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Diabetic Liver Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 March 2021) | Viewed by 60298

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Dr. Yoshio Sumida

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1. Department of Hepatology and Pancreatology, Aichi Medical University of Medicine, Nagakute, Aichi, Japan
2. Japan Strategic Medical Administration Research Center (J-SMARC), Nagoya, Aichi, Japan
Interests: nonalcoholic steatohepatitis; oxidative stress; hepatic fibrosis; diabetes mellitus; liver cirrhosis; hepatocellular carcinoma
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Special Issue Information

Dear Colleagues,

Nonalcoholic fatty liver disease (NAFLD) which is the most prevalent chronic liver disease, is associated with type 2 diabetes (T2D). Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to cirrhosis, hepatocellular carcinoma (HCC), and hepatic failure. Liver-related mortality is the 3rd leading cause in T2D patients. NASH can be called “diabetic liver disease (DLD)”. Accumulating evidence shows that PNPLA3 SNP is associated with fibrosis progression or HCC development. This Special Issue will include papers investigating the pathological mechanisms of T2DM and liver diseases such as NASH, and diagnostics using new biomarkers. Furthermore, experimental in vitro and in vivo studies and clinical studies examining potential new approaches to attenuate DLD are welcome. This Special Issue welcomes original research and review papers.

Keywords

Nonalcoholic fatty liver disease
Hepatocellular carcinoma
Nonalcoholic steatohepatitis
Type 2 diabetes
Hepatic fibrosis
Liver cirrhosis
PNPLA3

Published Papers (10 papers)

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Research

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21 pages, 2840 KiB

Open AccessArticle

Risperidone Exacerbates Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Renal Impairment in Obese Mice

by Hsiao-Pei Tsai, Po-Hsun Hou, Frank-Chiahung Mao, Chia-Chia Chang, Wei-Cheng Yang, Ching-Feng Wu, Huei-Jyuan Liao, Tzu-Chun Lin, Lan-Szu Chou, Li-Wei Hsiao and Geng-Ruei Chang

Int. J. Mol. Sci. 2021, 22(1), 409; https://doi.org/10.3390/ijms22010409 - 02 Jan 2021

Cited by 22 | Viewed by 4658

Abstract

Risperidone, a second-generation antipsychotic drug used for schizophrenia treatment with less-severe side effects, has recently been applied in major depressive disorder treatment. The mechanism underlying risperidone-associated metabolic disturbances and liver and renal adverse effects warrants further exploration. This research explores how risperidone influences weight, glucose homeostasis, fatty liver scores, liver damage, and renal impairment in high-fat diet (HFD)-administered C57BL6/J mice. Compared with HFD control mice, risperidone-treated obese mice exhibited increases in body, liver, kidney, and retroperitoneal and epididymal fat pad weights, daily food efficiency, serum triglyceride, blood urea nitrogen, creatinine, hepatic triglyceride, and aspartate aminotransferase, and alanine aminotransferase levels, and hepatic fatty acid regulation marker expression. They also exhibited increased insulin resistance and glucose intolerance but decreased serum insulin levels, Akt phosphorylation, and glucose transporter 4 expression. Moreover, their fatty liver score and liver damage demonstrated considerable increases, corresponding to increases in sterol regulatory element-binding protein 1 mRNA, fatty acid-binding protein 4 mRNA, and patatin-like phospholipid domain containing protein 3 expression. Finally, these mice demonstrated renal impairment, associated with decreases in glutathione peroxidase, superoxide dismutase, and catalase levels. In conclusion, long-term administration of risperidone may exacerbate diabetes syndrome, nonalcoholic fatty liver disease, and kidney injury. Full article

(This article belongs to the Special Issue Diabetic Liver Disease)

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14 pages, 2511 KiB

Open AccessArticle

Intracellular Toxic Advanced Glycation End-Products Promote the Production of Reactive Oxygen Species in HepG2 Cells

by Akiko Sakasai-Sakai, Takanobu Takata and Masayoshi Takeuchi

Int. J. Mol. Sci. 2020, 21(14), 4861; https://doi.org/10.3390/ijms21144861 - 09 Jul 2020

Cited by 19 | Viewed by 3194

Abstract

Hepatocyte cell death is a key process in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the factors responsible for and mechanisms underlying NASH-related cell death have not yet been elucidated in detail. We herein investigated the effects of intracellular glyceraldehyde (GA)-derived advanced glycation end-products (AGEs), named toxic AGEs (TAGE), on the production of reactive oxygen species (ROS), which have been implicated in the pathogenesis of NASH. Cell death related to intracellular TAGE accumulation was eliminated in the hepatocyte carcinoma cell line HepG2 by the antioxidant effects of N-acetyl-L-cysteine. The intracellular accumulation of TAGE increased ROS production and the expression of Nrf2, including its downstream gene. These results suggest that ROS are produced in association with the accumulation of TAGE and are a direct trigger for cell death. We also investigated the factors responsible for these increases in ROS. Catalase activity did not decrease with the accumulation of TAGE, while mitochondrial membrane depolarization was enhanced in cells treated with GA. These results indicate that TAGE play an important role in mitochondrial abnormalities and increases in ROS production, both of which are characteristic features of NASH. The suppression of TAGE accumulation has potential as a new therapeutic target in the progression of NASH. Full article

(This article belongs to the Special Issue Diabetic Liver Disease)

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17 pages, 5633 KiB

Open AccessArticle

Combined Treatment with Sodium-Glucose Cotransporter-2 Inhibitor (Canagliflozin) and Dipeptidyl Peptidase-4 Inhibitor (Teneligliptin) Alleviates NASH Progression in A Non-Diabetic Rat Model of Steatohepatitis

by Takahiro Ozutsumi, Tadashi Namisaki, Naotaka Shimozato, Kosuke Kaji, Yuki Tsuji, Daisuke Kaya, Yukihisa Fujinaga, Masanori Furukawa, Keisuke Nakanishi, Shinya Sato, Yasuhiko Sawada, Soichiro Saikawa, Koh Kitagawa, Hiroaki Takaya, Hideto Kawaratani, Mitsuteru Kitade, Kei Moriya, Ryuichi Noguchi, Takemi Akahane, Akira Mitoro and Hitoshi Yoshiji Show full author list Hide full author list

Int. J. Mol. Sci. 2020, 21(6), 2164; https://doi.org/10.3390/ijms21062164 - 21 Mar 2020

Cited by 12 | Viewed by 3621

Abstract

Hepatocellular carcinoma (HCC) is the strongest independent predictor of mortality in non-alcoholic steatohepatitis (NASH)-related cirrhosis. The effects and mechanisms of combination of sodium-dependent glucose cotransporter inhibitor and canagliflozin (CA) and dipeptidyl peptidase-4 inhibitor and teneligliptin (TE) on non-diabetic NASH progression were examined. CA and TE suppressed choline-deficient, L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. CA alone or with TE significantly decreased proinflammatory cytokine expression. CA and TE significantly attenuated hepatic lipid peroxidation. In vitro studies showed that TE alone or with CA inhibited cell proliferation and TGF-β1 and α1 (I)-procollagen mRNA expression in Ac-HSCs. CA+TE inhibited liver fibrogenesis by attenuating hepatic lipid peroxidation and inflammation and by inhibiting Ac-HSC proliferation with concomitant attenuation of hepatic lipid peroxidation. Moreover, CA+TE suppressed in vivo angiogenesis and oxidative DNA damage. CA or CA+TE inhibited HCC cells and human umbilical vein endothelial cell (HUVEC) proliferation. CA+TE suppressed vascular endothelial growth factor expression and promoted increased E-cadherin expression in HUVECs. CA+TE potentially exerts synergistic effects on hepatocarcinogenesis prevention by suppressing HCC cell proliferation and angiogenesis and concomitantly reducing oxidative stress and by inhibiting angiogenesis with attenuation of oxidative stress. CA+TE showed chemopreventive effects on NASH progression compared with single agent in non-diabetic rat model of NASH, concurrent with Ac-HSC and HCC cell proliferation, angiogenesis oxidative stress, and inflammation. Both agents are widely, safely used in clinical practice; combined treatment may represent a potential strategy against NASH. Full article

(This article belongs to the Special Issue Diabetic Liver Disease)

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11 pages, 2041 KiB

Open AccessArticle

FIB-4 Index and Diabetes Mellitus Are Associated with Chronic Kidney Disease in Japanese Patients with Non-Alcoholic Fatty Liver Disease

by Yuya Seko, Kohta Yano, Aya Takahashi, Shinya Okishio, Seita Kataoka, Keiichiroh Okuda, Naoki Mizuno, Masashi Takemura, Hiroyoshi Taketani, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Takeshi Okanoue and Yoshito Itoh

Int. J. Mol. Sci. 2020, 21(1), 171; https://doi.org/10.3390/ijms21010171 - 25 Dec 2019

Cited by 17 | Viewed by 3245

Abstract

Non-alcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). The aim of this retrospective study was to determine the risk factors for progression of CKD in patients with biopsy-proven NAFLD including patatin-like phospholipase domain containing 3 (PNPLA3) polymorphism. A total of 344 patients with biopsy-proven NAFLD were enrolled consecutively in this study. Multivariate analysis identified males (odds ratio (OR) 5.46), age (per 1 year, OR 1.07), and FIB-4 index (≥1.30, OR 3.85) as factors associated with CKD. Of the 154 patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min, 30 had a deterioration in CKD stage and 15 developed CKD after 3 years. Multivariate analysis identified diabetes mellitus (OR 2.44) as a risk factor for deterioration in CKD stage, while diabetes mellitus (OR 21.54) and baseline eGFR (per 1 mL/min OR 0.88) were risk factors for development of CKD. PNPLA3 did not affect the change in eGFR. In NAFLD patients, a high FIB-4 index was associated with CKD to increases in the index linked to reductions in eGFR. In order to prevent development of CKD, an appropriate therapy focusing on renal function is needed for NAFLD patients, especially those with diabetes. Full article

(This article belongs to the Special Issue Diabetic Liver Disease)

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Review

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19 pages, 1377 KiB

Open AccessReview

Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications

by Jiezhong Chen and Luis Vitetta

Int. J. Mol. Sci. 2020, 21(15), 5214; https://doi.org/10.3390/ijms21155214 - 23 Jul 2020

Cited by 141 | Viewed by 10058

Abstract

Gut microbiota dysregulation plays a key role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) through its metabolites. Therefore, the restoration of the gut microbiota and supplementation with commensal bacterial metabolites can be of therapeutic benefit against the disease. In this review, we summarize the roles of various bacterial metabolites in the pathogenesis of NAFLD and their therapeutic implications. The gut microbiota dysregulation is a feature of NAFLD, and the signatures of gut microbiota are associated with the severity of the disease through altered bacterial metabolites. Disturbance of bile acid metabolism leads to underactivation of bile acid receptors FXR and TGR5, causal for decreased energy expenditure, increased lipogenesis, increased bile acid synthesis and increased macrophage activity. Decreased production of butyrate results in increased intestinal inflammation, increased gut permeability, endotoxemia and systemic inflammation. Dysregulation of amino acids and choline also contributes to lipid accumulation and to a chronic inflammatory status. In some NAFLD patients, overproduction of ethanol produced by bacteria is responsible for hepatic inflammation. Many approaches including probiotics, prebiotics, synbiotics, faecal microbiome transplantation and a fasting-mimicking diet have been applied to restore the gut microbiota for the improvement of NAFLD. Full article

(This article belongs to the Special Issue Diabetic Liver Disease)

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22 pages, 614 KiB

Open AccessReview

Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

by Yoshio Sumida, Masashi Yoneda, Hidenori Toyoda, Satoshi Yasuda, Toshifumi Tada, Hideki Hayashi, Yoichi Nishigaki, Yusuke Suzuki, Takafumi Naiki, Asahiro Morishita, Hiroshi Tobita, Shuichi Sato, Naoto Kawabe, Shinya Fukunishi, Tadashi Ikegami, Takaomi Kessoku, Yuji Ogawa, Yasushi Honda, Takashi Nakahara, Kensuke Munekage, Tsunehiro Ochi, Koji Sawada, Atsushi Takahashi, Taeang Arai, Tomomi Kogiso, Satoshi Kimoto, Kengo Tomita, Kazuo Notsumata, Michihiro Nonaka, Kazuhito Kawata, Taro Takami, Takashi Kumada, Eiichi Tomita, Takeshi Okanoue, Atsushi Nakajima and Japan Study Group of NAFLD (JSG-NAFLD) Show full author list Hide full author list

Int. J. Mol. Sci. 2020, 21(14), 4939; https://doi.org/10.3390/ijms21144939 - 13 Jul 2020

Cited by 8 | Viewed by 4960

Abstract

Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called “diabetic hepatopathy or diabetic liver disease”. NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy. Full article

(This article belongs to the Special Issue Diabetic Liver Disease)

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18 pages, 412 KiB

Open AccessReview

Epidemiology, Pathogenesis, and Diagnostic Strategy of Diabetic Liver Disease in Japan

by Yoshio Sumida, Toshihide Shima, Yasuhide Mitsumoto, Takafumi Katayama, Atsushi Umemura, Kanji Yamaguchi, Yoshito Itoh, Masashi Yoneda and Takeshi Okanoue

Int. J. Mol. Sci. 2020, 21(12), 4337; https://doi.org/10.3390/ijms21124337 - 18 Jun 2020

Cited by 22 | Viewed by 3409

Abstract

Type 2 diabetes (T2D) is closely associated with nonalcoholic fatty liver disease (NAFLD). Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to cirrhosis, hepatocellular carcinoma (HCC), and hepatic decompensation. Patients with T2D have twice the risk of HCC incidence compared with those without T2D. Because the hepatic fibrosis grade is the main determinant of mortality in patients with NAFLD, identifying patients with advanced fibrosis using non-invasive tests (NITs) or imaging modalities is crucial. Globally, the fibrosis-4 index (FIB-4 index), NAFLD fibrosis score, and enhanced liver fibrosis test have been established to evaluate hepatic fibrosis. Two-step algorithms using FIB-4 index as first triaging tool are globally accepted. It remains unknown which kinds of NITs or elastography are best as the second step tool. In Japan, type IV collagen 7s or the CA-fibrosis index (comprising type IV collagen 7s and aspartate aminotransferase (AST)) is believed to precisely predict advanced fibrosis in NAFLD. Patients with NAFLD who have high non-invasive test results should be screened for HCC or esophageal varices. Risk factors of rapid fibrosis progression in NAFLD includes age, severe obesity, presence of T2D, menopause in women, and a patatin-like phospholipase domain containing the 3 GG genotype. Patients with NAFLD who have these risk factors should be intensively treated with lifestyle modification or pharmacotherapies for preventing liver-related mortality. Full article

(This article belongs to the Special Issue Diabetic Liver Disease)

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14 pages, 1548 KiB

Open AccessReview

Elastography Techniques for the Assessment of Liver Fibrosis in Non-Alcoholic Fatty Liver Disease

by Yasushi Honda, Masato Yoneda, Kento Imajo and Atsushi Nakajima

Int. J. Mol. Sci. 2020, 21(11), 4039; https://doi.org/10.3390/ijms21114039 - 05 Jun 2020

Cited by 34 | Viewed by 8550

Abstract

Non-alcoholic fatty liver disease (NAFLD) is expected to increase in prevalence because of the ongoing epidemics of obesity and diabetes, and it has become a major cause of chronic liver disease worldwide. Liver fibrosis is associated with long-term outcomes in patients with NAFLD. Liver biopsy is recommended as the gold standard method for the staging of liver fibrosis. However, it has several problems. Therefore, simple and noninvasive methods for the diagnosis and staging of liver fibrosis are urgently needed in place of biopsy. This review discusses recent studies of elastography techniques (vibration-controlled transient elastography, point shear wave elastography, two-dimensional shear wave elastography, and magnetic resonance elastography) that can be used for the assessment of liver fibrosis in patients with NAFLD. Full article

(This article belongs to the Special Issue Diabetic Liver Disease)

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17 pages, 1822 KiB

Open AccessReview

The Role of Insulin Resistance and Diabetes in Nonalcoholic Fatty Liver Disease

by Hideki Fujii, Norifumi Kawada and Japan Study Group of NAFLD (JSG-NAFLD)

Int. J. Mol. Sci. 2020, 21(11), 3863; https://doi.org/10.3390/ijms21113863 - 29 May 2020

Cited by 121 | Viewed by 8268

Abstract

Nonalcoholic fatty liver disease (NAFLD) consists of the entire spectrum of fatty liver disease in patients without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) to cirrhosis, with NASH recently shown as an important cause of hepatocellular carcinoma (HCC). There is a close relationship between insulin resistance (IR) and NAFLD, with a five-fold higher prevalence of NAFLD in patients with type 2 diabetes (T2DM) compared to that in patients without T2DM. IR is involved in the progression of disease conditions such as steatosis and NASH, as well as hepatic fibrosis progression. The mechanisms underlying these processes involve genetic factors, hepatic fat accumulation, alterations in energy metabolism, and inflammatory signals derived from various cell types including immune cells. In NASH-associated fibrosis, the principal cell type responsible for extracellular matrix production is the hepatic stellate cell (HSC). HSC activation by IR involves “direct” and “indirect” pathways. This review will describe the molecular mechanisms of inflammation and hepatic fibrosis in IR, the relationship between T2DM and hepatic fibrosis, and the relationship between T2DM and HCC in patients with NAFLD. Full article

(This article belongs to the Special Issue Diabetic Liver Disease)

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22 pages, 1900 KiB

Open AccessReview

Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis

by Yoshio Sumida, Masashi Yoneda, Katsutoshi Tokushige, Miwa Kawanaka, Hideki Fujii, Masato Yoneda, Kento Imajo, Hirokazu Takahashi, Yuichiro Eguchi, Masafumi Ono, Yuichi Nozaki, Hideyuki Hyogo, Masahiro Koseki, Yuichi Yoshida, Takumi Kawaguchi, Yoshihiro Kamada, Takeshi Okanoue, Atsushi Nakajima and Japan Study Group of NAFLD (JSG-NAFLD)

Int. J. Mol. Sci. 2020, 21(6), 1907; https://doi.org/10.3390/ijms21061907 - 11 Mar 2020

Cited by 46 | Viewed by 8946

Abstract

Liver-related diseases are the third-leading causes (9.3%) of mortality in type 2 diabetes (T2D) in Japan. T2D is closely associated with nonalcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. No pharmacotherapies are established for NASH patients with T2D. Though vitamin E is established as a first-line agent for NASH without T2D, its efficacy for NASH with T2D recently failed to be proven. The effects of pioglitazone on NASH histology with T2D have extensively been established, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and NAFLD (LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin has already entered the phase 3 trial (DEAN study). A key clinical need is to determine the kinds of antidiabetic drugs that are the most appropriate for the treatment of NASH to prevent the progression of hepatic fibrosis, resulting in HCC or liver-related mortality without increasing the risk of cardiovascular or renal events. Combination therapies, such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide/GLP-1, are under development. This review focused on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2D. Full article

(This article belongs to the Special Issue Diabetic Liver Disease)

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