|
1
|
Yadav M, Verma S, Tiwari P, Mugale MN. Unraveling the mechanisms of hepatogenous diabetes and its therapeutic perspectives. Life Sci 2024; 353:122934. [PMID: 39089644 DOI: 10.1016/j.lfs.2024.122934] [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: 05/09/2024] [Revised: 06/26/2024] [Accepted: 07/25/2024] [Indexed: 08/04/2024]
Abstract
The review focused mainly on the pathogenesis of hepatogenous diabetes (HD) in liver cirrhosis (LC). This review reveals parallels between the mechanisms of metabolic dysfunction observed in LC and type II diabetes (T2DM), suggesting a shared pathway leading to HD. It underscores the role of insulin in HD pathogenesis, highlighting key factors such as insulin signaling, glucose metabolism, insulin resistance (IR), and the influence of adipocytes. Furthermore, the impact of adipose tissue accumulation, fatty acid metabolism, and pro-inflammatory cytokines like Tumor necrosis factor-α (TNF-α) on IR are discussed in the context of HD. Altered signaling pathways, disruptions in the endocrine system, liver inflammation, changes in muscle mass and composition, and modifications to the gut microbiota collectively contribute to the complex interplay linking cirrhosis and HD. This study highlights how important it is to identify and treat this complex condition in cirrhotic patients by thoroughly analyzing the link between cirrhosis, IR, and HD. It also emphasizes the vitality of targeted interventions. Cellular and molecular investigations into IR have revealed potential therapeutic targets for managing and preventing HD.
Collapse
Affiliation(s)
- Manisha Yadav
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Smriti Verma
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Purnima Tiwari
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India
| | - Madhav Nilakanth Mugale
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
| |
Collapse
|
|
2
|
Sánchez-Salgado JC, Estrada-Soto S, García-Jiménez S, Montes S, Gómez-Zamudio J, Villalobos-Molina R. Analysis of Flavonoids Bioactivity for Cholestatic Liver Disease: Systematic Literature Search and Experimental Approaches. Biomolecules 2019; 9:biom9030102. [PMID: 30875780 PMCID: PMC6468533 DOI: 10.3390/biom9030102] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 03/07/2019] [Accepted: 03/07/2019] [Indexed: 12/12/2022] Open
Abstract
Flavonoids are naturally occurring compounds that show health benefits on the liver. However, there is little investigation about identification and evaluation of new flavonoid-containing drugs for cholestatic liver disease, one of the most common liver illnesses. We aimed to a systematic search regarding efficacy of flavonoids for treatment of cholestatic liver disease, and then evaluate naringenin (NG) as representative flavonoid in an obstructive cholestasis model. We searched for information of experimental and clinical studies in four major databases without time and language limits. Intervention was defined as any flavonoid derivate compared with other flavonoid, placebo, or without comparator. In addition, we evaluated NG on a bile duct-ligated model in order to contribute evidence of its actions. Eleven experimental reports that support the efficacy of flavonoids in cholestatic liver disease were identified. However, there was no homogeneity in efficacy endpoints evaluated and methodology. On the other hand, NG showed beneficial effects by improving specific metabolic (cholesterol and lipoproteins) and liver damage (bilirubin and alkaline phosphatase) biomarkers. The review lacks homogeneous evidence about efficacy of flavonoids in experimental settings, and is susceptible to risk for bias. NG only showed improvements in specific disease biomarkers. More investigation is still needed to determine its potential for drug development.
Collapse
Affiliation(s)
- Juan Carlos Sánchez-Salgado
- Instituto de Medicina Molecular y Ciencias Avanzadas, Mexico City 01900, Mexico.
- Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, MOR 62209, Mexico.
| | - Samuel Estrada-Soto
- Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, MOR 62209, Mexico.
| | - Sara García-Jiménez
- Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, MOR 62209, Mexico.
| | - Sergio Montes
- Instituto Nacional de Neurología y Neurocirugía, Mexico City 14269, Mexico.
| | - Jaime Gómez-Zamudio
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, México City 06720, Mexico.
| | - Rafael Villalobos-Molina
- Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Mexico.
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México 04510, México.
| |
Collapse
|
|
3
|
Kawaguchi Y, Mizuta T. Interaction between hepatitis C virus and metabolic factors. World J Gastroenterol 2014; 20:2888-2901. [PMID: 24659880 PMCID: PMC3961972 DOI: 10.3748/wjg.v20.i11.2888] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/15/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection disrupts the normal metabolism processes, but is also influenced by several of the host’s metabolic factors. An obvious and significantly detrimental pathophysiological feature of HCV infection is insulin resistance in hepatic and peripheral tissues. Substantial research efforts have been put forth recently to elucidate the molecular mechanism of HCV-induced insulin resistance, and several cytokines, such as tumor necrosis factor-α, have been identified as important contributors to the development of insulin resistance in the distant peripheral tissues of HCV-infected patients and animal models. The demonstrated etiologies of HCV-induced whole-body insulin resistance include oxidative stress, lipid metabolism abnormalities, hepatic steatosis and iron overload. In addition, myriad effects of this condition have been characterized, including glucose intolerance, resistance to antiviral therapy, progression of hepatic fibrosis, development of hepatocellular carcinoma, and general decrease in quality of life. Metabolic-related conditions and disorders, such as visceral obesity and diabetes mellitus, have been shown to synergistically enhance HCV-induced metabolic disturbance, and are associated with worse prognosis. Yet, the molecular interactions between HCV-induced metabolic disturbance and host-associated metabolic factors remain largely unknown. The diet and lifestyle recommendations for chronic hepatitis C are basically the same as those for obesity, diabetes, and metabolic syndrome. Specifically, patients are suggested to restrict their dietary iron intake, abstain from alcohol and tobacco, and increase their intake of green tea and coffee (to attain the beneficial effects of caffeine and polyphenols). While successful clinical management of HCV-infected patients with metabolic disorders has also been achieved with some anti-diabetic (i.e., metformin) and anti-lipid (i.e., statins) medications, it is recommended that sulfonylurea and insulin be avoided.
Collapse
|
|
4
|
Shan WF, Chen BQ, Zhu SJ, Jiang L, Zhou YF. Effects of GLUT4 expression on insulin resistance in patients with advanced liver cirrhosis. J Zhejiang Univ Sci B 2011; 12:677-82. [PMID: 21796809 DOI: 10.1631/jzus.b1100001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Decreased glucose tolerance and diabetes are frequently observed in advanced liver cirrhosis patients and may be related to insulin resistance. Glucose transporter-4 (GLUT4), one of the most important glucose transporters, plays a key role in the development of type 2 diabetes. In order to study the mechanism of insulin resistance in liver cirrhosis patients, we measured the insulin sensitivity index and determined the GLUT4 protein and mRNA contents of skeletal muscle by Western blotting and reverse transcription-polymerase chain reaction (RT-PCR), respectively, in normal people and liver cirrhosis patients. The results showed that the levels of glucose, insulin, and C-peptide in two liver cirrhosis groups were higher and the insulin sensitivity index lower than those of the normal control group. The sensitivity of insulin may decrease with the decline of liver function. However, the contents of GLUT4 protein and mRNA in patients with advanced liver cirrhosis were similar to those of normal controls. In conclusion, insulin resistance is observed in patients with advanced liver cirrhosis but may not be correlated with the skeletal contents of GLUT4 protein and mRNA.
Collapse
Affiliation(s)
- Wei-Feng Shan
- Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | | | | | | | | |
Collapse
|
|
5
|
Meng QH, Wang JH, Yu HW, Li J, Feng YM, Hou W, Zhang J, Zhang Q, Wang X, Wang X, Liu Y. Resting energy expenditure and substrate metabolism in Chinese patients with acute or chronic hepatitis B or liver cirrhosis. Intern Med 2010; 49:2085-91. [PMID: 20930434 DOI: 10.2169/internalmedicine.49.3967] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Patients with liver disease usually have an imbalanced nutrient and energy metabolism that leads to malnutrition and seriously affects their prognosis. Therefore, it is of great clinical interest to understand the resting energy expenditure (REE) and oxidation rates of glucose, fat, and protein in these patients. METHODS A total of 315 patients with liver diseases caused by hepatitis B virus were categorized into three groups: 20 acute hepatitis patients, 142 chronic hepatitis patients and 153 liver cirrhosis patients. The REE and the oxidation rates of glucose, fat and protein were assessed by indirect heat measurement. Energy intake data were also collected which were compared with the REE results. RESULTS The REE per kg (REE/kg) were 27.34 ± 5.46 kJ/kg, 21.67 ± 5.01 kJ/kg and 19.07 ± 4.45 kJ/kg in acute, chronic hepatitis and liver cirrhosis patients (p=0.000), respectively. Respiratory quotient (RQ) tended to be lower in patients with chronic hepatitis and liver cirrhosis than that in acute hepatitis patients (p=0.023). Energy, protein and carbohydrate intakes were lower in liver cirrhosis patients. CONCLUSION These data demonstrated that Chinese patients with chronic hepatitis B and liver cirrhosis had lower energy expenditure and abnormal substrate metabolism. Patients with chronic hepatitis and cirrhosis had a higher protein oxidation rate and a lower carbohydrate oxidation rate compared with acute hepatitis patients.
Collapse
Affiliation(s)
- Qing-Hua Meng
- Department of Hepatology, Capital University of Medical Science Affiliated Beijing You An Hospital, Beijing, China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
6
|
Fan CL, Wu YJ, Duan ZP, Zhang B, Dong PL, Ding HG. Resting energy expenditure and glucose, protein and fat oxidation in severe chronic virus hepatitis B patients. World J Gastroenterol 2008; 14:4365-4369. [PMID: 18666327 PMCID: PMC2731190 DOI: 10.3748/wjg.14.4365] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2008] [Revised: 05/23/2008] [Accepted: 05/30/2008] [Indexed: 02/06/2023] Open
Abstract
AIM To study and determine the resting energy expenditure (REE) and oxidation rates of glucose, fat and protein in severe chronic hepatitis B patients. METHODS A total of 100 patients with liver diseases were categorized into three groups: 16 in the acute hepatitis group, 56 in the severe chronic hepatitis group, and 28 in the cirrhosis group. The REE and the oxidation rates of glucose, fat and protein were assessed by indirect heat measurement using the CCM-D nutritive metabolic investigation system. RESULTS The REE of the severe chronic hepatitis group (20.7 +/- 6.1 kcal/d per kg) was significantly lower than that of the acute hepatitis group (P = 0.014). The respiratory quotient (RQ) of the severe chronic hepatitis group (0.84 +/- 0.06) was significantly lower than that of the acute hepatitis and cirrhosis groups (P = 0.001). The glucose oxidation rate of the severe hepatitis group (39.2%) was significantly lower than that of the acute hepatitis group and the cirrhosis group (P < 0.05), while the fat oxidation rate (39.8%) in the severe hepatitis group was markedly higher than that of the other two groups (P < 0.05). With improvement of liver function, the glucose oxidation rate increased from 41.7% to 60.1%, while the fat oxidation rate decreased from 26.3% to 7.6%. CONCLUSION The glucose oxidation rate is significantly decreased, and a high proportion of energy is provided by fat in severe chronic hepatitis. These results warrant a large clinical trail to assess the optimal nutritive support therapy for patients with severe liver disease.
Collapse
|
|
7
|
Holland-Fischer P, Andersen PH, Lund S, Pedersen SB, Vinter-Jensen L, Nielsen MF, Kaal A, Dall R, Schmitz O, Vilstrup H. Muscle GLUT4 in cirrhosis. J Hepatol 2007; 47:212-9. [PMID: 17448565 DOI: 10.1016/j.jhep.2007.02.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2006] [Revised: 02/06/2007] [Accepted: 02/20/2007] [Indexed: 01/17/2023]
Abstract
BACKGROUND/AIMS The insulin-dependent glucose transporter GLUT4 mediates 50-80% of whole body glucose uptake, but its relation to the frequent glucose intolerance in patients with liver cirrhosis is unknown. METHODS Thirty patients and seven healthy controls underwent a 2-h oral glucose tolerance test and later a muscle biopsy. Levels of GLUT4 total protein and mRNA content were determined in muscle biopsies by polyclonal antibody labelling and RT-PCR, respectively. RESULTS GLUT4 protein content in the cirrhosis group was not different from that of the controls, but at variance with the control subjects it correlated closely with measures of glucose tolerance (R(2)=0.45; p=0.003). GLUT4 mRNA of the patients with cirrhosis was reduced to 56% of control value (95% ci: 27-86%; p=0.015) and was inversely related to the level of basal hyper-insulinemia (R(2)=0.39; p=0.004). CONCLUSIONS In cirrhosis GLUT4 protein content was quantitatively intact, while limiting glucose tolerance. This indicates loss of redundancy of the major glucose transport system, possibly related to the markedly decreased expression of its gene. Hyper-insulinemia may be a primary event. Our findings implicate the muscular GLUT4 system in the glucose intolerance of liver cirrhosis by a mechanism different from that in diabetes.
Collapse
Affiliation(s)
- Peter Holland-Fischer
- Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, 44 Noerrebrogade, DK-8000 Aarhus C, Denmark.
| | | | | | | | | | | | | | | | | | | |
Collapse
|