura
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | - Tingting Shi
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | | | - Keiichi Okano
- Department of Gastroenterological Surgery, Kagawa, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University Faculty of Medicine, Kagawa, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Neurology, Kagawa, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectual University of Health Sciences, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa, Japan
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Sato D, Nakamura T, Amarume J, Yano M, Umehara Y, Nishina A, Tsutsumi K, Feng Z, Kusunoki M. Effects of dapagliflozin on adipose and liver fatty acid composition and mRNA expression involved in lipid metabolism in high-fat-fed rats. Endocr Metab Immune Disord Drug Targets 2022; 22:944-953. [PMID: 35255800 DOI: 10.2174/1871530322666220307153618] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/23/2021] [Accepted: 01/25/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND SGLT2 inhibitor enhances not only glucose excretion but also fatty acid utilization. Those facts suggest that SGLT2 inhibitor affects fat accumulation and lipid storage. OBJECTIVE In the present study, we evaluated the effects of dapagliflozin on fatty acid composition and gene expression involved in fatty acid metabolism in rat adipose and liver tissues. METHODS We administered 1 mg/kg/day dapagliflozin for 7 weeks to male high-fat-fed rats (DAPA group), and then weights and 22 fatty acid contents in the epididymal (EPI), mesenteric (MES), retroperitoneal (RET) and subcutaneous (SUB) adipose tissues, and the liver were compared with vehicle-administered control group. RESULTS In the EPI, RET, and SUB in the DAPA group, contents of several fatty acids were lower (P<0.05) than those in the control group while no significant difference was detected in tissue weight. In the MES, not only tissue weight but also wide variety of fatty acid contents including saturated, monounsaturated, and polyunsaturated fatty acids were lower (P<0.05). As for the liver tissue, no significant difference was observed in fatty acid contents between the groups. mRNA expression of Srebp1c in EPI was significantly higher (P<0.05) in the DAPA group than in the control group, while Scd1 expression in the liver was lower (P<0.01). CONCLUSION These results suggest that dapagliflozin might suppress lipid accumulation especially in the MES, and could reduce contents of fatty acids not in the liver but in adipose tissues in high-fat-fed rats. In addition, dapagliflozin could influence mRNA expression involved in lipogenesis in the EPI and liver.
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Affiliation(s)
- Daisuke Sato
- Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University (4-3-16 Johnan, Yonezawa 992-8510, Japan)
| | - Takao Nakamura
- Department of Biomedical Information Engineering, Graduate School of Medical Science, Yamagata University (2-2-2 Iida-nishi, Yamagata 990-9585, Japan)
| | - Jota Amarume
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University (4-3-16 Johnan, Yonezawa 992-8510, Japan)
| | - Mizuna Yano
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University (4-3-16 Johnan, Yonezawa 992-8510, Japan)
| | - Yuta Umehara
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University (4-3-16 Johnan, Yonezawa 992-8510, Japan)
| | - Atsuyoshi Nishina
- Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University (1-8-14 Kandasurugadai, Chiyoda-ku, 101-8308, Japan)
| | - Kazuhiko Tsutsumi
- Okinaka Memorial Institute for Medical Research (2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan)
| | - Zhonggang Feng
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University (4-3-16 Johnan, Yonezawa 992-8510, Japan)
| | - Masataka Kusunoki
- Research Center of Health, Physical Fitness and Sports, Nagoya University (Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan)
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Abstract
Sodium glucose cotransporter 2 (SGLT-2) inhibitors are the latest class of antidiabetic medications. They prevent glucose reabsorption in the proximal convoluted tubule to decrease blood sugar. Several animal studies revealed that SGLT-2 is profoundly involved in the inflammatory response, fibrogenesis, and regulation of numerous intracellular signaling pathways. Likewise, SGLT-2 inhibitors markedly attenuated inflammation and fibrogenesis and improved the function of damaged organ in animal studies, observational studies, and clinical trials. SGLT-2 inhibitors can decrease blood pressure and ameliorate hypertriglyceridemia and obesity. Likewise, they improve the outcome of cardiovascular diseases such as heart failure, arrhythmias, and ischemic heart disease. SGLT-2 inhibitors are associated with lower cardiovascular and all-cause mortality as well. Meanwhile, they protect against nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, acute kidney injury, and improve micro- and macroalbuminuria. SGLT-2 inhibitors can reprogram numerous signaling pathways to improve NAFLD, cardiovascular diseases, and renal diseases. For instance, they enhance lipolysis, ketogenesis, mitochondrial biogenesis, and autophagy while they attenuate the renin-angiotensin-aldosterone system, lipogenesis, endoplasmic reticulum stress, oxidative stress, apoptosis, and fibrogenesis. This review explains the beneficial effects of SGLT-2 inhibitors on NAFLD and cardiovascular and renal diseases and dissects the underlying molecular mechanisms in detail. This narrative review explains the beneficial effects of SGLT-2 inhibitors on NAFLD and cardiovascular and renal diseases using the results of latest observational studies, clinical trials, and meta-analyses. Thereafter, it dissects the underlying molecular mechanisms involved in the clinical effects of SGLT-2 inhibitors on these diseases.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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Lee JY, Lee M, Lee JY, Bae J, Shin E, Lee YH, Lee BW, Kang ES, Cha BS. Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway. Diabetes Metab J 2021; 45:921-932. [PMID: 33611885 PMCID: PMC8640151 DOI: 10.4093/dmj.2020.0187] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 08/19/2020] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that exhibit multiple extraglycemic effects. However, there are conflicting results regarding the effects of SGLT2 inhibition on energy expenditure and thermogenesis. Therefore, we investigated the effect of ipragliflozin (a selective SGLT2 inhibitor) on energy metabolism. METHODS Six-week-old male 129S6/Sv mice with a high propensity for adipose tissue browning were randomly assigned to three groups: normal chow control, 60% high-fat diet (HFD)-fed control, and 60% HFD-fed ipragliflozin-treated groups. The administration of diet and medication was continued for 16 weeks. RESULTS The HFD-fed mice became obese and developed hepatic steatosis and adipose tissue hypertrophy, but their random glucose levels were within the normal ranges; these features are similar to the metabolic features of a prediabetic condition. Ipragliflozin treatment markedly attenuated HFD-induced hepatic steatosis and reduced the size of hypertrophied adipocytes to that of smaller adipocytes. In the ipragliflozin treatment group, uncoupling protein 1 (Ucp1) and other thermogenesis-related genes were significantly upregulated in the visceral and subcutaneous adipose tissue, and fatty acid oxidation was increased in the brown adipose tissue. These effects were associated with a significant reduction in the insulin-to-glucagon ratio and the activation of the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway in the liver and adipose tissue. CONCLUSION SGLT2 inhibition by ipragliflozin showed beneficial metabolic effects in 129S6/Sv mice with HFD-induced obesity that mimics prediabetic conditions. Our data suggest that SGLT2 inhibitors, through their upregulation of energy expenditure, may have therapeutic potential in prediabetic obesity.
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Affiliation(s)
- Ji-Yeon Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Minyoung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Young Lee
- Department of Molecular, Cellular and Cancer Biology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
| | - Jaehyun Bae
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Eugene Shin
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
| | - Yong-ho Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
| | - Byung-Wan Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Seok Kang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
| | - Bong-Soo Cha
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
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Padda J, Khalid K, Khedr A, Tasnim F, Al-Ewaidat OA, Cooper AC, Jean-Charles G. Non-Alcoholic Fatty Liver Disease and Its Association With Diabetes Mellitus. Cureus 2021; 13:e17321. [PMID: 34557367 PMCID: PMC8449987 DOI: 10.7759/cureus.17321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2021] [Indexed: 11/29/2022] Open
Abstract
There is a bidirectional relationship between non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). The liver has a vital role in the pathophysiology of both diseases as it leads to the development of insulin resistance (IR), which in turn results in NAFLD and T2DM. It has been shown that T2DM increases the risk of NAFLD progression. Furthermore, the presence of NAFLD raises the probability of T2DM complications, which explains the increased rates of NAFLD screening in patients with T2DM. In addition, there are common management options for the two diseases. Lifestyle changes can play a role in the initial management of both diseases. Medications that are used to treat T2DM are also used in the management of NAFLD, such as metformin, thiazolidinediones (TZD), glucagon-like peptide-1 (GLP-1) analogues, and dipeptidyl peptidase-4 (DPP4) inhibitors. Bariatric surgery is often used as a last resort and has shown promising results. Lifestyle interventions with diet and exercise are important postoperatively to maintain the weight loss. There are many novel treatments that are being investigated for the treatment of NAFLD, targeting multiple pathophysiologic pathways. This review aims to shed some light on the intricate relationship between NAFLD and T2DM and how IR links both diseases. We also try to raise awareness among clinicians about this relationship and how the presence of one disease should raise a high index of suspicion for the existence of the other.
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Affiliation(s)
| | | | - Anwar Khedr
- Internal Medicine, JC Medical Center, Orlando, USA
| | | | | | | | - Gutteridge Jean-Charles
- Internal Medicine, JC Medical Center, Orlando, USA.,Internal Medicine, Advent Health & Orlando Health Hospital, Orlando, USA
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Makri ES, Goulas A, Polyzos SA. Sodium-glucose co-transporter 2 inhibitors in nonalcoholic fatty liver disease. Eur J Pharmacol 2021; 907:174272. [PMID: 34147478 DOI: 10.1016/j.ejphar.2021.174272] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 06/03/2021] [Accepted: 06/14/2021] [Indexed: 12/15/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered the most prevalent chronic hepatic disease, as it has been estimated that one of four individuals in the general population has been affected by NAFLD. The evolution of the referred entity, which includes nonalcoholic steatohepatitis (NASH) and hepatic fibrosis, may have crucial and even fatal consequences, leading to cirrhosis and hepatocellular carcinoma. Although NAFLD has also been linked with cardiovascular and renal diseases, and all-cause mortality increment, pharmacological therapy is as yet an unfulfilled demand. Since NAFLD is closely associated with type 2 diabetes mellitus (T2DM), a variety of anti-diabetic drugs have been investigated for their effectiveness towards NAFLD. Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) improve blood glucose levels through increasing renal glucose excretion and they are recommended as one of standard therapeutic categories for T2DM patients. Based on preclinical animal studies, SGLT-2i have shown a beneficial effect on NAFLD, inducing histologically proven amelioration of hepatic steatosis, inflammation and fibrosis. Promising data have been also derived by clinical trials, which have indicated a potentially beneficial effect of SGLT-2i on NAFLD, at least in terms of liver function tests and imaging. Thus, it is not strange that there are many ongoing trials on the effect of various SGLT-2i in NAFLD. In conclusion, current evidence concerning the effect of SGLT-2i on NAFLD is encouraging; however, data from ongoing clinical trials with histological endpoints are awaited.
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Affiliation(s)
- Evangelia S Makri
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Campus of Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Campus of Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Campus of Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
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Tobe K, Maegawa H, Nakamura I, Uno S. Effect of ipragliflozin on liver function in Japanese type 2 diabetes mellitus patients: subgroup analysis of a 3-year post-marketing surveillance study (STELLA-LONG TERM). Endocr J 2021; 68:905-918. [PMID: 33827996 DOI: 10.1507/endocrj.ej20-0765] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The STELLA-LONG TERM prospective post-marketing surveillance study assessed ipragliflozin in Japanese patients with type 2 diabetes mellitus (T2DM). This subgroup analysis of patients with liver impairment used the final 3-year results. Data on patients, adverse drug reactions (ADRs), and changes in glycemic parameters and liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [γ-GTP] and alkaline phosphatase [ALP]) were collected, and the fatty liver index (FLI) was calculated. In the effectiveness analysis (n = 8,763), baseline liver function was normal in 2,605 patients (ALT <31/<21 U/L [men/women]) and abnormal in 3,277 (ALT ≥31/≥21 U/L). The abnormal liver function group had higher mean body weight and BMI than the normal liver function group (p < 0.001). In the safety analysis (n = 11,051), urinary tract infections, genital infections and hepatic disorders were more common in the abnormal than normal liver function group (2.25% vs. 1.07%; 1.78% vs. 1.14% and 1.85% vs. 1.01%). In the abnormal liver function group, there were significant (p < 0.001) decreases from baseline at 36 months in AST and ALT (from 38.8 and 53.7 U/L to 29.3 and 37.7 U/L, respectively), γ-GTP (from 75.4 to 51.7 U/L) and ALP (from 254.8 to 234.5 U/L), which were greater than in the normal liver function group. FLI reductions at 36 months were significant (p < 0.001) in subgroups with baseline FLI of ≥30 or ≥60. In conclusion, ipragliflozin improved liver function over 3 years in patients with impaired liver function, although ADRs occurred more frequently than in the normal liver function group.
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Affiliation(s)
- Kazuyuki Tobe
- First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, 930-0194, Japan
| | - Hiroshi Maegawa
- Department of Medicine, Shiga University of Medical Science, Shiga, 520-2192, Japan
| | - Ichiro Nakamura
- Operational Excellence, Medical Affairs Japan, Astellas Pharma Inc., Tokyo, 103-8411, Japan
| | - Satoshi Uno
- Data Science, Development, Astellas Pharma Inc., Tokyo, 103-8411, Japan
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21
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Watanabe T, Ito M, Suzuki H, Terada K, Noguchi S. Reduced deliquescency of isosorbide by cocrystallization and mechanisms for hygroscopicity. Int J Pharm 2021; 607:120959. [PMID: 34333025 DOI: 10.1016/j.ijpharm.2021.120959] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 07/14/2021] [Accepted: 07/27/2021] [Indexed: 10/20/2022]
Abstract
Isosorbide (ISO) is an effective hyperosmotic agent that can be administrated orally and is used as a therapeutic agent for brain pressure drop, glaucoma, and Meniere's disease. However, the critical relative humidity (CRH) of ISO is about 48% RH at 25 °C, and it deliquesces in humid environments. In this study, we attempted to reduce the deliquescence of ISO using cocrystallization and analyze the water adsorption mechanism from the crystal structure. Four new ISO cocrystals with piperazine (PZ), hydrochlorothiazide (HCT), 3,5-dihydroxybenzoic acid (35DHBA), or gallic acid (GA) were identified. The dynamic vapor sorption analyses demonstrated that all the cocrystals showed higher CRHs than the ISO crystal. Although water adsorption below the CRH was observed for all cocrystals, the water molecules adsorbed in the ISO-PZ and ISO-GA cocrystals were lower than those in the ISO crystal. Investigation of the crystal structures suggested that the amount of water adsorbed might be related to the degree of exposure of the ISO hydroxyl groups on the crystal surface. Given the CRH, water adsorption below the CRH, thermal stability, apparent dissolution rate, and toxicity level of the coformer, the ISO-GA cocrystal is the most suitable for preparing a solid formulation of ISO.
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Affiliation(s)
- Tatsuya Watanabe
- Laboratory of Pharmaceutics, Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8514, Japan
| | - Masataka Ito
- Laboratory of Pharmaceutics, Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8514, Japan.
| | - Hironori Suzuki
- Laboratory of Pharmaceutics, Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8514, Japan
| | - Katsuhide Terada
- Laboratory of Pharmaceutics, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki, Gunma 370-0033, Japan
| | - Shuji Noguchi
- Laboratory of Pharmaceutics, Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8514, Japan
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22
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Lin CY, Adhikary P, Cheng K. Cellular protein markers, therapeutics, and drug delivery strategies in the treatment of diabetes-associated liver fibrosis. Adv Drug Deliv Rev 2021; 174:127-139. [PMID: 33857552 PMCID: PMC8217274 DOI: 10.1016/j.addr.2021.04.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/18/2021] [Accepted: 04/08/2021] [Indexed: 02/08/2023]
Abstract
Liver fibrosis is the excessive accumulation of extracellular matrix due to chronic injuries, such as viral infection, alcohol abuse, high-fat diet, and toxins. Liver fibrosis is reversible before it progresses to cirrhosis and hepatocellular carcinoma. Type 2 diabetes significantly increases the risk of developing various complications including liver diseases. Abundant evidence suggests that type 2 diabetes and liver diseases are bidirectionally associated. Patients with type 2 diabetes experience more severe symptoms and accelerated progression of live diseases. Obesity and insulin resistance resulting from hyperlipidemia and hyperglycemia are regarded as the two major risk factors that link type 2 diabetes and liver fibrosis. This review summarizes possible mechanisms of the association between type 2 diabetes and liver fibrosis. The cellular protein markers that can be used for diagnosis and therapy of type 2 diabetes-associated liver fibrosis are discussed. We also highlight the potential therapeutic agents and their delivery systems that have been investigated for type 2 diabetes-associated liver fibrosis.
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Affiliation(s)
- Chien-Yu Lin
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, United States
| | - Pratik Adhikary
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, United States
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, United States.
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23
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Zhang E, Zhao Y, Hu H. Impact of Sodium Glucose Cotransporter 2 Inhibitors on Nonalcoholic Fatty Liver Disease Complicated by Diabetes Mellitus. Hepatol Commun 2021; 5:736-748. [PMID: 34027265 PMCID: PMC8122372 DOI: 10.1002/hep4.1611] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 08/25/2020] [Accepted: 08/30/2020] [Indexed: 02/06/2023] Open
Abstract
Sodium glucose cotransporter 2 (SGLT2), a type of membrane protein highly expressed in the kidney, can regulate plasma glucose through the glomerular filtration process by reabsorption from the kidney. SGLT2 inhibitors, which are newly developed oral antidiabetic drugs, can play a role in liver diseases by inhibiting SGLT2-mediated renal glucose reabsorption and inducing glycosuria. Nonalcoholic fatty liver disease (NAFLD) is the most common type of liver disease, resulting in severe liver dysfunction. During the progression of NAFLD, there are some hallmark complications, including lipid metabolism disorders, inflammation induction, and hepatocyte death. Herein, we review several SGLT2 inhibitors that are capable of protecting individuals with NAFLD from severe complications by inhibiting de novo lipogenesis, oxidative responses, inflammation induction, and hepatocyte death.
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Affiliation(s)
- Enxiang Zhang
- Key Laboratory of Growth Regulation and Transformation Research of Zhejiang ProvinceSchool of Life SciencesWestlake Institute for Advanced StudyWestlake UniversityShilongshanHangzhouChina.,Beijing Advanced Innovation Center for Food Nutrition and Human HealthCollege of Food Science and Nutritional EngineeringChina Agricultural UniversityBeijingChina.,Department of Biochemistry, Molecular Biology, and BiophysicsUniversity of MinnesotaMinneapolisMN
| | - Yang Zhao
- Department of CardiologyZhejiang Provincial People's HospitalHangzhouChina.,Cardiovascular DivisionDepartment of MedicineUniversity of MinnesotaMinneapolisMN
| | - Hongbo Hu
- Beijing Advanced Innovation Center for Food Nutrition and Human HealthCollege of Food Science and Nutritional EngineeringChina Agricultural UniversityBeijingChina
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24
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Lamos EM, Kristan M, Siamashvili M, Davis SN. Effects of anti-diabetic treatments in type 2 diabetes and fatty liver disease. Expert Rev Clin Pharmacol 2021; 14:837-852. [PMID: 33882758 DOI: 10.1080/17512433.2021.1917374] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are significant non-communicable diseases that often affect individuals concurrently. In individuals with both T2DM and NAFLD, there is evidence that anti-diabetic therapies may demonstrate potential combined beneficial metabolic and reduced hepatic inflammatory effects.Areas covered: A PubMed and Google Scholar search was performed to find relevant literature. Included studies focused on individuals with T2DM and NAFLD receiving anti-diabetic treatments including bariatric surgery, insulin sensitizers, incretin mimetics, and SGLT2 inhibitors. Additional articles highlight investigational treatments.Expert opinion: In individuals with T2DM and NAFLD, 5-10% weight loss or bariatric surgery if unable to lose weight or maintain weight loss are appropriate. GLP-1 receptor agonists and SGLT2 inhibitors result in weight loss, appear safe and may provide beneficial hepatic outcomes. Whether their effects are related to favorable weight changes or intrinsic hepatic effects is unclear. Thiazolidinediones have advantageous anti-hyperglycemic and hepatic effects but individuals must be monitored for weight gain and edema. Metformin and DPP-4 inhibitor beneficial hepatic effects remain debated. There are opportunities to standardize markers and imaging of NAFLD. Studies powered to evaluate the possible cardiovascular benefits of anti-diabetic therapies in individuals with T2DM and NAFLD are needed.
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Affiliation(s)
- Elizabeth M Lamos
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Megan Kristan
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Maka Siamashvili
- Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA
| | - Stephen N Davis
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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25
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Chrysavgis L, Papatheodoridi AM, Chatzigeorgiou A, Cholongitas E. The impact of sodium glucose co-transporter 2 inhibitors on non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2021; 36:893-909. [PMID: 33439540 DOI: 10.1111/jgh.15202] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/29/2020] [Accepted: 07/23/2020] [Indexed: 12/13/2022]
Abstract
Affecting one fourth of the global population, non-alcoholic fatty liver disease (NAFLD) is the commonest chronic liver disorder. It encompasses the simple liver fat accumulation to more progressive steatosis, inflammation, and fibrosis characterized as non-alcoholic steatohepatitis (NASH) and in some cases cirrhosis and hepatocellular carcinoma. NAFLD regularly coexists with metabolic disorders, such as obesity and mostly type 2 diabetes mellitus (T2DM). A relatively new class of antidiabetic drugs, the sodium glucose co-transporter 2 (SGLT2) inhibitors exert their action by increasing the urinary glucose and calorie excretion leading to ameliorated plasma glucose levels and lower bodyweight. Recently, several animal studies and human clinical trial have emphasized the possible beneficial impact of SGLT2 inhibitors on NAFLD and its progression to NASH. In this present review, we summarize the current literature regarding the efficacy of the aforementioned category of drugs on anthropometric, laboratory, and histological features of patients with NAFLD. Conclusively, as SGLT2 inhibitors seem to be an appealing therapeutic opportunity for NAFLD management, we identify the open issues and questions to be addressed in order to clarify the impact in choosing antidiabetic medication to treat NAFLD patients associated with T2DM.
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Affiliation(s)
- Lampros Chrysavgis
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | | | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School of National and Kapodistrian University, General Hospital of Athens "Laiko", Athens, Greece
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26
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Sinha B, Datta D, Ghosal S. Meta-analysis of the effects of sodium glucose cotransporter 2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes. JGH Open 2021; 5:219-227. [PMID: 33553659 PMCID: PMC7857274 DOI: 10.1002/jgh3.12473] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 11/17/2020] [Accepted: 11/25/2020] [Indexed: 12/13/2022]
Abstract
Background and Aim Sodium glucose cotransporter 2 inhibitors (SGLT‐2i), by way of their unique mode of action, present an attractive strategy for the treatment of type 2 diabetes and non‐alcoholic fatty liver disease (NAFLD), which often coexist and may lead to severe complications. However, the evidence for treatment with SGLT‐2i is limited to small heterogeneous studies. Therefore, this meta‐analysis was conducted to deduce the effects of SGLT‐2i in NAFLD with type 2 diabetes (T2D). Methods A web‐based search identified nine randomized controlled trials from the Cochrane Library, Embase, and PubMed for this meta‐analysis. The Comprehensive Meta‐Analysis Software version 3 was used to calculate the effect size. Result The outcomes of interest were analyzed from a pooled population of 11 369 patients—7281 on SGLT‐2i and 4088 in the control arm. SGLT‐2i therapy produced a statistically significant improvement in alanine aminotransferase [standardised mean difference (SDM), −0.21, 95% confidence interval (CI), −0.32 to −0.10, P < 0.01], aspartate aminotransferase (Standardised mean difference (SDM), −0.15, 95% CI, −0.24 to −0.07, P < 0.01), and liver fat as measured by proton density fat fraction (SDM, −0.98, 95% CI, −1.53 to −0.44, P < 0.01) in comparison to standard of care or placebo. In addition, there was a significant reduction in glycosylated hemoglobin (SDM, −0.37, 95% CI, −0.60 to −0.14, P < 0.01) and weight (SDM, −0.58, 95% CI, −0.93 to −0.23, P < 0.01) in the SGLT‐2i arm. Conclusion This meta‐analysis provides a convincing signal that SGLT‐2i have a salutary effect on NAFLD in type 2 diabetes (T2D), probably driven by an improvement of glycemia and body weight, which in turn attenuates hepatic inflammation and hepatic fat accumulation.
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Affiliation(s)
- Binayak Sinha
- Department of Endocrinology, AMRI Hospitals Kolkata India
| | - Debasis Datta
- Department of Hepatology, Fortis Hospital Kolkata India
| | - Samit Ghosal
- Department of Endocrinology, Nightingale Hospital Kolkata India
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27
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Athyros VG, Polyzos SA, Kountouras J, Katsiki N, Anagnostis P, Doumas M, Mantzoros CS. Non-Alcoholic Fatty Liver Disease Treatment in Patients with Type 2 Diabetes Mellitus; New Kids on the Block. Curr Vasc Pharmacol 2020; 18:172-181. [PMID: 30961499 DOI: 10.2174/1570161117666190405164313] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 10/22/2018] [Accepted: 10/28/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD), affecting over 25% of the general population worldwide, is characterized by a spectrum of clinical and histological manifestations ranging from simple steatosis (>5% hepatic fat accumulation without inflammation) to non-alcoholic steatohepatitis (NASH) which is characterized by inflammation, and finally fibrosis, often leading to liver cirrhosis, and hepatocellular carcinoma. Up to 70% of patients with type 2 diabetes mellitus (T2DM) have NAFLD, and diabetics have much higher rates of NASH compared with the general non-diabetic population. OBJECTIVE The aim of this study is to report recent approaches to NAFLD/NASH treatment in T2DM patients. To-date, there are no approved treatments for NAFLD (apart from lifestyle measures). RESULTS Current guidelines (2016) from 3 major scientific organizations suggest that pioglitazone and vitamin E may be useful in a subset of patients for adult NAFLD/NASH patients with T2DM. Newer selective PPAR-γ modulators (SPPARMs, CHRS 131) have shown to provide even better results with fewer side effects in both animal and human studies in T2DM. Newer antidiabetic drugs might also be useful, but detailed studies with histological outcomes are largely lacking. Nevertheless, prior animal and human studies on incretin mimetics, glucagon-like peptide-1 receptor agonists (GLP-1 RA) approved for T2DM treatment, have provided indirect evidence that they may also ameliorate NAFLD/NASH, whereas dipeptidyl dipeptidase-4 inhibitors (DDP-4i) were not better than placebo in reducing liver fat in T2DM patients with NAFLD. Sodium-glucoseco-transporter-2 inhibitors (SGLT2i) have been reported to improve NAFLD/NASH. Statins, being necessary for most patients with T2DM, may also ameliorate NAFLD/NASH, and could potentially reinforce the beneficial effects of the newer antidiabetic drugs, if used in combination, but this remains to be identified. CONCLUSION Newer antidiabetic drugs (SPPARMs, GLP-1 RA and SGLT2i) alone or in combination and acting alone or with potent statin therapy which is recommended in T2DM, might contribute substantially to NAFLD/NASH amelioration, possibly reducing not only liver-specific but also cardiovascular morbidity. These observations warrant long term placebo-controlled randomized trials with appropriate power and outcomes, focusing on the general population and more specifically on T2DM with NAFLD/NASH. Certain statins may be useful for treating NAFLD/NASH, while they substantially reduce cardiovascular disease risk.
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Affiliation(s)
- Vasilios G Athyros
- 2nd Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Jiannis Kountouras
- 2nd Department of Internal Medicine, Division of Gastroenterology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Niki Katsiki
- 2nd Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece
| | | | - Michael Doumas
- 2nd Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece.,VAMC and George Washington University, Washington, DC, United States
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
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Tahara A, Takasu T. SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone prevents progression of nonalcoholic steatohepatitis in a type 2 diabetes rodent model. Physiol Rep 2020; 7:e14286. [PMID: 31782258 PMCID: PMC6883099 DOI: 10.14814/phy2.14286] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) has become the most common cause of chronic liver disease worldwide in recent years. The pathogenesis of NASH is closely linked to metabolic diseases such as insulin resistance, obesity, dyslipidemia, and type 2 diabetes. However, there is currently no pharmacological agent for preventing the progression of NASH. Sodium-glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion by inhibiting renal glucose reabsorption, and improve various pathological conditions of type 2 diabetes, including insulin resistance. In the present study, we examined the effects of ipragliflozin, a SGLT2-selective inhibitor, alone and in combination with pioglitazone on NASH in high-fat diet-fed KK/Ay type 2 diabetic mice. Type 2 diabetic mice with NASH exhibited steatosis, inflammation, and fibrosis in the liver as well as hyperglycemia, insulin resistance, and obesity, features that are observed in human NASH. Four-week repeated administration of ipragliflozin (0.1-3 mg/kg) led to significant improvements in hyperglycemia, insulin resistance, and obesity in addition to hyperlipidemia and liver injury including hepatic steatosis and fibrosis. Moreover, ipragliflozin reduced inflammation and oxidative stress in the liver. Repeated administration of pioglitazone (3-30 mg/kg) also significantly improved various parameters of diabetes and NASH, excluding obesity. Furthermore, combined treatment comprising ipragliflozin (1 mg/kg) and pioglitazone (10 mg/kg) additively improved these parameters. These findings indicate that the SGLT2-selective inhibitor ipragliflozin improves hyperglycemia as well as NASH in type 2 diabetic mice. Therefore, treatment with ipragliflozin monotherapy or coadministered with pioglitazone is expected to be a potential therapeutic option for the treatment of type 2 diabetes with NASH.
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Affiliation(s)
- Atsuo Tahara
- Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan
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Suga T, Sato K, Ohyama T, Matsui S, Kobayashi T, Tojima H, Horiguchi N, Yamazaki Y, Kakizaki S, Nishikido A, Okamura T, Yamada M, Kitamura T, Uraoka T. Ipragliflozin-induced improvement of liver steatosis in obese mice may involve sirtuin signaling. World J Hepatol 2020; 12:350-362. [PMID: 32821334 PMCID: PMC7407917 DOI: 10.4254/wjh.v12.i7.350] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/20/2020] [Accepted: 06/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sodium glucose cotransporter 2 (SGLT2) inhibitors are newly developed oral antidiabetic drugs. SGLT2 is primarily expressed in the kidneys and reabsorbs approximately 90% of the glucose filtered by the renal glomeruli. SGLT2 inhibitors lower glucose levels independently of insulin action by facilitating urinary glucose excretion. The SGLT2 inhibitor ipragliflozin has reportedly improved liver steatosis in animal models and clinical studies. However, the mechanisms by which SGLT2 inhibitors improve liver steatosis are not fully understood. AIM To investigate the ameliorative effects of ipragliflozin on liver steatosis and the mechanisms of these effects in obese mice. METHODS We analyzed 8-wk-old male obese (ob/ob) mice that were randomly divided into a group receiving a normal chow diet and a group receiving a normal chow diet supplemented with ipragliflozin (3 mg/kg or 10 mg/kg) for 4 wk. We also analyzed their lean sex-matched littermates receiving a normal chow diet as another control group. Body weight and liver weight were evaluated, and liver histology, immunoblotting, and reverse transcription-polymerase chain reaction analyses were performed. RESULTS Hepatic lipid accumulation was significantly ameliorated in ob/ob mice treated with 10 mg/kg ipragliflozin compared to untreated ob/ob mice irrespective of body weight changes. Ipragliflozin had no appreciable effects on hepatic oxidative stress-related gene expression levels or macrophage infiltration, but significantly reduced hepatic interleukin-1β (IL-1β) mRNA expression levels. Ipragliflozin increased both the mRNA and protein expression levels of sirtuin 1 (SIRT1) in the liver. The hepatic mRNA levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα), and fibroblast growth factor-21 (FGF21) were also significantly higher in ipragliflozin-treated ob/ob mice than in untreated ob/ob mice. CONCLUSION Our study suggests that the liver steatosis-ameliorating effects of ipragliflozin in ob/ob mice may be mediated partly by hepatic SIRT1 signaling, possibly through the PGC-1α/PPARα-FGF21 pathway.
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Affiliation(s)
- Takayoshi Suga
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan
| | - Ken Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan.
| | - Tatsuya Ohyama
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan
| | - Sho Matsui
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Gunma, Japan
| | - Takeshi Kobayashi
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan
| | - Hiroki Tojima
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan
| | - Norio Horiguchi
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan
| | - Yuichi Yamazaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan
| | - Ayaka Nishikido
- Department of Medicine and Molecular Science, Gunma Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan
| | - Takashi Okamura
- Department of Medicine and Molecular Science, Gunma Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan
| | - Masanobu Yamada
- Department of Medicine and Molecular Science, Gunma Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan
| | - Tadahiro Kitamura
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Gunma, Japan
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan
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30
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Ipragliflozin-induced improvement of liver steatosis in obese mice may involve sirtuin signaling. World J Hepatol 2020. [DOI: 10.4254/wjgh.v12.i7.351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Abstract
Non-alcoholic fatty liver disease is a chronic liver disease which is closely associated with components of the metabolic syndrome. Its high clinical burden results from the growing prevalence, inherent cardiometabolic risk and potential of progressing to cirrhosis. Patients with non-alcoholic fatty liver disease show variable rates of disease progression through a histological spectrum ranging from steatosis to steatohepatitis with or without fibrosis. The presence and severity of fibrosis are the most important prognostic factors in non-alcoholic fatty liver disease. This necessitates risk stratification of patients by fibrosis stage using combinations of non-invasive methods, such as composite scoring systems and/or transient elastography. A multidisciplinary approach to treatment is advised, centred on amelioration of cardiometabolic risk through lifestyle and pharmacological interventions. Despite the current lack of licensed, liver-targeted pharmacotherapy, several promising agents are undergoing late-phase clinical trials to complement standard management in patients with advanced disease. This review summarises the current concepts in diagnosis and disease progression of non-alcoholic liver disease, focusing on pragmatic approaches to risk assessment and management in both primary and secondary care settings.
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Affiliation(s)
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK
| | - Jeremy F Cobbold
- Oxford Liver Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
- Correspondence should be addressed to J Cobbold:
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Marjot T, Green CJ, Charlton CA, Cornfield T, Hazlehurst J, Moolla A, White S, Francis J, Neubauer S, Cobbold JFL, Hodson L, Tomlinson JW. Sodium-glucose cotransporter 2 inhibition does not reduce hepatic steatosis in overweight, insulin-resistant patients without type 2 diabetes. JGH Open 2020; 4:433-440. [PMID: 32514450 PMCID: PMC7273735 DOI: 10.1002/jgh3.12274] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 10/03/2019] [Accepted: 10/07/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND AIM Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the leading indication for liver transplant and is associated with increased cardiovascular and liver mortality, yet there are no licensed therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used for their glucose-lowering effects in patients with type 2 diabetes (T2D). Preclinical models have suggested a beneficial impact on NAFLD, but clinical data are limited, and there are currently no data on patients without T2D. We aimed to investigate the impact of SGLT2 inhibition on NAFLD in overweight, nondiabetic patients and establish the effect these agents may have on the processes that regulate hepatic steatosis in vivo. METHODS We conducted an open-label, experimental medicine pilot study on insulin-resistant overweight/obese individuals (n = 10) using gold-standard noninvasive assessments of NAFLD phenotype, including magnetic resonance spectroscopy, two-step hyperinsulinemic euglycemic clamps, and stable isotope tracers to assess lipid and glucose metabolism. Investigations were performed before and after a 12-week treatment with the SGLT2 inhibitor, dapagliflozin. RESULTS Despite a body weight reduction of 4.4 kg, hepatic steatosis was unchanged following treatment. Hepatic glucose production increased, and there was impairment of glucose disposal during the low-dose insulin infusion. Although circulating, nonesterified, fatty acid levels did not change, the ability of insulin to suppress lipolysis was reduced. CONCLUSIONS SGLT2 inhibition for 12 weeks does not improve hepatic steatosis in patients without T2D. Additional studies in patients with established T2D or impairments of fasting or postprandial glucose homeostasis are needed to determine whether SGLT2 inhibition represents a viable therapeutic strategy for NAFLD. (http://clinicaltrials.gov Number NCT02696941).
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Affiliation(s)
- Thomas Marjot
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research CentreUniversity of Oxford, John Radcliffe HospitalOxfordUK
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research CentreUniversity of Oxford, Churchill HospitalOxfordUK
| | - Charlotte J Green
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research CentreUniversity of Oxford, Churchill HospitalOxfordUK
| | - Catriona A Charlton
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research CentreUniversity of Oxford, Churchill HospitalOxfordUK
| | - Thomas Cornfield
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research CentreUniversity of Oxford, Churchill HospitalOxfordUK
| | - Jonathan Hazlehurst
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research CentreUniversity of Oxford, Churchill HospitalOxfordUK
- Institute of Metabolism and Systems ResearchUniversity of BirminghamBirminghamUK
- Centre of Endocrinology, Diabetes and MetabolismQueen Elizabeth Hospital Birmingham, Birmingham Health PartnersBirminghamUK
| | - Ahmad Moolla
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research CentreUniversity of Oxford, Churchill HospitalOxfordUK
| | - Sarah White
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research CentreUniversity of Oxford, Churchill HospitalOxfordUK
| | - Jane Francis
- Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of MedicineUniversity of OxfordOxfordUK
| | - Stefan Neubauer
- Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of MedicineUniversity of OxfordOxfordUK
| | - Jeremy FL Cobbold
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research CentreUniversity of Oxford, John Radcliffe HospitalOxfordUK
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research CentreUniversity of Oxford, Churchill HospitalOxfordUK
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research CentreUniversity of Oxford, Churchill HospitalOxfordUK
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Kinoshita T, Shimoda M, Nakashima K, Fushimi Y, Hirata Y, Tanabe A, Tatsumi F, Hirukawa H, Sanada J, Kohara K, Irie S, Kimura T, Nakamura Y, Nishioka M, Obata A, Nakanishi S, Mune T, Kaku K, Kaneto H. Comparison of the effects of three kinds of glucose-lowering drugs on non-alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, open-label, three-arm, active control study. J Diabetes Investig 2020; 11:1612-1622. [PMID: 32329963 PMCID: PMC7610105 DOI: 10.1111/jdi.13279] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 03/13/2020] [Accepted: 04/12/2020] [Indexed: 12/14/2022] Open
Abstract
Aims/Introduction Non‐alcoholic fatty liver disease (NAFLD) is often observed in individuals with type 2 diabetes mellitus, and it is known that the presence of type 2 diabetes mellitus leads to the aggravation of NAFLD. The aim of this study was to compare the possible effects of three kinds of oral hypoglycemic agents on NAFLD in individuals with type 2 diabetes mellitus. Materials and Methods We carried out a prospective clinical trial (a randomized and open‐label study) in patients with type 2 diabetes mellitus and NAFLD. A total of 98 patients were randomly allocated either to the dapagliflozin (n = 32), pioglitazone (n = 33) or glimepiride (n = 33) group, and the patients took these drugs for 28 weeks. The primary end‐point was the change of the liver‐to‐spleen ratio on abdominal computed tomography. Results There was no difference in baseline clinical characteristics among the three groups. Dapagliflozin, pioglitazone and glimepiride ameliorated hyperglycemia similarly. Bodyweight and visceral fat area were significantly decreased only in the dapagliflozin group. Serum adiponectin levels were markedly increased in the pioglitazone group compared with the other two groups. Dapagliflozin and pioglitazone, but not glimepiride, significantly increased the liver‐to‐spleen ratio, and the effects of dapagliflozin and pioglitazone on the liver‐to‐spleen ratio were comparable. Conclusions The present study showed that the decrease of visceral fat area and the increase of adiponectin level contributed to the improvement of NAFLD in patients with type 2 diabetes mellitus. Furthermore, dapagliflozin and pioglitazone exerted equivalent beneficial effects on NAFLD in patients with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action.
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Affiliation(s)
- Tomoe Kinoshita
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Masashi Shimoda
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Koji Nakashima
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Yoshiro Fushimi
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Yurie Hirata
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Akihito Tanabe
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Fuminori Tatsumi
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Hidenori Hirukawa
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Junpei Sanada
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Kenji Kohara
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Shintaro Irie
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Tomohiko Kimura
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Yoshiko Nakamura
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Momoyo Nishioka
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Atsushi Obata
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Shuhei Nakanishi
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Tomoatsu Mune
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
| | - Kohei Kaku
- Kawasaki Medical School, Kurashiki, Japan
| | - Hideaki Kaneto
- Division of Diabetes, Metabolism and Endocrinology, Kawasaki Medical School, Kurashiki, Japan
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Abstract
Background and aim: Sodium-glucose cotransporter (SGLT) 2 is responsible for most of the glucose reabsorption in the kidneys and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In recent years, nonalcoholic steatohepatitis (NASH), the pathogenesis of which is strongly associated with insulin resistance, obesity, and type 2 diabetes, has become a considerable healthcare burden worldwide. However, there is currently no established pharmacotherapy for NASH. Here, we investigated the therapeutic effects of the SGLT2 selective inhibitor ipragliflozin alone and in combination with metformin on NASH in high fat and cholesterol diet-fed KK/Ay type 2 diabetic mice.Results: This diabetic model had hyperglycemia, insulin resistance, and obesity, and also exhibited steatosis, inflammation, and fibrosis in the liver, pathological features resembling those in human NASH. Four-week repeated administration of ipragliflozin significantly improved not only hyperglycemia, insulin resistance, and obesity but also hyperlipidemia and NASH-associated symptoms including hepatic steatosis and fibrosis. In addition, ipragliflozin attenuated inflammation and oxidative stress in the liver. Repeated administration of metformin also significantly improved symptoms of type 2 diabetes with NASH to a comparable degree to that by ipragliflozin. In addition, combination treatment with ipragliflozin and metformin additively improved these symptoms.Conclusions: These results demonstrate that the SGLT2 selective inhibitor ipragliflozin improves not only hyperglycemia but also NASH in type 2 diabetic mice, suggesting that treatment with ipragliflozin alone and in combination with metformin may be effective for treating type 2 diabetes with NASH.
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Affiliation(s)
- Atsuo Tahara
- Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan
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Takeshita Y, Kanamori T, Tanaka T, Kaikoi Y, Kita Y, Takata N, Iida N, Arai K, Yamashita T, Harada K, Gabata T, Nakamura H, Kaneko S, Takamura T. Study Protocol for Pleiotropic Effects and Safety of Sodium-Glucose Cotransporter 2 Inhibitor Versus Sulfonylurea in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. Diabetes Ther 2020; 11:549-560. [PMID: 31956961 PMCID: PMC6995806 DOI: 10.1007/s13300-020-00762-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Clinicopathological analyses revealed that reduction in HbA1c and use of insulin independently contribute to reduction in liver fibrosis scores during the course of nonalcoholic fatty liver disease (NAFLD) development. We will test our hypothesis that lowering glucose and increasing insulin reduce liver fibrosis in NAFLD. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower insulin levels and sulfonylureas increase insulin levels, while both lower glucose levels. METHODS This study is a 48-week, one-center (only Kanazawa University Hospital), open-label, randomized, parallel trial. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily 20 mg tofogliflozin or 0.5 mg glimepiride. The sample size was calculated to be 14 in each group with a significance level of 0.05 and power of 0.90. The design required 40 evaluable patients in this study. The primary endpoint of this study will be the improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. The secondary efficacy endpoints in the present study include organ-specific insulin sensitivity, insulin/glucagon secretion, ectopic fat accumulation, bioelectrical impedance analysis, sympathetic nerve activity, comprehensive gene expression analyses in the liver and blood cells, and gut microbiota profiling. PLANNED OUTCOMES Recruitment into this study started in November 2015 and will end in September 2020, with 40 patients randomized into the two groups. The treatment follow-up of the participants is currently ongoing and is due to finish by the end of 2022. The findings of this trial will be disseminated through peer-reviewed publications and international presentations. TRIAL REGISTRATION This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000020544) and ClinicalTrials.gov (NCT02649465).
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Affiliation(s)
- Yumie Takeshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Takehiro Kanamori
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Takeo Tanaka
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yuka Kaikoi
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yuki Kita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Noboru Takata
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Noriho Iida
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan
| | - Toshifumi Gabata
- Department of Radiology, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Hiroyuki Nakamura
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.
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David-Silva A, Esteves JV, Morais MRPT, Freitas HS, Zorn TM, Correa-Giannella ML, Machado UF. Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice. Diabetes Metab Syndr Obes 2020; 13:739-751. [PMID: 32231437 PMCID: PMC7085338 DOI: 10.2147/dmso.s242282] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 02/29/2020] [Indexed: 12/11/2022] Open
Abstract
PURPOSE NAFLD is a hepatic component of type 2 diabetes mellitus (T2D), in which impaired hepatic glucose production plays an important role. Inhibitors of sodium glucose transporter 2 (SGLT2) reduce glycemia and exert beneficial effects on diabetic complications. Recently, dual SGLT1/2 inhibition has been proposed to be more effective in reducing glycemia. We hypothesized that improving hepatic glucose metabolism induced by SGLT1/2 inhibition could be accompanied by beneficial effects on NAFLD progression. METHODS Glycemic homeostasis, hepatic glucose production and NAFLD features were investigated in obese T2D mice, treated with SGLT1/2 inhibitor phlorizin for 1 week. RESULTS T2D increased glycemia; insulinemia; hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and glucose transporter 2 (Slc2a2 gene); hepatocyte nuclear factors 1A/4A/3B-binding activity in Slc2a2; endogenous glucose production; liver weight, plasma transaminase concentration as well as hepatic inflammation markers, and induced histological signals of non-alcoholic steatohepatitis (NASH, according to NASH-CRN Pathology Committee System). Phlorizin treatment restored all these parameters (mean NASH score reduced from 5.25 to 2.75 P<0.001); however, plasma transaminase concentration was partially reverted and some hepatic inflammation markers remained unaltered. CONCLUSION NAFLD accompanies altered hepatic glucose metabolism in T2D mice and that greatly ameliorated through short-term treatment with the dual SGLT1/2 inhibitor. This suggests that altered hepatic glucose metabolism participates in T2D-related NAFLD and highlights the pharmacological inhibition of SGLTs as a useful approach not only for controlling glycemia but also for mitigating development and/or progression of NAFLD.
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Affiliation(s)
- Aline David-Silva
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - João Victor Esteves
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Mychel Raony P T Morais
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Helayne Soares Freitas
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Telma Maria Zorn
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Maria Lucia Correa-Giannella
- Laboratório de Carboidratos e Radioimunoensaio, LIM-18, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Ubiratan Fabres Machado
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Correspondence: Ubiratan Fabres Machado Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, São Paulo, SP05508-900, BrazilTel +55 11 30917494 Email
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Yabiku K, Nakamoto K, Tsubakimoto M. Effects of Sodium-Glucose Cotransporter 2 Inhibition on Glucose Metabolism, Liver Function, Ascites, and Hemodynamics in a Mouse Model of Nonalcoholic Steatohepatitis and Type 2 Diabetes. J Diabetes Res 2020; 2020:1682904. [PMID: 33457424 PMCID: PMC7785390 DOI: 10.1155/2020/1682904] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 12/08/2020] [Accepted: 12/11/2020] [Indexed: 12/15/2022] Open
Abstract
Many blood glucose-lowering drugs cannot be used once patients with type 2 diabetes (T2D) and nonalcoholic fatty liver disease develop nonalcoholic steatohepatitis (NASH). Therefore, such patients often require insulin treatment. We aimed to determine the effect of sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin monotherapy on glucose metabolism in a mouse model of NASH/T2D, with a focus on its diuretic effects. To imitate ascites and to determine its severity by imaging, meglumine sodium amidotrizoate (MSA) was infused into the abdominal cavities of mice. The reduction in ascites induced by dapagliflozin was compared with that induced by furosemide using microcomputed tomography. The effects of each drug on hemodynamics were also compared. A dapagliflozin-related improvement in glucose tolerance was achieved in mice fed a high-fat diet (HFD) or an HFD + methionine-and-choline-deficient diet (MCDD). In dapagliflozin-treated NASH mice, hypoglycemia was not identified during 24-hour casual blood glucose monitoring. In the dapagliflozin and furosemide-treated groups, the time taken for the resolution of artificial ascites was significantly shorter than in the untreated group, and there were no significant differences between these groups. Furosemide significantly reduced the blood pressure and significantly increased the heart rate of the mice. Dapagliflozin caused a mild decrease in systolic, but not diastolic blood pressure, and the heart rate and circulating catecholamine and renin-aldosterone concentrations were unaffected. Dapagliflozin treatment improved glycemic control in the NASH mice versus untreated mice. Thus, dapagliflozin had a prompt diuretic effect but did not adversely affect the hemodynamics of mice with NASH and T2D. Therefore, it may be useful for the treatment of patients with both T2D and liver cirrhosis.
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Affiliation(s)
- Koichi Yabiku
- University of the Ryukyus, Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, Okinawa, Japan
| | | | - Maho Tsubakimoto
- Department of Radiology, Graduate School of Medical Science, University of the Ryukyus, Okinawa, Japan
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Raj D, Tomar B, Lahiri A, Mulay SR. The gut-liver-kidney axis: Novel regulator of fatty liver associated chronic kidney disease. Pharmacol Res 2019; 152:104617. [PMID: 31881272 DOI: 10.1016/j.phrs.2019.104617] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 12/09/2019] [Accepted: 12/21/2019] [Indexed: 12/12/2022]
Abstract
Increased interest in understanding the liver-kidney axis in health and disease during the last decade unveiled multiple recent evidence that suggested a strong association of fatty liver diseases with chronic kidney disease (CKD). Low-grade systemic inflammation is thought to be the major contributing factor to the pathogenesis of CKD associated with fatty liver. However, other contributing factors largely remained unclear, for example, gut microbiota and intestinal barrier integrity. Homeostasis of the gut microbiome is very crucial for the health of an individual. Imbalance in the gut microbiota leads to various diseases like fatty liver disease and CKD. On the contrary, disease conditions can also distinctly change gut microbiota. In this review, we propose the pathogenic role of the gut-liver-kidney axis in the development and progression of CKD associated with chronic fatty liver diseases, either non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in experimental models and humans. Further, we discuss the therapeutic potential and highlight the future research directions for therapeutic targeting of the gut-liver-kidney axis.
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Affiliation(s)
- Desh Raj
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India
| | - Bhawna Tomar
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Amit Lahiri
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India
| | - Shrikant R Mulay
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.
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Pharmacological Therapy of Non-Alcoholic Fatty Liver Disease: What Drugs Are Available Now and Future Perspectives. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16224334. [PMID: 31703268 PMCID: PMC6888162 DOI: 10.3390/ijerph16224334] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 11/01/2019] [Accepted: 11/03/2019] [Indexed: 12/25/2022]
Abstract
The non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common cause of chronic liver disease as well as the first cause of liver transplantation. NAFLD is commonly associated with metabolic syndrome (MetS), and this is the most important reason why it is extremely difficult to treat this disease bearing in mind the enormous amount of interrelationships between the liver and other systems in maintaining the metabolic health. The treatment of NAFLD is a key point to prevent NASH progression to advanced fibrosis, to prevent cirrhosis and to prevent the development of its hepatic complications (such as liver decompensation and HCC) and even extrahepatic one. A part of the well-known healthy effect of diet and physical exercise in this setting it is important to design the correct pharmaceutical strategy in order to antagonize the progression of the disease. In this regard, the current review has the scope to give a panoramic view on the possible pharmacological treatment strategy in NAFLD patients.
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Tang Y, Sun Q, Bai XY, Zhou YF, Zhou QL, Zhang M. Effect of dapagliflozin on obstructive sleep apnea in patients with type 2 diabetes: a preliminary study. Nutr Diabetes 2019; 9:32. [PMID: 31685792 PMCID: PMC6828696 DOI: 10.1038/s41387-019-0098-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 05/23/2019] [Accepted: 06/13/2019] [Indexed: 12/14/2022] Open
Abstract
Objective The aim of this case-control study was to assess the efficacy of dapagliflozin combined with metformin for type-2 diabetes mellitus (T2DM) with obstructive sleep apnea hypopnea syndrome (OSAHS). Methods A total of 36 patients with newly-diagnosed T2DM and OSAHS were randomized divided into two groups. Eighteen OSAHS patients with T2DM, who were treated with dapagliflozin and metformin, were assigned as the dapagliflozin group. These patients were given dapagliflozin and metformin for 24 weeks between February 2017 and February 2018. Another 18 OSAHS patients with T2DM, who were treated with glimepiride and metformin for 24 weeks, were assigned as the control group. Fasting plasma glucose (FPG) level, postprandial blood glucose (PPG), hemoglobin A1C (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), blood lipids, body mass index (BMI), blood pressure, apnea-hypopnea index (AHI), minimum oxygen saturation (LSpO2), and Epworth Somnolence Scale (ESS) score were measured before and at 24 weeks after the initiation of treatment. Results In the dapagliflozin group, triglyceride (TG), systolic pressure (SBP) and diastolic pressure (DBP) significantly decreased following treatment, while high-density lipoprotein cholesterol (HDL-C) significantly increased (P < 0.05). Furthermore, a reduction in AHI, an increase in LSpO2 and a decrease in ESS score were observed in the dapagliflozin group (P < 0.05), but not in the control group. Moreover, blood glucose, HbA1c, HOMA-IR, and BMI significantly decreased in these two groups, and the decrease was more significant in the dapagliflozin group. Conclusion These present results indicate that dapagliflozin can significantly reduce glucose, BMI, blood pressure and AHI, and improve hypoxemia during sleep and excessive daytime sleepiness, which thereby has potential as an effective treatment approach for OSAHS.
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Affiliation(s)
- Yi Tang
- Department of Endocrinology, The Fifth People's Hospital of Chengdu, 611130, Chengdu, P.R. China
| | - Qin Sun
- Center of Diabetes Mellitus, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, 610072, Chengdu, P. R. China.
| | - Xiao-Yan Bai
- Department of Respiratory, The Fifth People's Hospital of Chengdu, 611130, Chengdu, P.R. China
| | - Yun-Fan Zhou
- Department of Endocrinology, The Third People's Hospital of Chengdu, 610000, Chengdu, P.R. China
| | - Qiong-Lan Zhou
- Department of Endocrinology, People's Hospital of Yilong County, 637676, Yilong, P.R. China
| | - Min Zhang
- Center of Diabetes Mellitus, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, 610072, Chengdu, P. R. China.
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Yanai H, Hakoshima M, Katsuyama H. The Possible Mechanisms for Improvement of Liver Function due to Sodium-Glucose Cotransporter-2 Inhibitors. J Clin Med Res 2019; 11:769-772. [PMID: 31803320 PMCID: PMC6879019 DOI: 10.14740/jocmr4019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 10/18/2019] [Indexed: 12/25/2022] Open
Affiliation(s)
- Hidekatsu Yanai
- Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba, Japan
| | - Mariko Hakoshima
- Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba, Japan
| | - Hisayuki Katsuyama
- Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba, Japan
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Katsiki N, Perakakis N, Mantzoros C. Effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: Ex quo et quo vadimus? Metabolism 2019; 98:iii-ix. [PMID: 31301336 DOI: 10.1016/j.metabol.2019.07.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Accepted: 07/08/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Niki Katsiki
- Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America
| | - Nikolaos Perakakis
- Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America
| | - Christos Mantzoros
- Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America.
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Dokmak A, Almeqdadi M, Trivedi H, Krishnan S. Rise of sodium-glucose cotransporter 2 inhibitors in the management of nonalcoholic fatty liver disease. World J Hepatol 2019; 11:562-573. [PMID: 31388398 PMCID: PMC6669193 DOI: 10.4254/wjh.v11.i7.562] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/12/2019] [Accepted: 06/27/2019] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the Western world. It is more prevalent in male gender, and with increasing age, obesity, and insulin resistance. Besides weight loss, there are limited treatment options. The use of anti-diabetic medications has been studied with mixed results. In this review, we discuss the use of anti-diabetic medications in the management of NAFLD with a specific focus on sodium-glucose cotransporter 2 inhibitors. We shed light on the evidence supporting their use in detail and discuss limitations and future directions.
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Affiliation(s)
- Amr Dokmak
- Division of Medicine, St. Elizabeth’s Medical Center, Brighton, MA 02135, United States
- Tufts University School of Medicine, Boston, MA 02111, United States
| | - Mohammad Almeqdadi
- Division of Medicine, St. Elizabeth’s Medical Center, Brighton, MA 02135, United States
- Tufts University School of Medicine, Boston, MA 02111, United States
| | - Hirsh Trivedi
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
| | - Sandeep Krishnan
- Tufts University School of Medicine, Boston, MA 02111, United States
- Division of Gastroenterology, St. Elizabeth’s Medical Center, Brighton, MA 02135, United States
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Inoue M, Hayashi A, Taguchi T, Arai R, Sasaki S, Takano K, Inoue Y, Shichiri M. Effects of canagliflozin on body composition and hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease. J Diabetes Investig 2019; 10:1004-1011. [PMID: 30461221 PMCID: PMC6626966 DOI: 10.1111/jdi.12980] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 10/22/2018] [Accepted: 11/16/2018] [Indexed: 12/19/2022] Open
Abstract
AIMS/INTRODUCTION Non-alcoholic fatty liver disease is frequently associated with type 2 diabetes, and constitutes an important risk factor for the development of hepatic fibrosis and hepatocellular carcinoma. Because there remains no effective drug therapy for non-alcoholic fatty liver disease associated with type 2 diabetes, we evaluated the efficacy of sodium-glucose cotransporter 2 inhibitor. METHODS AND MATERIALS In the present pilot, prospective, non-randomized, open-label, single-arm study, we evaluated the effect of 100 mg canagliflozin administered once daily for 12 months on serological markers, body composition measured by bioelectrical impedance analysis method and hepatic fat fraction measured by magnetic resonance imaging in type 2 diabetes patients with non-alcoholic fatty liver disease. RESULTS Canagliflozin significantly reduced body and fat mass, and induced a slight decrease in lean body or muscle mass that did not reach significance at 6 and 12 months. Reductions in fat mass in each body segment (trunk, arms and legs) were evident, whereas those in lean body mass were not. The hepatic fat fraction was reduced from a baseline of 17.6 ± 7.5% to 12.0 ± 4.6% after 6 months and 12.1 ± 6.1% after 12 months (P < 0.0005 and P < 0.005), whereas serum liver enzymes and type IV collagen concentrations improved. From a mean baseline hemoglobin A1c of 8.7 ± 1.4%, canagliflozin significantly reduced hemoglobin A1c after 6 and 12 months to 7.3 ± 0.6% and 7.7 ± 0.7% (P < 0.0005 and P < 0.01). CONCLUSIONS Canagliflozin reduced body mass, fat mass and hepatic fat content without significantly reducing muscle mass.
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Affiliation(s)
- Mitsuko Inoue
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
| | - Akinori Hayashi
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
| | - Tomomi Taguchi
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
| | - Riina Arai
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
| | - Sayaka Sasaki
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
| | - Koji Takano
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
| | - Yusuke Inoue
- Department of Diagnostic RadiologyKitasato University School of MedicineKanagawaJapan
| | - Masayoshi Shichiri
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
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Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:7092151. [PMID: 31341533 PMCID: PMC6612399 DOI: 10.1155/2019/7092151] [Citation(s) in RCA: 419] [Impact Index Per Article: 69.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 05/20/2019] [Indexed: 02/08/2023]
Abstract
Cardiovascular disease is a leading cause of death and reduced quality of life, proven by the latest data of the Global Burden of Disease Study, and is only gaining in prevalence worldwide. Clinical trials have identified chronic inflammatory disorders as cardiovascular risks, and recent research has revealed a contribution by various inflammatory cells to vascular oxidative stress. Atherosclerosis and cardiovascular disease are closely associated with inflammation, probably due to the close interaction of inflammation with oxidative stress. Classical therapies for inflammatory disorders have demonstrated protective effects in various models of cardiovascular disease; especially established drugs with pleiotropic immunomodulatory properties have proven beneficial cardiovascular effects; normalization of oxidative stress seems to be a common feature of these therapies. The close link between inflammation and redox balance was also supported by reports on aggravated inflammatory phenotype in the absence of antioxidant defense proteins (e.g., superoxide dismutases, heme oxygenase-1, and glutathione peroxidases) or overexpression of reactive oxygen species producing enzymes (e.g., NADPH oxidases). The value of immunomodulation for the treatment of cardiovascular disease was recently supported by large-scale clinical trials demonstrating reduced cardiovascular mortality in patients with established atherosclerotic disease when treated by highly specific anti-inflammatory therapies (e.g., using monoclonal antibodies against cytokines). Modern antidiabetic cardiovascular drugs (e.g., SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 analogs) seem to share these immunomodulatory properties and display potent antioxidant effects, all of which may explain their successful lowering of cardiovascular risk.
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Takasu T, Takakura S. Effect of ipragliflozin, an SGLT2 inhibitor, on cardiac histopathological changes in a non-diabetic rat model of cardiomyopathy. Life Sci 2019; 230:19-27. [PMID: 31125563 DOI: 10.1016/j.lfs.2019.05.051] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/14/2019] [Accepted: 05/20/2019] [Indexed: 01/14/2023]
Abstract
AIMS We investigated the effect of the selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin on cardiac dysfunction and histopathology in a non-diabetic rat model of cardiomyopathy. MAIN METHODS Ipragliflozin was mixed with chow (0.01%, w/w) and administered to male DahlS.Z-Leprfa/Leprfa (DS/obese) rats for 8 weeks. Male DahlS.Z-Lepr+/Lepr+ (DS/lean) rats of the same age were used as controls. Systolic blood pressure (SBP) and heart rate (HR) were measured every 4 weeks. After 8 weeks of treatment, echocardiography and histopathological examinations were performed. Further, the effect of ipragliflozin on blood and urine parameters were investigated. KEY FINDINGS In the DS/obese rats, ipragliflozin delayed the age-related increase in SBP without affecting HR, reduced left ventricular (LV) mass and intraventricular septal thickness in echocardiography, and ameliorated hypertrophy of cardiomyocytes and LV fibrosis in histopathological examination. Although ipragliflozin significantly increased both urine volume and urinary glucose excretion in DS/obese rats, it did not alter plasma glucose levels. SIGNIFICANCE Ipragliflozin prevented LV hypertrophy and fibrosis in non-diabetic DS/obese rats without affecting plasma glucose levels. These findings suggest that SGLT2 inhibitors have a cardio-protective effect in non-diabetic patients with cardiomyopathy.
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Affiliation(s)
- Toshiyuki Takasu
- Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
| | - Shoji Takakura
- Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan
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Jeznach-Steinhagen A, Ostrowska J, Czerwonogrodzka-Senczyna A, Boniecka I, Shahnazaryan U, Kuryłowicz A. Dietary and Pharmacological Treatment of Nonalcoholic Fatty Liver Disease. ACTA ACUST UNITED AC 2019; 55:medicina55050166. [PMID: 31137547 PMCID: PMC6571590 DOI: 10.3390/medicina55050166] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 02/18/2019] [Accepted: 05/15/2019] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the developed world. Simple hepatic steatosis is mild, but the coexistence of steatohepatitis (NASH) and fibrosis increases the risk of hepatocellular carcinoma. Proper dietary and pharmacological treatment is essential for preventing NAFLD progression. The first-line treatment should include dietary intervention and increased physical activity. The diet should be based on the food pyramid, with a choice of products with low glycemic index, complex carbohydrates in the form of low-processed cereal products, vegetables, and protein-rich products. Usage of insulin-sensitizing substances, pro- and prebiotics, and vitamins should also be considered. Such a therapeutic process is intended to support both liver disease and obesity-related pathologies, including insulin resistance, diabetes, dyslipidemia, and blood hypertension. In the pharmacological treatment of NAFLD, apart from pioglitazone, there are new classes of antidiabetic drugs that are of value, such as glucagon-like peptide 1 analogs and sodium/glucose cotransporter 2 antagonists, while several other compounds that target different pathogenic pathways are currently being tested in clinical trials. Liver biopsies should only be considered when there is a lack of decline in liver enzymes after 6 months of the abovementioned treatment. Dietary intervention is recommended in all patients with NAFLD, while pharmacological treatment is recommended especially for those with NASH and showing significant fibrosis in a biopsy.
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Affiliation(s)
- Anna Jeznach-Steinhagen
- Clinical Dietetics Department, Medical University of Warsaw, 01-445 Warsaw, Poland.
- Diabetologic Outpatients Department, Institute of Mother and Child, 01-211 Warsaw, Poland.
| | - Joanna Ostrowska
- Clinical Dietetics Department, Medical University of Warsaw, 01-445 Warsaw, Poland.
| | | | - Iwona Boniecka
- Clinical Dietetics Department, Medical University of Warsaw, 01-445 Warsaw, Poland.
- Department of General, Oncological, Metabolic and Thoracic Surgery, Military Institute of Aviation Medicine, 01-755 Warsaw, Poland.
| | - Urszula Shahnazaryan
- Department of Internal Diseases and Endocrinology, Medical University of Warsaw, 02-097 Warsaw, Poland.
| | - Alina Kuryłowicz
- Department of Internal Diseases and Endocrinology, Medical University of Warsaw, 02-097 Warsaw, Poland.
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Kim JW, Lee YJ, You YH, Moon MK, Yoon KH, Ahn YB, Ko SH. Effect of sodium-glucose cotransporter 2 inhibitor, empagliflozin, and α-glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes. J Cell Biochem 2019; 120:8534-8546. [PMID: 30474134 DOI: 10.1002/jcb.28141] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Accepted: 11/05/2018] [Indexed: 01/24/2023]
Abstract
OBJECTIVE We investigated the effects of sodium-glucose cotransporter 2 inhibitor, empagliflozin, and α-glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes (T2DM). METHODS Empagliflozin (OLETF-EMPA) or voglibose (OLETF-VOG) was administered to Otsuka Long-Evans Tokushima fatty (OLETF) rats once daily for 12 weeks. Control Long-Evans Tokushima Otsuka (LETO) and OLETF (OLETF-C) rats received saline. RESULTS Blood glucose levels were significantly suppressed in OLETF-EMPA and OLETF-VOG compared with the OLETF-C group. The liver fat content was significantly higher in the OLETF-C group than in the OLETF-EMPA and OLETF-VOG. Hepatic gene expressions involved in gluconeogenesis (glucose 6-phosphatase [G6Pase], fructose-1,6-bisphosphatase [FBP1], and phosphoenolpyruvate carboxykinase [PEPCK]) and lipogenesis (acetyl-CoA carboxylase [ACC], fatty acid synthase [FAS], and sterol regulatory element-binding transcription factor 1c [SREBP-1c]) were significantly decreased in the OLETF-EMPA group compared with other OLETF groups (OLETF-C and OLETF-VOG). Sirtuin 1 (SIRT1) expression level and SIRT1 activity were markedly reduced in OLETF-C rats; however, its expression increased in the OLETF-EMPA and OLETF-VOG. AMP-activated protein kinase (AMPK) phosphorylation level was remarkably increased by empagliflozin treatment in OLETF rats compared with other OLETF groups. Long-term empagliflozin and voglibose treatment reduced hepatic steatosis with suppression of gluconeogenesis and lipogenesis pathway in OLETF rats. CONCLUSION We suggest that this metabolic improvement might be related to SIRT1 and AMPK pathway in T2DM. But empagliflozin is thought to have more advantage to prevent hepatic steatosis than voglibose in T2DM.
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Affiliation(s)
- Ji-Won Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ye-Jee Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Young-Hye You
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Min Kyong Moon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul University College of Medicine, Seoul, Korea
| | - Kun-Ho Yoon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yu-Bae Ahn
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Hyun Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Nakamura I, Maegawa H, Tobe K, Uno S. Safety and Effectiveness of Ipragliflozin for Type 2 Diabetes in Japan: 12-Month Interim Results of the STELLA-LONG TERM Post-Marketing Surveillance Study. Adv Ther 2019; 36:923-949. [PMID: 30767112 PMCID: PMC6824450 DOI: 10.1007/s12325-019-0895-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Indexed: 12/25/2022]
Abstract
Introduction The present interim report of the STELLA-LONG TERM study aimed to examine the safety and effectiveness of ipragliflozin in real-word clinical practice in Japan using data up to 12 months. We also evaluated the effect of ipragliflozin on aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in patients with normal vs. abnormal liver function. Methods This is an ongoing 3-year post-marketing surveillance study. We analyzed data from Japanese type 2 diabetes mellitus (T2DM) patients who were first prescribed ipragliflozin between 17 July 2014 and 16 October 2015 at participating centers in Japan, and whose data were locked by 16 January 2018. The incidence of adverse drug reactions (ADRs) was evaluated for safety. Changes in glycemic control and body weight were evaluated for effectiveness. The effect on liver function was evaluated by changes in the fatty liver index, and changes in AST and ALT were evaluated in patients with normal and abnormal liver function. Results The safety analysis set comprised 11,051 patients and the efficacy analysis set comprised 8788 patients. The incidence rates of ADRs and serious ADRs were 14.6% (1616/11,051) and 0.97% (107/11,051), respectively. Significant reductions (all P < 0.001 vs. baseline, paired t test) in glycated hemoglobin (− 0.8%), fasting plasma glucose (− 31.9 mg/dL), body weight (− 2.9 kg), and fatty liver index (− 8.7) were observed. In patients with normal liver function at baseline, no clinically significant changes in AST and ALT were observed. In patients with abnormal liver function at baseline, clinically and statistically significant decreases (P < 0.05 vs. baseline, two-sample t test) in AST (− 9.0 U/L) and ALT (− 14.7 U/L) levels were observed. Conclusion Ipragliflozin was effective and well tolerated in Japanese patients with T2DM over 12 months in the real-world clinical setting. Improvements in liver function parameters (AST and ALT) were observed in T2DM patients with abnormal liver function. Trial Registration ClinicalTrials.gov identifier, NCT02479399. Funding Astellas Pharma Inc., Japan.
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Affiliation(s)
| | - Hiroshi Maegawa
- Department of Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Kazuyuki Tobe
- First Department of Internal Medicine, University of Toyama, Toyama, Japan
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Cusi K, Bril F, Barb D, Polidori D, Sha S, Ghosh A, Farrell K, Sunny NE, Kalavalapalli S, Pettus J, Ciaraldi TP, Mudaliar S, Henry RR. Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes. Diabetes Obes Metab 2019; 21:812-821. [PMID: 30447037 DOI: 10.1111/dom.13584] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 11/06/2018] [Accepted: 11/14/2018] [Indexed: 12/17/2022]
Abstract
AIM To evaluate the impact of the sodium glucose co-transporter 2 inhibitor canagliflozin on intrahepatic triglyceride (IHTG) accumulation and its relationship to changes in body weight and glucose metabolism. MATERIALS AND METHODS In this double-blind, parallel-group, placebo-controlled, 24-week trial subjects with inadequately controlled type 2 diabetes mellitus (T2DM; HbA1c = 7.7% ± 0.7%) from two centres were randomly assigned (1:1) to canagliflozin 300 mg or placebo. We measured IHTG by proton-magnetic resonance spectroscopy (primary outcome), hepatic/muscle/adipose tissue insulin sensitivity during a 2-step euglycaemic insulin clamp, and beta-cell function during a mixed meal tolerance test. Analyses were per protocol. RESULTS Between 8 September 2014-13 June 2016, 56 patients were enrolled. Canagliflozin reduced HbA1c (placebo-subtracted change: -0.71% [-1.08; -0.33]) and body weight (-3.4% [-5.4; -1.4]; both P ≤ 0.001). A numerically larger absolute decrease in IHTG occurred with canagliflozin (-4.6% [-6.4; -2.7]) versus placebo (-2.4% [-4.2; -0.6]; P = 0.09). In patients with non-alcoholic fatty liver disease (n = 37), the decrease in IHTG was -6.9% (-9.5; -4.2) versus -3.8% (-6.3; -1.3; P = 0.05), and strongly correlated with the magnitude of weight loss (r = 0.69, P < 0.001). Body weight loss ≥5% with a ≥30% relative reduction in IHTG occurred more often with canagliflozin (38% vs. 7%, P = 0.009). Hepatic insulin sensitivity improved with canagliflozin (P < 0.01), but not muscle or adipose tissue insulin sensitivity. Beta-cell glucose sensitivity, insulin clearance, and disposition index improved more with canagliflozin (P < 0.05). CONCLUSIONS Canagliflozin improves hepatic insulin sensitivity and insulin secretion and clearance in patients with T2DM. IHTG decreases in proportion to the magnitude of body weight loss, which tended to be greater and occur more often with canagliflozin.
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Affiliation(s)
- Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida
- Malcom Randall Veterans Administration Medical Center, Gainesville, Florida
| | - Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida
| | - Diana Barb
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida
| | - David Polidori
- Janssen Research & Development, LLC, San Diego, California
| | - Sue Sha
- Janssen Research & Development, LLC, Raritan, New Jersey
| | - Atalanta Ghosh
- Janssen Research & Development, LLC, Raritan, New Jersey
| | | | - Nishanth E Sunny
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida
| | - Srilaxmi Kalavalapalli
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida
| | - Jeremy Pettus
- VA San Diego Healthcare System and Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, California
| | - Theodore P Ciaraldi
- VA San Diego Healthcare System and Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, California
| | - Sunder Mudaliar
- VA San Diego Healthcare System and Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, California
| | - Robert R Henry
- VA San Diego Healthcare System and Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, California
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