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Xiang Y, Shen L, Xue Y, Wang Z, Zhou R, Cao Y, Zhu Z, Xu P, Yu X, Fang P, Shang W. Efficacy and safety of diacerein monotherapy in adults with obesity: A randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 2024; 26:5293-5303. [PMID: 39192530 DOI: 10.1111/dom.15881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 08/29/2024]
Abstract
AIM To assess the efficacy and safety of diacerein monotherapy in adults with obesity. METHODS Forty-two adults with obesity participated in the study and were randomly assigned to receive diacerein or placebo in addition to lifestyle modification for 14 weeks, in a double-blinded fashion. Differences in changes in body weight, body composition, metabolic variables, fatty liver-related indicators, cardiovascular system variables, lifestyle score and metabolic factors were compared. RESULTS Post-treatment weight loss percentage from baseline was -6.56% (-8.71%, -4.41%) in the diacerein group and -0.59% (-2.74%, 1.56%) in the placebo group. Compared with the placebo group, the diacerein group showed significant improvements in body composition, metabolic variables and indicators related to fatty liver. In addition, after 14 weeks of treatment, diacerein led to a significant reduction in serum visfatin concentration versus the placebo group. The reductions in total body fat mass and visceral fat area mediated the weight loss induced by diacerein. No significant differences were found between the groups in the number of adverse events and safety variables. CONCLUSIONS For adults with obesity, diacerein led to a clinically meaningful weight loss and provided multiple metabolic benefits with acceptable safety. These results support that diacerein is a promising candidate medicine to be developed for obesity management.
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Affiliation(s)
- Yingying Xiang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lixuan Shen
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yingying Xue
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ziwei Wang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ruonan Zhou
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yue Cao
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ziwei Zhu
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Pingyuan Xu
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xizhong Yu
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Penghua Fang
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenbin Shang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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Varra FN, Varras M, Varra VK, Theodosis-Nobelos P. Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation‑mediating treatment options (Review). Mol Med Rep 2024; 29:95. [PMID: 38606791 PMCID: PMC11025031 DOI: 10.3892/mmr.2024.13219] [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: 10/25/2023] [Accepted: 01/17/2024] [Indexed: 04/13/2024] Open
Abstract
Obesity reaches up to epidemic proportions globally and increases the risk for a wide spectrum of co‑morbidities, including type‑2 diabetes mellitus (T2DM), hypertension, dyslipidemia, cardiovascular diseases, non‑alcoholic fatty liver disease, kidney diseases, respiratory disorders, sleep apnea, musculoskeletal disorders and osteoarthritis, subfertility, psychosocial problems and certain types of cancers. The underlying inflammatory mechanisms interconnecting obesity with metabolic dysfunction are not completely understood. Increased adiposity promotes pro‑inflammatory polarization of macrophages toward the M1 phenotype, in adipose tissue (AT), with subsequent increased production of pro‑inflammatory cytokines and adipokines, inducing therefore an overall, systemic, low‑grade inflammation, which contributes to metabolic syndrome (MetS), insulin resistance (IR) and T2DM. Targeting inflammatory mediators could be alternative therapies to treat obesity, but their safety and efficacy remains to be studied further and confirmed in future clinical trials. The present review highlights the molecular and pathophysiological mechanisms by which the chronic low‑grade inflammation in AT and the production of reactive oxygen species lead to MetS, IR and T2DM. In addition, focus is given on the role of anti‑inflammatory agents, in the resolution of chronic inflammation, through the blockade of chemotactic factors, such as monocytes chemotractant protein‑1, and/or the blockade of pro‑inflammatory mediators, such as IL‑1β, TNF‑α, visfatin, and plasminogen activator inhibitor‑1, and/or the increased synthesis of adipokines, such as adiponectin and apelin, in obesity‑associated metabolic dysfunction.
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Affiliation(s)
- Fani-Niki Varra
- Department of Pharmacy, School of Health Sciences, Frederick University, Nicosia 1036, Cyprus
- Medical School, Dimocritus University of Thrace, Alexandroupolis 68100, Greece
| | - Michail Varras
- Fourth Department of Obstetrics and Gynecology, ‘Elena Venizelou’ General Hospital, Athens 11521, Greece
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Antar SA, Ashour NA, Sharaky M, Khattab M, Ashour NA, Zaid RT, Roh EJ, Elkamhawy A, Al-Karmalawy AA. Diabetes mellitus: Classification, mediators, and complications; A gate to identify potential targets for the development of new effective treatments. Biomed Pharmacother 2023; 168:115734. [PMID: 37857245 DOI: 10.1016/j.biopha.2023.115734] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/13/2023] [Accepted: 10/13/2023] [Indexed: 10/21/2023] Open
Abstract
Nowadays, diabetes mellitus has emerged as a significant global public health concern with a remarkable increase in its prevalence. This review article focuses on the definition of diabetes mellitus and its classification into different types, including type 1 diabetes (idiopathic and fulminant), type 2 diabetes, gestational diabetes, hybrid forms, slowly evolving immune-mediated diabetes, ketosis-prone type 2 diabetes, and other special types. Diagnostic criteria for diabetes mellitus are also discussed. The role of inflammation in both type 1 and type 2 diabetes is explored, along with the mediators and potential anti-inflammatory treatments. Furthermore, the involvement of various organs in diabetes mellitus is highlighted, such as the role of adipose tissue and obesity, gut microbiota, and pancreatic β-cells. The manifestation of pancreatic Langerhans β-cell islet inflammation, oxidative stress, and impaired insulin production and secretion are addressed. Additionally, the impact of diabetes mellitus on liver cirrhosis, acute kidney injury, immune system complications, and other diabetic complications like retinopathy and neuropathy is examined. Therefore, further research is required to enhance diagnosis, prevent chronic complications, and identify potential therapeutic targets for the management of diabetes mellitus and its associated dysfunctions.
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Affiliation(s)
- Samar A Antar
- Center for Vascular and Heart Research, Fralin Biomedical Research Institute, Virginia Tech, Roanoke, VA 24016, USA; Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta 34518, Egypt
| | - Nada A Ashour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| | - Marwa Sharaky
- Cancer Biology Department, Pharmacology Unit, National Cancer Institute (NCI), Cairo University, Cairo, Egypt
| | - Muhammad Khattab
- Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Cairo, Egypt
| | - Naira A Ashour
- Department of Neurology, Faculty of Physical Therapy, Horus University, New Damietta 34518, Egypt
| | - Roaa T Zaid
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt
| | - Eun Joo Roh
- Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Ahmed Elkamhawy
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Ahmed A Al-Karmalawy
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt
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Rai U, Senapati D, Arora MK. Insights on the role of anti-inflammatory and immunosuppressive agents in the amelioration of diabetes. Diabetol Int 2023; 14:134-144. [PMID: 37090130 PMCID: PMC10113422 DOI: 10.1007/s13340-022-00607-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/30/2022] [Indexed: 11/18/2022]
Abstract
Diabetes is a major health problem worldwide. It is a chronic metabolic disorder that produces overt hyperglycemic condition that occurs either when the pancreas does not produce enough insulin due to excessive destruction of pancreatic β-cells (type 1 diabetes) or due to development of insulin resistance (type 2 diabetes). An autoimmune condition known as type 1 diabetes (T1D) results in the targeted immune death of β-cells that produce insulin. The only available treatment for T1D at the moment is the lifelong use of insulin. Multiple islet autoantibody positivity is used to diagnose T1D. There are four standard autoantibodies observed whose presence shows the development of T1D: antibodies against insulin, glutamic acid decarboxylase (GAD65), zinc T8 transporter (ZnT8), and tyrosine phosphatase-like protein (ICA512). In type 2 diabetes (T2D), an inflammatory response precipitates as a consequence of the immune response to high blood glucose level along with the presence of inflammation mediators produced by macrophages and adipocytes in fat tissue. The slow and chronic inflammatory condition of adipose tissue produces insulin resistance leading to increased stress on pancreatic β-cells to produce more insulin to compensate for the insulin resistance. Thus, this stress condition exacerbates the apoptosis of β-cells leading to insufficient production of insulin, resulting in hyperglycemia which signifies late stage T2D. Therefore, the therapeutic utilization of immunosuppressive agents may be a better alternative over the use of insulin and oral hypoglycemic agents for the treatment of T1D and T2D, respectively. This review enlightens the immune intervention for the prevention and amelioration of T1D and T2D in humans with main focus on the antigen-specific immune suppressive therapy.
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Affiliation(s)
- Uddipak Rai
- School of Pharmaceutical and Population Health Informatics, DIT University, 248009, Dehradun, Uttarakhand India
| | - Dhirodatta Senapati
- School of Pharmaceutical and Population Health Informatics, DIT University, 248009, Dehradun, Uttarakhand India
| | - Mandeep Kumar Arora
- School of Pharmaceutical and Population Health Informatics, DIT University, 248009, Dehradun, Uttarakhand India
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Li D, Zhong J, Zhang Q, Zhang J. Effects of anti-inflammatory therapies on glycemic control in type 2 diabetes mellitus. Front Immunol 2023; 14:1125116. [PMID: 36936906 PMCID: PMC10014557 DOI: 10.3389/fimmu.2023.1125116] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/15/2023] [Indexed: 03/05/2023] Open
Abstract
Background The overall evidence base of anti-inflammatory therapies in patients with type 2 diabetes mellitus (T2DM) has not been systematically evaluated. The purpose of this study was to assess the effects of anti-inflammatory therapies on glycemic control in patients with T2DM. Methods PubMed, Embase, Web of Science, and Cochrane Library were searched up to 21 September 2022 for randomized controlled trials (RCTs) with anti-inflammatory therapies targeting the proinflammatory cytokines, cytokine receptors, and inflammation-associated nuclear transcription factors in the pathogenic processes of diabetes, such as interleukin-1β (IL-1β), interleukin-1β receptor (IL-1βR), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB). We synthesized data using mean difference (MD) and 95% confidence interval (CI). Heterogeneity between studies was assessed by I2 tests. Sensitivity and subgroup analyses were also conducted. Results We included 16 RCTs comprising 3729 subjects in the meta-analyses. Anti-inflammatory therapies can significantly reduce the level of fasting plasma glucose (FPG) (MD = - 10.04; 95% CI: -17.69, - 2.40; P = 0.01), glycated haemoglobin (HbA1c) (MD = - 0.37; 95% CI: - 0.51, - 0.23; P < 0.00001), and C-reactive protein (CRP) (MD = - 1.05; 95% CI: - 1.50, - 0.60; P < 0.00001) compared with control, and therapies targeting IL-1β in combination with TNF-α have better effects on T2DM than targeting IL-1β or TNF-α alone. Subgroup analyses suggested that patients with short duration of T2DM may benefit more from anti-inflammatory therapies. Conclusion Our meta-analyses indicate that anti-inflammatory therapies targeting the pathogenic processes of diabetes can significantly reduce the level of FPG, HbA1c, and CRP in patients with T2DM.
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Affiliation(s)
- Dandan Li
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jiaxin Zhong
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Qirui Zhang
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jingjing Zhang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- *Correspondence: Jingjing Zhang,
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Belyaeva IB, Mazurov VI. Pleiotropic effects of diacerein in comorbid patients with osteoarthritis. MODERN RHEUMATOLOGY JOURNAL 2022; 16:98-104. [DOI: 10.14412/1996-7012-2022-4-98-104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
The article presents an analysis of the therapeutic effect of the drug diacerein (D), which has been used in osteoarthritis (OA) for more than 20 years and is included in the clinical guidelines of the Association of Rheumatologists of Russia (2021) and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal diseases (ESCEO, 2019) for the treatment of OA. The main pathogenic effect of D in OA is to suppress the synthesis of interleukin 1, stimulate the production of articular cartilage proteoglycans, and slow down abnormal remodeling of the subchondral bone. The advantages of D in the treatment of patients with OA and comorbidities are presented – a prolonged anti-inflammatory and analgesic effect and good tolerability. These properties of D allow to control the symptoms of OA and improve the quality of life of patients. The structure-modifying effect of D is based on its ability to stimulate the synthesis of articular cartilage proteoglycans with long-term use and prevent abnormal remodeling of the subchondral bone, which leads to a decrease in the risk of OA progression and a delay in total joint arthroplasty. An important advantage of D is its positive metabolic effect in patients with type 2 diabetes mellitus and obesity, which is associated with the ability of D to reduce the level of glycated hemoglobin and body mass index. Data are presented on the absence of adverse cardiovascular effects when using D, which allows us to recommend its use in patients with OA who have comorbid cardiovascular diseases, as well as contraindications for non-steroidal anti-inflammatory drugs.
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Affiliation(s)
- I. B. Belyaeva
- North-Western State Medical University named after I.I. Mechnikov, Ministry of Health of Russia
| | - V. I. Mazurov
- North-Western State Medical University named after I.I. Mechnikov, Ministry of Health of Russia
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Diacerein ameliorates letrozole-induced polycystic ovarian syndrome in rats. Biomed Pharmacother 2022; 149:112870. [PMID: 35367769 DOI: 10.1016/j.biopha.2022.112870] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 03/02/2022] [Accepted: 03/23/2022] [Indexed: 11/22/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most common gynaecological endocrine disease that causes anovulatory infertility. The current study aimed to explore the possible role of diacerein (DIA), an IL-1β inhibitor, in treating letrozole-induced PCOS in rats that exhibit the metabolic and endocrinal criteria of PCOS patients. PCOS was induced in female Wistar rats by the oral administration of letrozole (1 mg/kg, per orally, p.o.) for 21 days. Rats were then treated with DIA (25 mg/kg/day, p.o.), DIA (50 mg/kg/day, p.o.), or metformin (2 mg/100 g/day, p.o.) for 14 days after the PCOS induction. PCOS resulted in a significantly higher body weight, ovarian weight, ovarian size, and cysts, as well as an elevation in serum testosterone, LH, insulin, glycemia, and lipid profile levels. All of these effects were significantly reduced by the DIA administration. Additionally, DIA remarkably inhibited the letrozole-induced oxidative stress in the ovaries, muscles, and liver by reducing the upraised levels of malondialdehyde and total nitrite and increasing the suppressed levels of superoxide dismutase and catalase. DIA enhanced the protective proteins Keap-1, Nrf2, and OH-1 levels. Finally, DIA inhibited the elevated mRNA levels of NLRP3 and caspase-1, the up-regulated inflammatory cytokines IL-6, TNF-α, and the IL-1β/NFκB signaling pathway. Our results proved that DIA ameliorates letrozole-induced PCOS through its antioxidant and anti-inflammatory properties.
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Jangsiripornpakorn J, Srisuk S, Chailurkit L, Nimitphong H, Saetung S, Ongphiphadhanakul B. The glucose-lowering effect of low-dose diacerein and its responsiveness metabolic markers in uncontrolled diabetes. BMC Res Notes 2022; 15:91. [PMID: 35246243 PMCID: PMC8896078 DOI: 10.1186/s13104-022-05974-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 02/14/2022] [Indexed: 11/30/2022] Open
Abstract
Objective Diacerein inhibits the synthesis and activity of pro-inflammatory cytokines, decreases macrophage infiltration in adipose tissue and thus increases insulin sensitivity and signalling. We conducted this study to determine the efficacy of low-dose diacerein in improving glycaemic control in type 2 diabetes mellitus (T2DM) patients with inadequate glycaemic control and to identify the metabolic determinants for such improvement. We randomised 25 T2DM patients with poor glycaemic control, despite being treated with at least three glucose-lowering agents, to receive diacerein 50 mg once-daily (n = 18) or placebo (n = 17) for 12 weeks. Changes in glycated haemoglobin (HbA1c) were evaluated at the 4th and 12th weeks. Metabolic profiling was performed using liquid chromatography electrospray ionisation quadrupole time-of-flight mass spectrometry. Results HbA1c levels were significantly reduced from baseline in the diacerein group at 12 weeks (− 0.6%, p < 0.05), whereas fasting plasma glucose (FPG) levels were not significantly decreased (− 18.9 mg/dl, p = 0.06). Partial least squares-discriminant analysis demonstrated an association between the serum abundance of threo-isocitric acid (ICA) and HbA1c response in the diacerein group. After adjusting for serum high-sensitivity C-reactive protein, ICA was still significantly related to the change in HbA1c. Retrospective trial registration Current Controlled Trials TCTR20200820004, 20 August 2020. Supplementary Information The online version contains supplementary material available at 10.1186/s13104-022-05974-9.
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Affiliation(s)
| | - Sasima Srisuk
- Bangkok Metropolitan Administration General Hospital, Bangkok, Thailand
| | - Laor Chailurkit
- Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Sunee Saetung
- Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Boonsong Ongphiphadhanakul
- Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. .,Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama 6th Road, Bangkok, 10400, Thailand.
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9
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Samaha MM, Helal MG, El-Sherbiny M, Said E, Salem HA. Diacerein versus adipoRon as adiponectin modulators in experimentally-induced end-stage type 2 diabetes mellitus in rats. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 90:103806. [PMID: 34974166 DOI: 10.1016/j.etap.2021.103806] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 12/25/2021] [Accepted: 12/28/2021] [Indexed: 06/14/2023]
Abstract
The objective of the present study is to evaluate and compare the possible anti-diabetic effects of adipoRon and diacerein in type 2 diabetes mellitus (T2DM) rats. T2DM is marked by impaired oxidative, inflammatory and metabolic signaling. Indeed, T2DM progression is associated with elevated HbA1C%, low adiponectin and insulin concentration. Moreover, in this study epididymal adipose tissue and soleus muscle MDA contents significantly escalated, while serum TAC and epididymal adipose Nrf2 significantly declined. Nevertheless, serum TNF-α, epididymal NLRP3, NF-κB, PPARγ and CD68 expression rose significantly with a parallel significant reduction in serum IL-10 and soleus muscle expression of IRS1. Both adipoRon and diacerein significantly improved adiponectin and insulin secretion with augmentation of anti-oxidant defenses and diminution of oxidative burden, with obvious anti-inflammatory consequences (p < 0.05). Thus, adipoRon and diacerein positively modulated adiponectin expression with down-regulation of NF-κB/NLRP3/PPARγ expression with subsequent improvement in glycemic control, inflammatory and oxidative signaling.
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Affiliation(s)
- Mahmoud M Samaha
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Manar G Helal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, Almaarefa University, P.O. Box 71666, Riyadh, 11597, Saudi Arabia; Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Eman Said
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Faculty of Pharmacy, New Mansoura University, 7723730 New Mansoura, Egypt.
| | - Hatem A Salem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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10
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Rohm TV, Meier DT, Olefsky JM, Donath MY. Inflammation in obesity, diabetes, and related disorders. Immunity 2022; 55:31-55. [PMID: 35021057 PMCID: PMC8773457 DOI: 10.1016/j.immuni.2021.12.013] [Citation(s) in RCA: 897] [Impact Index Per Article: 299.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 12/13/2021] [Accepted: 12/17/2021] [Indexed: 01/13/2023]
Abstract
Obesity leads to chronic, systemic inflammation and can lead to insulin resistance (IR), β-cell dysfunction, and ultimately type 2 diabetes (T2D). This chronic inflammatory state contributes to long-term complications of diabetes, including non-alcoholic fatty liver disease (NAFLD), retinopathy, cardiovascular disease, and nephropathy, and may underlie the association of type 2 diabetes with other conditions such as Alzheimer's disease, polycystic ovarian syndrome, gout, and rheumatoid arthritis. Here, we review the current understanding of the mechanisms underlying inflammation in obesity, T2D, and related disorders. We discuss how chronic tissue inflammation results in IR, impaired insulin secretion, glucose intolerance, and T2D and review the effect of inflammation on diabetic complications and on the relationship between T2D and other pathologies. In this context, we discuss current therapeutic options for the treatment of metabolic disease, advances in the clinic and the potential of immune-modulatory approaches.
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Affiliation(s)
- Theresa V. Rohm
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Daniel T. Meier
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031 Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, CH-4031 Basel, Switzerland
| | - Jerrold M. Olefsky
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Marc Y. Donath
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031 Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, CH-4031 Basel, Switzerland.,Correspondence:
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11
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Jiang L, Zhou J, Zhang L, Du Y, Jiang M, Xie L, Ma Z, Chen F. The association between serum interleukin-1 beta and heparin sulphate in diabetic nephropathy patients. Glycoconj J 2022; 38:697-707. [PMID: 34997893 PMCID: PMC8821487 DOI: 10.1007/s10719-021-10035-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 12/02/2021] [Accepted: 12/17/2021] [Indexed: 12/15/2022]
Abstract
Inflammation is considered an important mechanism in the development of diabetes mellitus (DM) and persists for a long time before the occurrence of diabetic nephropathy (DN). Many studies have demonstrated that a decrease in the endothelial glycocalyx (EG) is negatively correlated with proteinuria. To elucidate whether EG damage induced by inflammasomes in DM patients leads to the occurrence of microalbuminuria (MA) and accelerates the progression of DN, this study screened 300 diagnosed DM patients. Finally, 70 type 2 diabetes patients were invited to participate in this study and were divided into two groups: the T2DM group (patients with normal MA and without diabetic retinopathy, n = 35) and the T2DN group (patients with increased MA and diabetic retinopathy, n = 35). Circulating heparin sulphate (HS, EG biomarkers) and interleukin-1 beta (IL-1β, inflammasome biomarkers) of the patients were measured by ELISA. Laboratory data were measured using routine laboratory methods. Patients in the T2DN group had increased serum HS, increased IL-1β, increased CRP, decreased haemoglobin, and increased neutrophils compared to patients in the T2DM group (all P < 0.05). Increased HS and decreased haemoglobin were independently associated with T2DN patients. ROC curves showed that the AUC of HS for the prediction of T2DN was 0.67 (P < 0.05). The combination of HS and haemoglobin yielded a significant increasement in the AUC (0.75, P < 0.001) with optimal sensitivity (71.2%) and specificity (79%). Furthermore, serum IL-1β was positively correlated with HS and was an independent associated factor of HS in the T2DN group. The relationship between HS and IL-1β was not significant in the T2DM group. Our findings surgessed the inflammasome may be associated with and promote damage to the EG during the disease course of DN that manifests as increased MA.
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Affiliation(s)
- Liqiong Jiang
- Department of Nephrology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
| | - Jianying Zhou
- Department of Endocrinology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Li Zhang
- Clinical Lab, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Yufeng Du
- Department of Nephrology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Mingming Jiang
- Department of Nephrology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Liqian Xie
- Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhenni Ma
- Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Fengling Chen
- Department of Hemodialysis Center, the First Affiliated Hospital of Soochow University, Suzhou, China.
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12
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Garcia-Oropesa EM, Martinez-Lopez YE, Ruiz-Cejudo SM, Martínez-Ezquerro JD, Diaz-Badillo A, Ramirez-Pfeiffer C, Bustamante-Fuentes A, Lopez-Sosa EB, Moctezuma-Chavez OO, Nava-Gonzalez EJ, Perales-Torres AL, Perez-Navarro LM, Rosas-Diaz M, Carter K, Tapia B, Lopez-Alvarenga JC. Looking for Crumbs in the Obesity Forest: Anti-obesity Interventions and Obesity-Associated Cardiometabolic Traits in the Mexican Population. History and Systematic Review With Meta-Analyses. Front Med (Lausanne) 2021; 8:665023. [PMID: 34805192 PMCID: PMC8595206 DOI: 10.3389/fmed.2021.665023] [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: 02/06/2021] [Accepted: 09/24/2021] [Indexed: 11/30/2022] Open
Abstract
Mexicans and Mexican Americans share culture, genetic background, and predisposition for chronic complications associated with obesity and diabetes making imperative efficacious treatments and prevention. Obesity has been treated for centuries focused-on weight loss while other treatments on associated conditions like gout, diabetes (T2D), and hypertriglyceridemia. To date, there is no systematic review that synthesizes the origin of obesity clinics in Mexico and the efforts to investigate treatments for obesity tested by randomized clinical trials (RCT). We conducted systematic searches in Pubmed, Scopus, and Web of Science to retrieve anti-obesity RCT through 2019 and without an inferior temporal limit. The systematic review included RCT of anti-obesity treatments in the Mexican adult population, covering alternative medicine, pharmacological, nutritional, behavioral, and surgical interventions reporting metabolism-associated traits such as BMI, weight, waist circumference, triglycerides, glucose, among others. Only the studies with at least 3 months of treatment were included in the meta-analyses in order to reduce placebo effects. We found 634 entries, after removal of duplicates and screening the studies based on eligibility criteria, we analyzed 43 national, and 2 multinational-collaborative studies. Most of the national studies had small sample sizes, and the implemented strategies do not have replications in the population. The nutrition/behavioral interventions were difficult to blind, and most studies have medium-to-high risk of bias. Nutritional/behavioral interventions and medications showed effects on BMI, waist circumference, and blood pressure. Simple measures like pure water instead of sweet beverages decrease triglycerides and systolic blood pressure. Dark chocolate showed the highest effect for BMI and high blood pressure, and treatment with insulin increased weight in those with T2D. The study of obesity in Mexico has been on-going for more than four decades, the interest on RCT just increased until this millennium, but with small sample sizes and lack of replication. The interventions affect different cardiometabolic associated traits, which should be analyzed in detail in the population living near the Mexico-U.S. border; therefore, bi-national collaboration is desirable to disentangle the cultural effects on this population's treatment response. Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020221436, identifier: CRD42020221436.
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Affiliation(s)
- Esperanza M Garcia-Oropesa
- Laboratorio de Biología Molecular, Unidad Académica Multidisciplinaria Reynosa Aztlán (UAMRA), Universidad Autónoma de Tamaulipas, Reynosa, Mexico
| | - Yoscelina E Martinez-Lopez
- Programa de Doctorado en Ciencias Médicas y de la Salud, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Sonia María Ruiz-Cejudo
- Unidad de Investigación Epidemiológica y en Servicios de Salud, Área Envejecimiento (UIESSAE), Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.,Programa de Maestría y Doctorado en Música, Cognición Musical, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - José Darío Martínez-Ezquerro
- Unidad de Investigación Epidemiológica y en Servicios de Salud, Área Envejecimiento (UIESSAE), Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.,Centro de Ciencias de la Complejidad (C3), Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Alvaro Diaz-Badillo
- Department of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Edinburg, TX, United States.,Programa de Maestría en Salud Pública, Universidad México-Americana del Norte (UMAN), Reynosa, Mexico
| | - Carlos Ramirez-Pfeiffer
- Programa de Maestría en Salud Pública, Universidad México-Americana del Norte (UMAN), Reynosa, Mexico
| | | | | | | | - Edna J Nava-Gonzalez
- Facultad de Salud Pública y Nutrición, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - Adriana L Perales-Torres
- Laboratorio de Bromatología, Unidad Académica Multidisciplinaria Reynosa Aztlán (UAMRA), Universidad Autónoma de Tamaulipas Reynosa-Aztlán, Reynosa, Mexico
| | - Lucia M Perez-Navarro
- Servicio de Nefrología, Dirección de Investigación, Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
| | - Marisol Rosas-Diaz
- Laboratorio de Biología Molecular, Unidad Académica Multidisciplinaria Reynosa Aztlán (UAMRA), Universidad Autónoma de Tamaulipas, Reynosa, Mexico
| | - Kathleen Carter
- Research and Education Library of the School of Medicine, Education & Academic Affairs, University of Texas Rio Grande Valley, Edinburg, TX, United States
| | - Beatriz Tapia
- Office of Faculty Affairs and Department of Pediatrics, School of Medicine, The University of Texas Rio Grande Valley, Harlingen, TX, United States
| | - Juan C Lopez-Alvarenga
- Department of Human Genetics, School of Medicine, The University of Texas Rio Grande Valley, Edinburg, TX, United States.,Programa de Maestría en Salud Pública, Universidad México-Americana del Norte (UMAN), Reynosa, Mexico
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13
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Martorell M, Castro N, Victoriano M, Capó X, Tejada S, Vitalini S, Pezzani R, Sureda A. An Update of Anthraquinone Derivatives Emodin, Diacerein, and Catenarin in Diabetes. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:3313419. [PMID: 34589130 PMCID: PMC8476274 DOI: 10.1155/2021/3313419] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/09/2021] [Indexed: 12/15/2022]
Abstract
Diabetes is part of metabolic diseases and is characterized by high blood sugar levels over a prolonged period as result of an insulin-deficient production or an inappropriate response to insulin by our cells. This chronic disease was the direct cause of 1.6 million deaths in 2016 as reported by the World Health Organization. Emodin is a natural product and active ingredient of various Chinese herbs with the chemical formula 1,3,8-trihydroxy-6-methylanthraquinone. Diacerein is another naturally occurring anthraquinone (1,8-diacetoxy-3-carboxyanthraquinone) commonly used as commercial drug to treat osteoarthritis. These two anthraquinone derivatives have been shown to exert antidiabetic activities. Emodin seems to enhance the glucose tolerance and insulin sensibility via activation of PPARγ and modulation of metabolic-related genes. Diacerein seems to decrease inflammatory cytokines and increase insulin secretion enhancing insulin sensibility and therefore improving glucose control. Other naturally occurring anthraquinone derivatives, such as catenarin (1,4,6,8-tetrahydroxy-3-methylanthraquinone), have been shown to have antidiabetic activities although few studies have been performed. The synthesis of new emodin derivatives is increasing, but these new molecules have not been tested for diabetes treatment. In the current work, available literature on anthraquinone derivatives' effects in diabetes disease is reviewed. Moreover, we discuss the chemistry, food sources, bioavailability, and toxicity of the naturally occurring anthraquinone with antidiabetic effects.
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Affiliation(s)
- Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepción, Concepción 4070386, Chile
- Centre for Healthy Living, University of Concepción, Concepción 4070386, Chile
| | - Natalia Castro
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepción, Concepción 4070386, Chile
| | - Montserrat Victoriano
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepción, Concepción 4070386, Chile
| | - Xavier Capó
- Research Group in Community Nutrition and Oxidative Stress, University Research Institute of Health Sciences (IUNICS), University of the Balearic Islands, Palma de Mallorca 07122, Spain
| | - Silvia Tejada
- Laboratory of Neurophysiology, Department of Biology, University Research Institute of Health Sciences (IUNICS), University of Balearic Islands, Palma E-07122, Balearic Islands, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, Madrid E-28029, Spain
- Research Institute of the Balearic Islands, Palma de Mallorca E-07120, Spain
| | - Sara Vitalini
- Department of Agricultural and Environmental Sciences, Università degli Studi di Milano, Via G. Celoria 2 20133, Milan, Italy
| | - Raffaele Pezzani
- Phytotherapy Lab (PhT-Lab), Endocrinology Unit, Department of Medicine (DIMED), University of Padova, via Ospedale 105, Padova 35128, Italy
- AIROB, Associazione Italiana per la Ricerca Oncologica di Base, Padova, Italy
| | - Antoni Sureda
- Research Group in Community Nutrition and Oxidative Stress, University Research Institute of Health Sciences (IUNICS), University of the Balearic Islands, Palma de Mallorca 07122, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, Madrid E-28029, Spain
- Research Institute of the Balearic Islands, Palma de Mallorca E-07120, Spain
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14
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de Oliveira SA, Cerri PS, Sasso-Cerri E. Impaired macrophages and failure of steroidogenesis and spermatogenesis in rat testes with cytokines deficiency induced by diacerein. Histochem Cell Biol 2021; 156:561-581. [PMID: 34515835 PMCID: PMC8436873 DOI: 10.1007/s00418-021-02023-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2021] [Indexed: 12/13/2022]
Abstract
The role of cytokines in testicular function under normal conditions has not been completely understood. Here, we evaluated testicular macrophages (TM), steroidogenesis by Leydig cells (LC) and seminiferous tubules integrity in cytokines-deficient rat testes induced by diacerein, an anti-inflammatory drug that inhibits interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α). Male rats received daily 100 mg/kg of diacerein (DIAG; n = 8) or saline (CG; n = 8) for 30 days. Serum testosterone (T) levels were measured and the seminiferous tubule (ST) area, epithelial area (EA), frequency of damaged ST and number of Sertoli cells (SC) were evaluated. TUNEL method and immunoreactions for detection of pro-IL-1β, TNF-α, steroidogenic acute regulatory protein (StAR), 17β-hydroxysteroid dehydrogenase (17β-HSD), androgen receptor (AR) and scavenger receptor for hemoglobin-haptoglobin complexes (CD163), a TM marker, were performed. Testicular AR, 17β-HSD and IL-1β levels were detected by Western blot. Data were submitted to Student t test (p ≤ 0.05). In DIAG, T and testicular AR, 17β-HSD and IL-1β levels decreased significantly (p < 0.05). The number of TUNEL-positive interstitial cells increased and LC showed weak StAR, 17β-HSD and AR immunoexpression in association with reduced IL-1β immunoexpression and number of CD163-positive TM in the interstitial tissue from diacerein-treated rats. Numerous damaged ST were found in DIAG, and reduction in the EA were associated with germ cells death. Moreover, the number of SC reduced and weak AR and TNF-α immunoexpression was observed in SC and germ cells, respectively. The cytokines deficiency induced by diacerein impairs TM, LC and spermatogenesis, and points to a role of IL-1β in steroidogenesis under normal conditions. In the ST, the weak AR and TNF-α immunoexpression in SC and germ cells, respectively, reinforces the idea that TNF-α plays a role in the SC androgenic control.
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Affiliation(s)
| | - Paulo Sérgio Cerri
- Laboratory of Histology and Embryology, Department of Morphology, Genetics, Orthodontics and Pediatric Dentistry, Dental School - São Paulo State University (UNESP), Rua Humaitá, 1680, Araraquara, SP, CEP: 14801-903, Brazil
| | - Estela Sasso-Cerri
- Laboratory of Histology and Embryology, Department of Morphology, Genetics, Orthodontics and Pediatric Dentistry, Dental School - São Paulo State University (UNESP), Rua Humaitá, 1680, Araraquara, SP, CEP: 14801-903, Brazil.
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15
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Koufakis T, Dimitriadis G, Metallidis S, Zebekakis P, Kotsa K. The role of autoimmunity in the pathophysiology of type 2 diabetes: Looking at the other side of the moon. Obes Rev 2021; 22:e13231. [PMID: 33682984 DOI: 10.1111/obr.13231] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/17/2021] [Accepted: 02/18/2021] [Indexed: 12/12/2022]
Abstract
Efforts to unravel the pathophysiological mechanisms of type 2 diabetes (T2D) have been traditionally trapped into a metabolic perspective. However, T2D is a phenotypically and pathophysiologically heterogenous disorder, and the need for a tailored approach in its management is becoming increasingly evident. There is emerging evidence that irregular immune responses contribute to the development of hyperglycemia in T2D and, inversely, that insulin resistance is a component of the pathogenesis of autoimmune diabetes. Nevertheless, it has not yet been fully elucidated to what extent the presence of conventional autoimmune markers, such as autoantibodies, in subjects with T2D might affect the natural history of the disease and particularly each response to various treatments. The challenge for future research in the field is the discovery of novel genetic, molecular, or phenotypical indicators that would enable the characterization of specific subpopulations of people with T2D who would benefit most from the addition of immunomodulatory therapies to standard glucose-lowering treatment. This narrative review aims to discuss the plausible mechanisms through which the immune system might be implicated in the development of metabolic disturbances in T2D and obesity and explore a potential role of immunotherapy in the future management of the disorder and its complications.
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Affiliation(s)
- Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - George Dimitriadis
- Athens University Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Symeon Metallidis
- Infectious Diseases Division, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Pantelis Zebekakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.,Infectious Diseases Division, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
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16
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Ghanbari M, Momen Maragheh S, Aghazadeh A, Mehrjuyan SR, Hussen BM, Abdoli Shadbad M, Dastmalchi N, Safaralizadeh R. Interleukin-1 in obesity-related low-grade inflammation: From molecular mechanisms to therapeutic strategies. Int Immunopharmacol 2021; 96:107765. [PMID: 34015596 DOI: 10.1016/j.intimp.2021.107765] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/27/2021] [Accepted: 05/04/2021] [Indexed: 12/13/2022]
Abstract
Since adipose tissue (AT) can upregulate pro-inflammatory interleukins (ILs) via storing extra lipids in obesity, obesity is considered the leading cause of chronic low-grade inflammation. These ILs can pave the way for the infiltration of immune cells into the AT, ultimately resulting in low-grade inflammation and dysregulation of adipocytes. IL-1, which is divided into two subclasses, i.e., IL-1α and IL-1β, is a critical pro-inflammatory factor. In obesity, IL-1α and IL-1β can promote insulin resistance via impairing the function of adipocytes and promoting inflammation. The current study aims to review the detailed molecular mechanisms and the roles of IL-1α and IL-1β and their antagonist, interleukin-1 receptor antagonist(IL-1Ra), in developing obesity-related inflammatory complications, i.e., type II diabetes (T2D), non-alcoholic steatohepatitis (NASH), atherosclerosis, and cognitive disorders. Besides, the current study discusses the recent advances in natural drugs, synthetic agents, and gene therapy approaches to treat obesity-related inflammatory complications via suppressing IL-1.
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Affiliation(s)
- Mohammad Ghanbari
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | - Aida Aghazadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | | | - Mahdi Abdoli Shadbad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Dastmalchi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Reza Safaralizadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
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17
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Almezgagi M, Zhang Y, Hezam K, Shamsan E, Gamah M, Al-Shaebi F, Abbas AB, Shoaib M, Saif B, Han Y, Jia R, Zhang W. Diacerein: Recent insight into pharmacological activities and molecular pathways. Biomed Pharmacother 2020; 131:110594. [PMID: 32858499 DOI: 10.1016/j.biopha.2020.110594] [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: 05/09/2020] [Revised: 07/11/2020] [Accepted: 07/29/2020] [Indexed: 12/18/2022] Open
Abstract
Diacerein is a symptomatic slow-acting drug in osteoarthritis (SYSADOA) and the active metabolite is rhein. It is a non-steroidal anti-inflammatory drug with unique pharmacological properties as anti-oxidant and anti-apoptosis. Diacerein has recently shown to have a potential role by mediating anti-inflammatory as well as anti-oxidant and anti-apoptosis in kidney injury, diabetes mullites, and a beneficial effect on pain relief. It may have a therapeutic role in cancer, ulcerative colitis, testicular injury and cervical hyperkeratosis. Furthermore, diacerein has a valuable addition in combination therapy as a synergetic agent. This review, the first of its kind, highlights the proposed roles of diacerein in osteoarthritis and discusses recent results supporting its emerging roles with a particular focus on how these new insights may facilitate the rational development of diacerein for targeted therapies in the future.
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Affiliation(s)
- Maged Almezgagi
- The Key Laboratory of High-Altitude Medical Application of Qinghai Province, Qinghai Xining 810001, China; Department of Immunology, Medical College of Qinghai University, Qinghai Xining 810001, China; Department of Medical Microbiology, Faculty of Sciences, Ibb University, Ibb City 70270, Yemen
| | - Yu Zhang
- Department of Immunology, Medical College of Qinghai University, Qinghai Xining 810001, China
| | - Kamal Hezam
- Nankai University School of Medicine, Tianjin 300071, China
| | - Emad Shamsan
- Department of Immunology, Medical College of Qinghai University, Qinghai Xining 810001, China
| | - Mohammed Gamah
- The Key Laboratory of High-Altitude Medical Application of Qinghai Province, Qinghai Xining 810001, China; Department of Immunology, Medical College of Qinghai University, Qinghai Xining 810001, China
| | - Fadhl Al-Shaebi
- Department of Immunology, Hebei Medical University, Shijiazhuang, Hebei 050017, China
| | - Abdul Baset Abbas
- Department of Medical Microbiology, Faculty of Sciences, Ibb University, Ibb City 70270, Yemen
| | - Muhammad Shoaib
- Department of Immunology, Medical College of Qinghai University, Qinghai Xining 810001, China
| | - Bassam Saif
- Department of Medical Microbiology, Faculty of Sciences, Ibb University, Ibb City 70270, Yemen
| | - Ying Han
- The Key Laboratory of High-Altitude Medical Application of Qinghai Province, Qinghai Xining 810001, China
| | - Ruhan Jia
- The Key Laboratory of High-Altitude Medical Application of Qinghai Province, Qinghai Xining 810001, China
| | - Wei Zhang
- The Key Laboratory of High-Altitude Medical Application of Qinghai Province, Qinghai Xining 810001, China; Department of Immunology, Medical College of Qinghai University, Qinghai Xining 810001, China.
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18
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Wang L, Liu T, Liang R, Wang G, Liu Y, Zou J, Liu N, Zhang B, Liu Y, Ding X, Cai X, Wang Z, Xu X, Ricordi C, Wang S, Shen Z. Mesenchymal stem cells ameliorate β cell dysfunction of human type 2 diabetic islets by reversing β cell dedifferentiation. EBioMedicine 2020; 51:102615. [PMID: 31918404 PMCID: PMC7000334 DOI: 10.1016/j.ebiom.2019.102615] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 12/05/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023] Open
Abstract
Background A physiological hallmark of patients with type 2 diabetes mellitus (T2DM) is β cell dysfunction. Despite adequate treatment, it is an irreversible process that follows disease progression. Therefore, the development of novel therapies that restore β cell function is of utmost importance. Methods This study aims to unveil the mechanistic action of mesenchymal stem cells (MSCs) by investigating its impact on isolated human T2DM islets ex vivo and in vivo. Findings We propose that MSCs can attenuate β cell dysfunction by reversing β cell dedifferentiation in an IL-1Ra-mediated manner. In response to the elevated expression of proinflammatory cytokines in human T2DM islet cells, we observed that MSCs was activated to secret IL-1R antagonist (IL-1Ra) which acted on the inflammed islets and reversed β cell dedifferentiation, suggesting a crosstalk between MSCs and human T2DM islets. The co-transplantation of MSCs with human T2DM islets in diabetic SCID mice and intravenous infusion of MSCs in db/db mice revealed the reversal of β cell dedifferentiation and improved glycaemic control in the latter. Interpretation This evidence highlights the potential of MSCs in future cell-based therapies regarding the amelioration of β cell dysfunction.
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Affiliation(s)
- Le Wang
- Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China; NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China
| | - Tengli Liu
- NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China; Diabetes Research Institute Federation, Hollywood, FL 33021, USA
| | - Rui Liang
- NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China; Diabetes Research Institute Federation, Hollywood, FL 33021, USA
| | - Guanqiao Wang
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Yaojuan Liu
- NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China
| | - Jiaqi Zou
- NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China
| | - Na Liu
- NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China
| | - Boya Zhang
- Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Yan Liu
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Xuejie Ding
- Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Xiangheng Cai
- The First Central Clinical College, Tianjin Medical University, Tianjin, 300192, China
| | - Zhiping Wang
- Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Xiumin Xu
- Diabetes Research Institute, Cell Transplant Centre; Department of Surgery; Department Medicine; Miller School of Medicine, University of Miami, Miami, FL 33136, USA; The Cure Alliance, Miami, FL 33137, USA; Diabetes Research Institute Federation, Hollywood, FL 33021, USA
| | - Camillo Ricordi
- Diabetes Research Institute, Cell Transplant Centre; Department of Surgery; Department Medicine; Miller School of Medicine, University of Miami, Miami, FL 33136, USA; The Cure Alliance, Miami, FL 33137, USA; Diabetes Research Institute Federation, Hollywood, FL 33021, USA
| | - Shusen Wang
- Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China; NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China; Diabetes Research Institute Federation, Hollywood, FL 33021, USA.
| | - Zhongyang Shen
- Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China.
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19
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Guo S, Guo X, Zhang H, Zhang X, Li Z. The Effect of Diacerein on Type 2 Diabetic Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Trial Sequential Analysis. J Diabetes Res 2020; 2020:2593792. [PMID: 32104712 PMCID: PMC7035565 DOI: 10.1155/2020/2593792] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 01/02/2020] [Indexed: 02/07/2023] Open
Abstract
AIMS To figure out the effect of diacerein supplementation on type 2 diabetes mellitus (T2DM). METHODS An electronic search was processed on Pubmed, Embase, and Cochrane library for randomized controlled trials (RCTs) comparing the efficacy of diacerein with placebo on T2DM. The primary outcome was fasting blood glucose (FBG). Trial sequential analysis (TSA) was used to test the reliability of this pooled outcome. Secondary outcomes were glycosylated hemoglobin A1c (HbA1c), body mass index (BMI), lipid profiles, hematological indexes including hematocrit and platelet count, and systematic inflammatory level expressed as a C-reactive protein (CRP) level. Safety outcome was the rate of complications. The difference in continuous data was measured by mean difference (MD) and 95% confidence interval (CI), while the difference of dichotomous data was calculated by relative risk (RR) and 95% CI. A two-tailed P < 0.05 was regarded as statistically significant. RESULTS Five RCTs with 278 participants were included. Compared with control, diacerein provided significant improvement on FBG (MD -0.52; 95% CI (-0.89~-0.14); P < 0.05 was regarded as statistically significant. P < 0.05 was regarded as statistically significant. P < 0.05 was regarded as statistically significant. P < 0.05 was regarded as statistically significant. P < 0.05 was regarded as statistically significant. CONCLUSION Based on the current analysis, diacerein as an add-on treatment provided better glycemic control for T2DM but this benefit requires more verification. Compared with control, additional diacerein also lowered body weight and CRP level in T2DM, but increased the rate of gastrointestinal syndromes.
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Affiliation(s)
- Shizhe Guo
- Internal Medicine Base, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Xianshan Guo
- Department of Endocrinology, Xinxiang Central Hospital, Xinxiang, Henan 453000, China
| | - Hongya Zhang
- Central Laboratory, Yang Pu District Center of Disease Control and Prevention, Shanghai 200090, China
| | - Xuan'e Zhang
- Department of Endocrinology, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Zhen Li
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
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Ibarra Urizar A, Prause M, Wortham M, Sui Y, Thams P, Sander M, Christensen GL, Billestrup N. Beta-cell dysfunction induced by non-cytotoxic concentrations of Interleukin-1β is associated with changes in expression of beta-cell maturity genes and associated histone modifications. Mol Cell Endocrinol 2019; 496:110524. [PMID: 31362031 DOI: 10.1016/j.mce.2019.110524] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 06/12/2019] [Accepted: 07/24/2019] [Indexed: 10/26/2022]
Abstract
Decreased insulin secretory capacity in Type 2 diabetes mellitus is associated with beta-cell dedifferentiation and inflammation. We hypothesize that prolonged exposure of beta-cells to low concentrations of IL-1β induce beta-cell dedifferentiation characterized by impaired glucose-stimulated insulin secretion, reduced expression of key beta-cell genes and changes in histone modifications at gene loci known to affect beta-cell function. Ten days exposure to IL-1β at non-cytotoxic concentrations reduced insulin secretion and beta-cell proliferation and decreased expression of key beta-cell identity genes, including MafA and Ucn3 and decreased H3K27ac at the gene loci, suggesting that inflammatory cytokines directly affects the epigenome. Following removal of IL-1β, beta-cell function was normalized and mRNA expression of beta-cell identity genes, such as insulin and Ucn3 returned to pre-stimulation levels. Our findings indicate that prolonged exposure to low concentrations of IL-1β induces epigenetic changes associated with loss of beta-cell identity as observed in Type 2 diabetes.
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Affiliation(s)
- Adriana Ibarra Urizar
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
| | - Michala Prause
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
| | - Matthew Wortham
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Yinghui Sui
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Peter Thams
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
| | - Maike Sander
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Gitte Lund Christensen
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark; Department of Biomedical Laboratory Science, Metropolitan University College, Copenhagen, 2200, Denmark
| | - Nils Billestrup
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark; Lead Contact Nils Billestrup, Department of Biomedical Science, University of Copenhagen, Copenhagen, 2200, Denmark.
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21
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Yaribeygi H, Atkin SL, Simental-Mendía LE, Barreto GE, Sahebkar A. Anti-inflammatory effects of resolvins in diabetic nephropathy: Mechanistic pathways. J Cell Physiol 2019; 234:14873-14882. [PMID: 30746696 DOI: 10.1002/jcp.28315] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 01/19/2019] [Accepted: 01/24/2019] [Indexed: 01/24/2023]
Abstract
The incidence of diabetes mellitus is growing rapidly. The exact pathophysiology of diabetes is unclear, but there is increasing evidence of the role of the inflammatory response in both developing diabetes as well as its complications. Resolvins are naturally occurring polyunsaturated fatty acids that are found in fish oil and sea food that have been shown to possess anti-inflammatory actions in several tissues including the kidneys. The pathways by which resolvins exert this anti-inflammatory effect are unclear. In this review we discuss the evidence showing that resolvins can suppress inflammatory responses via at least five molecular mechanisms through inhibition of the nucleotide-binding oligomerization domain protein 3 inflammasome, inhibition of nuclear factor κB molecular pathways, improvement of oxidative stress, modulation of nitric oxide synthesis/release and prevention of local and systemic leukocytosis. Complete understanding of these molecular pathways is important as this may lead to the development of new effective therapeutic strategies for diabetes and diabetic nephropathy.
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Affiliation(s)
- Habib Yaribeygi
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia.,Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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22
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Abd-Ellatif RN, Hegab II, Atef MM, Sadek MT, Hafez YM. Diacerein protects against glycerol-induced acute kidney injury: Modulating oxidative stress, inflammation, apoptosis and necroptosis. Chem Biol Interact 2019; 306:47-53. [PMID: 30974099 DOI: 10.1016/j.cbi.2019.04.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/31/2019] [Accepted: 04/05/2019] [Indexed: 12/18/2022]
Abstract
Necroptosis is suggested to have an important role in the pathogenesis of rhabdomyolysis induced acute kidney injury (AKI). In this study, the renoprotective effect of diacerein on glycerol-induced AKI was investigated. Twenty four male albino rats were included in this study and divided into four groups: (group I) saline control group, (group II) glycerol-treated group, (groups III&IV) diacerein + glycerol -treated groups (25 and 50 mg/kg/day) respectively. Renal malondialdehyde (MDA) level in addition to catalase and heme oxygenase (HO) activities were estimated. Comet assay and histopathological changes were evaluated. The levels of pro-apoptotic Bcl-2-associated X (Bax) protein, tumor necrosis factor alpha (TNF-α) and receptor-interacting serine/threonine-protein kinases 3 (RIPK3) were measured by ELISA. RIPK3 and mixed lineage kinase domain-like pseudokinase (MLKL) mRNA expression were assessed by real time PCR. Glycerol treatment caused significant renal histological abnormalities and functional impairment (increased urea and creatinine). Increased levels of renal MDA with concomitant decrease in renal catalase activity and significant DNA damage in comet assay were observed. High expression of RIPK3 and MLKL in the glycerol-treated group with marked elevation of Bax, TNF-α and RIPK3 levels and HO-1 activity were also documented. Diacerein treatment dependently attenuated glycerol induced structural and functional changes in kidney and significantly elicit reduction of renal tissue oxidative damage whereas it decreased renal expression of RIPK3 and MLKL, and decreased Bax, TNF-α and RIPK3 levels and HO-1 activity. CONCLUSION: These results demonstrated that diacerein might have potential application in the amelioration of AKI via its anti-oxidant, anti-inflammatory, anti-apoptotic and anti-necroptotic effects.
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Affiliation(s)
| | - Islam Ibrahim Hegab
- Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Marwa Mohamed Atef
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt.
| | - Mona Tayssir Sadek
- Department of Histology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Yasser Mostafa Hafez
- Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
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Tsalamandris S, Antonopoulos AS, Oikonomou E, Papamikroulis GA, Vogiatzi G, Papaioannou S, Deftereos S, Tousoulis D. The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives. Eur Cardiol 2019; 14:50-59. [PMID: 31131037 PMCID: PMC6523054 DOI: 10.15420/ecr.2018.33.1] [Citation(s) in RCA: 801] [Impact Index Per Article: 133.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 02/18/2019] [Indexed: 02/06/2023] Open
Abstract
Diabetes is a complex metabolic disorder affecting the glucose status of the human body. Chronic hyperglycaemia related to diabetes is associated with end organ failure. The clinical relationship between diabetes and atherosclerotic cardiovascular disease is well established. This makes therapeutic approaches that simultaneously target diabetes and atherosclerotic disease an attractive area for research. The majority of people with diabetes fall into two broad pathogenetic categories, type 1 or type 2 diabetes. The role of obesity, adipose tissue, gut microbiota and pancreatic beta cell function in diabetes are under intensive scrutiny with several clinical trials to have been completed while more are in development. The emerging role of inflammation in both type 1 and type 2 diabetes (T1D and T1D) pathophysiology and associated metabolic disorders, has generated increasing interest in targeting inflammation to improve prevention and control of the disease. After an extensive review of the possible mechanisms that drive the metabolic pattern in T1D and T2D and the inflammatory pathways that are involved, it becomes ever clearer that future research should focus on a model of combined suppression for various inflammatory response pathways.
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Affiliation(s)
- Sotirios Tsalamandris
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Alexios S Antonopoulos
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Evangelos Oikonomou
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - George-Aggelos Papamikroulis
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Georgia Vogiatzi
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Spyridon Papaioannou
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Spyros Deftereos
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Dimitris Tousoulis
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
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Chang WC, Chu MT, Hsu CY, Wu YJJ, Lee JY, Chen TJ, Chung WH, Chen DY, Hung SI. Rhein, An Anthraquinone Drug, Suppresses the NLRP3 Inflammasome and Macrophage Activation in Urate Crystal-Induced Gouty Inflammation. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:135-151. [PMID: 30612459 DOI: 10.1142/s0192415x19500071] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Rhein, an anthraquinone drug, is a widely used traditional Chinese medicine. Rhein is a major bioactive metabolite of diacerein which has been approved for treating osteoarthritis with a good safety profile in humans. Gouty arthritis is an inflammatory disease characterized by urate crystal-induced NLRP3 inflammasome activation with up-regulated caspase-1 protease and IL-1 β in macrophages. Inhibition of the NLRP3 inflammasome formation has been considered as a potential therapeutic avenue for treating or preventing many inflammatory diseases. This study aimed to evaluate the anti-inflammatory effects of rhein on gouty arthritis. Rhein within the physiological levels of humans showed no toxicity on the cell viability and differentiation, but significantly decreased the production of IL-1 β , TNF- α and caspase-1 protease in urate crystal-activated macrophages. Compared to medium controls, rhein at the therapeutic concentration (2.5 μ g/mL) effectively inhibited IL-1 β production by 47% ( P=0.002 ). Rhein did not affect the mRNA levels of CASP1, NLRP3 and ASC, but suppressed the protein expression and enzyme activity of caspase-1. Immunofluorescence confocal microscopy further revealed that rhein suppressed the aggregation of ASC speck and inhibited the formation of NLRP3 inflammasome. Rhein of 5 μ g/mL significantly decreased the ASC speck to 36% ( P=0.0011 ), and reduced the NLRP3 aggregates to 37.5% ( P=0.014 ). Our data demonstrate that rhein possesses pharmacological activity to suppress caspase-1 protease activity and IL-1 β production by interfering with the formation of NLRP3 multiprotein complex. These results suggest that rhein has therapeutic potential for treating NLRP3 inflammasome-mediated diseases such as gouty arthritis.
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Affiliation(s)
- Wan-Chun Chang
- * Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Mu-Tzu Chu
- * Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chih-Yuan Hsu
- * Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yeong-Jian Jan Wu
- † Department of Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Keelung, Taiwan
| | | | - Ting-Jui Chen
- * Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,§ Department of Dermatology, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
| | - Wen-Hung Chung
- ¶ Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, College of Medicine and Chang Gung University, Taipei, Taiwan
| | - Der-Yuan Chen
- ∥ Rheumatology and Immunology Center, China Medical University Hospital; Department of Medicine, China Medical University, Taichung, Taiwan
| | - Shuen-Iu Hung
- * Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
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Lytrivi M, Igoillo-Esteve M, Cnop M. Inflammatory stress in islet β-cells: therapeutic implications for type 2 diabetes? Curr Opin Pharmacol 2018; 43:40-45. [PMID: 30142486 DOI: 10.1016/j.coph.2018.08.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 07/25/2018] [Accepted: 08/02/2018] [Indexed: 01/05/2023]
Abstract
Type 2 diabetes is a common complex disease. Relatively little is known about the underlying pathophysiology. Mild islet inflammation has been suggested to play a pathogenic role; here we review the available evidence. Mild islet inflammation is histologically detected in pancreas sections of type 2 diabetic patients. In experimental models, it can be triggered by excess nutrients, amyloid, lipopolysaccharide, and endoplasmic reticulum and oxidative stress. Transcriptome studies do not consistently identify pro-inflammatory gene expression signatures in type 2 diabetic islets, and genetic evidence calls into question the causality of inflammation. Several anti-inflammatory medications confer a modest glucose-lowering effect, supporting the role for inflammation in type 2 diabetes. Whether these anti-inflammatory therapies target inflammation in islets or in other metabolically relevant tissues remains unknown.
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Affiliation(s)
- Maria Lytrivi
- ULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium; Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium.
| | - Mariana Igoillo-Esteve
- ULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - Miriam Cnop
- ULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium; Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium.
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26
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Tres GS, Fuchs SC, Piovesan F, Koehler-Santos P, Pereira FDS, Camey S, Lisboa HK, Moreira LB. Effect of Diacerein on Metabolic Control and Inflammatory Markers in Patients with Type 2 Diabetes Using Antidiabetic Agents: A Randomized Controlled Trial. J Diabetes Res 2018; 2018:4246521. [PMID: 29805981 PMCID: PMC5902058 DOI: 10.1155/2018/4246521] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 01/17/2018] [Accepted: 02/15/2018] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Studies have shown that T2DM is an inflammatory disease. Thus, the present study was aimed at evaluating whether diacerein could improve the metabolic and inflammatory profile among patients with T2DM under long-term treatment with glucose-lowering agents. METHODS This is a double-blind, parallel, placebo-controlled trial with 72 participants randomly assigned to diacerein 50 mg or placebo for 12 weeks. The primary endpoint was the between-group difference in change in HbA1c. Secondary endpoints included the proportion of patients achieving metabolic control [HbA1c ≤ 7.0% (53 mmol/mol)] and change in inflammatory mediators. RESULTS Participants in the diacerein group had greater reductions in mean HbA1c level in comparison to placebo (-0.98; 95% CI: -2.02 to 0.05, P = 0.06), independently of confounding factors. The difference in HbA1c level was -1.3 (95% CI: -2.3 to -0.4) in favor of diacerein (P = 0.007) in those with <14 years of diabetes duration versus 0.05 (-0.7 to 0.8; P = 0.9) in those with longer duration. The diacerein group had a 50% increase in the number of participants at the lowest TNF-α level (≤1.46 pg/mL). CONCLUSIONS In patients with long-established T2DM under long-term treatment with glucose-lowering agents, diacerein improves metabolic control as measured by HbA1c level and has a favorable impact on inflammatory profile. CLINICAL TRIAL REGISTRY This trial is registered with Brazilian Clinical Trials Registry (ReBEC) number RBR-29j956.
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Affiliation(s)
- Glaucia S. Tres
- Postgraduate Program in Cardiology, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos 2600, 90035-003 Porto Alegre, RS, Brazil
- Hospital São Vicente de Paulo, School of Medicine, Universidade de Passo Fundo (UPF), R. Teixeira Soares 808, 99010-080 Passo Fundo, RS, Brazil
| | - Sandra C. Fuchs
- Postgraduate Program in Cardiology, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos 2600, 90035-003 Porto Alegre, RS, Brazil
| | - Fabiana Piovesan
- Postgraduate Program in Cardiology, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos 2600, 90035-003 Porto Alegre, RS, Brazil
- Hospital São Vicente de Paulo, School of Medicine, Universidade de Passo Fundo (UPF), R. Teixeira Soares 808, 99010-080 Passo Fundo, RS, Brazil
| | - Patricia Koehler-Santos
- Unidade de Análises Moleculares e de Proteínas (UAMP), Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos 2350, 90035-903 Porto Alegre, RS, Brazil
| | - Fernanda dos S. Pereira
- Unidade de Análises Moleculares e de Proteínas (UAMP), Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos 2350, 90035-903 Porto Alegre, RS, Brazil
| | - Suzi Camey
- Postgraduate Program in Cardiology, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos 2600, 90035-003 Porto Alegre, RS, Brazil
- Department of Statistics, Mathematics Institute, Universidade Federal do Rio Grande do Sul, R. Ramiro Barcelos 2350, 90035-903 Porto Alegre, RS, Brazil
- Biostatistics Unit, GPPG, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos 2350, 90035-903 Porto Alegre, RS, Brazil
| | - Hugo K. Lisboa
- Hospital São Vicente de Paulo, School of Medicine, Universidade de Passo Fundo (UPF), R. Teixeira Soares 808, 99010-080 Passo Fundo, RS, Brazil
| | - Leila B. Moreira
- Postgraduate Program in Cardiology, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos 2600, 90035-003 Porto Alegre, RS, Brazil
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Zhang Q, Zhou J, Wang Y, Chen D. The effect and safety of diacerein in patients with type 2 diabetes mellitus : a systematic review and meta-analysis. AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL IMMUNOLOGY 2017; 6:97-106. [PMID: 29348985 PMCID: PMC5768895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Accepted: 11/17/2017] [Indexed: 06/07/2023]
Abstract
The Background: Diacerein has been proposed as a treatment option for management of type 2 diabetes due to its anti-inflammatory properties. PURPOSE The aim of this systematic review and meta-analysis of randomized controlled trials (RCTs) is to examine the effect and safety of diacerein in patients with type 2 diabetes. DATA SOURCES AND STUDY SELECTION We searched Pubmed, Embase, and Cochrane Library for RCTs published from database inception to September 2017. DATA EXTRACTION AND DATA SYNTHESIS Among 44 studies that were initially identified, four were eligible and were included in the following analysis. Diacerein significantly reduced fasting glycemia [weighted mean differences (WMD) -0.66, 95% confidence interval (95% CI) -1.16 to -0.16] and glycated hemoglobin A1c (HbA1c ) (WMD -0.85, 95% CI -1.44 to -0.26). And the patients with a diacerein supplementation duration of ≤12 weeks had a greater decrease of fasting glycemia and HbA1c than the supplementation duration of >12 weeks. Furthermore, compared with placebo, diacerein revealed a significant increase in the relative risk (RR) of gastrointestinal symptoms (RR=2.50, 95% CI: 1.10 to 5.65), especially in the study subgroup with supplementation duration of >12 weeks (RR=4.01, 95% CI: 2.32 to 6.95). LIMITATIONS The sample size was relatively small and the duration of included studies was short so that the treatment efficacy and safety for longer duration was unknown. CONCLUSIONS Although further studies are needed, our findings clearly provide support to the use of diacerein in the clinical management of subjects with type 2 diabetes.
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Affiliation(s)
- Qi Zhang
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan UniversityChengdu 610041, Sichuan, China
| | - Junteng Zhou
- Department of Cardiology, West China Hospital of Sichuan UniversityChengdu 610041, Sichuan, China
| | - Yushu Wang
- Department of Cardiology, West China Hospital of Sichuan UniversityChengdu 610041, Sichuan, China
| | - Decai Chen
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan UniversityChengdu 610041, Sichuan, China
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Piovesan F, Tres GS, Moreira LB, Andrades ME, Lisboa HK, Fuchs SC. Effect of diacerein on renal function and inflammatory cytokines in participants with type 2 diabetes mellitus and chronic kidney disease: A randomized controlled trial. PLoS One 2017; 12:e0186554. [PMID: 29049415 PMCID: PMC5648185 DOI: 10.1371/journal.pone.0186554] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 09/30/2017] [Indexed: 01/13/2023] Open
Abstract
Diacerein seems to improve metabolic control and reduce inflammatory marker levels in individuals with type 2 diabetes mellitus (Type 2 DM), but for participants with chronic kidney disease (CKD) its effect is unknown. This study aimed to evaluate the effect of diacerein vs. placebo on urinary albumin/creatinine ratio (ACR), glomerular filtration rate (GFR), and inflammatory cytokines in type 2 DM participants with CKD. Blood pressure (BP) and metabolic control were secondary outcomes. This randomized, placebo-controlled, parallel trial of adjuvant treatment of type 2 DM with diacerein enrolled seventy-two participants with CKD, aged 30–80 years, with glycated hemoglobin levels from 53–97 mmol/mol (7.0–11.0%), receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antidiabetic agents. Participants randomized to diacerein or placebo were followed-up up to 90 days. Both groups had a marked reduction in ACR, but there was no effect on glomerular filtration rate. While the diacerein group had reduced TNF-α levels at the 75th percentile with a borderline significance (P = 0.05), there were no changes in the IL levels at the 75th percentile. Diacerein prevented the increase in blood glucose to the level observed in the placebo group (P = 0.04), improving metabolic control by 74%, reducing 24-hour diastolic BP, nighttime systolic and diastolic BP compared to the placebo group. In conclusion, among patients with type 2 DM and CKD, diacerein does not have an effect on ACR or GFR, but slows metabolic control deterioration and is associated with lower nighttime systolic and diastolic blood pressure. Trial registration: Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clinicos; ReBeC) U1111-1156-0255
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Affiliation(s)
- Fabiana Piovesan
- Postgraduate Program in Cardiology, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos, Porto Alegre, RS, Brazil
- Hospital São Vicente de Paulo, School of Medicine, Universidade de Passo Fundo (UPF), R. Teixeira Soares, Passo Fundo, RS, Brazil
| | - Glaucia S. Tres
- Postgraduate Program in Cardiology, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos, Porto Alegre, RS, Brazil
- Hospital São Vicente de Paulo, School of Medicine, Universidade de Passo Fundo (UPF), R. Teixeira Soares, Passo Fundo, RS, Brazil
| | - Leila B. Moreira
- Postgraduate Program in Cardiology, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos, Porto Alegre, RS, Brazil
| | - Michael E. Andrades
- Postgraduate Program in Cardiology, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos, Porto Alegre, RS, Brazil
- Unidade de Análises Moleculares e de Proteínas (UAMP), Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos, Porto Alegre, RS, Brazil
| | - Hugo K. Lisboa
- Hospital São Vicente de Paulo, School of Medicine, Universidade de Passo Fundo (UPF), R. Teixeira Soares, Passo Fundo, RS, Brazil
| | - Sandra C. Fuchs
- Postgraduate Program in Cardiology, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos, Porto Alegre, RS, Brazil
- Centro de Pesquisa Clinica (CPC), 5o. andar. Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), R. Ramiro Barcelos, Porto Alegre, RS, Brazil
- * E-mail:
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Cardoso CRL, Leite NC, Carlos FO, Loureiro AA, Viegas BB, Salles GF. Efficacy and Safety of Diacerein in Patients With Inadequately Controlled Type 2 Diabetes: A Randomized Controlled Trial. Diabetes Care 2017; 40:1356-1363. [PMID: 28818994 DOI: 10.2337/dc17-0374] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 05/11/2017] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To assess, in a randomized, double-blind, and placebo-controlled trial, the efficacy and safety of diacerein, an immune modulator anti-inflammatory drug, in improving glycemic control of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Eighty-four patients with HbA1c between 7.5 and 9.5% (58-80 mmol/mol) were randomized to 48-week treatment with placebo (n = 41) or diacerein 100 mg/day (n = 43). The primary outcome was the difference in mean HbA1c changes during treatment. Secondary outcomes were other efficacy and safety measurements. A general linear regression with repeated measures, adjusted for age, sex, diabetes duration, and each baseline value, was used to estimate differences in mean changes. Both intention-to-treat (ITT) analysis and per-protocol analysis (excluding 10 patients who interrupted treatment) were performed. RESULTS Diacerein reduced HbA1c compared with placebo by 0.35% (3.8 mmol/mol; P = 0.038) in the ITT analysis and by 0.41% (4.5 mmol/mol; P = 0.023) in the per-protocol analysis. The peak of effect occurred at the 24th week of treatment (-0.61% [6.7 mmol/mol; P = 0.014] and -0.78% [8.5 mmol/mol; P = 0.005], respectively), but it attenuated toward nonsignificant differences at the 48th week. No significant effect of diacerein was observed in other efficacy and safety measures. Diarrhea occurred in 65% of patients receiving diacerein and caused treatment interruption in 16%. Seven patients in the diacerein group reduced insulin dosage, whereas 10 in the placebo group increased it; however, mild hypoglycemic events were equally observed. CONCLUSIONS Diacerein reduced mean HbA1c levels, with peak of effect at the 24th week of treatment. The drug was well tolerated and may be indicated as adjunct treatment in patients with type 2 diabetes, particularly in those with osteoarthritis.
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Affiliation(s)
- Claudia R L Cardoso
- Department of Internal Medicine, University Hospital Clementino Fraga Filho, and School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Nathalie C Leite
- Department of Internal Medicine, University Hospital Clementino Fraga Filho, and School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda O Carlos
- Department of Internal Medicine, University Hospital Clementino Fraga Filho, and School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Andréia A Loureiro
- Department of Internal Medicine, University Hospital Clementino Fraga Filho, and School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Bianca B Viegas
- Department of Internal Medicine, University Hospital Clementino Fraga Filho, and School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Gil F Salles
- Department of Internal Medicine, University Hospital Clementino Fraga Filho, and School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Wang Z, Yang L, Fan H, Wu P, Zhang F, Zhang C, Liu W, Li M. Screening of a natural compound library identifies emodin, a natural compound from Rheum palmatum Linn that inhibits DPP4. PeerJ 2017; 5:e3283. [PMID: 28507818 PMCID: PMC5428354 DOI: 10.7717/peerj.3283] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 04/07/2017] [Indexed: 12/11/2022] Open
Abstract
Historically, Chinese herbal medicines have been widely used in the treatment of hyperglycemia, but the mechanisms underlying their effectiveness remain largely unknown. Here, we screened a compound library primarily comprised of natural compounds extracted from herbs and marine organisms. The results showed that emodin, a natural compound from Rheum palmatum Linn, inhibited DPP4 activity with an in vitro IC50 of 5.76 µM without inhibiting either DPP8 or DPP9. A docking model revealed that emodin binds to DPP4 protein through Glu205 and Glu206, although with low affinity. Moreover, emodin treatment (3, 10 and 30 mg/kg, P.O.) in mice decreased plasma DPP4 activity in a dose-dependent manner. Our study suggests that emodin inhibits DPP4 activity and may represent a novel therapeutic for the treatment of type 2 diabetes.
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Affiliation(s)
- Zhaokai Wang
- College of Life Sciences, Fujian Normal University, Fuzhou, P. R. China.,Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, State Oceanic Administration, Xiamen, P. R. China
| | - Longhe Yang
- Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, State Oceanic Administration, Xiamen, P. R. China
| | - Hu Fan
- Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, State Oceanic Administration, Xiamen, P. R. China
| | - Peng Wu
- Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, State Oceanic Administration, Xiamen, P. R. China
| | - Fang Zhang
- Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, State Oceanic Administration, Xiamen, P. R. China
| | - Chao Zhang
- Engineering Research Center of Marine Biological Resource Comprehensive Utilization, Third Institute of Oceanography, State Oceanic Administration, Xiamen, P. R. China
| | - Wenjie Liu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen, P. R. China
| | - Min Li
- College of Life Sciences, Fujian Normal University, Fuzhou, P. R. China
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Combination Therapies of Diacerein and Febuxostat Inhibit IL-1β Responses and Improve Clinical Symptoms in Patients With Refractory Gout. Am J Ther 2017; 24:e290-e297. [DOI: 10.1097/mjt.0000000000000284] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Villar MMD, Martínez-Abundis E, Preciado-Márquez RO, González-Ortiz M. Effect of diacerein as an add-on to metformin in patients with type 2 diabetes mellitus and inadequate glycemic control. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2017; 61:188-192. [PMID: 28225996 PMCID: PMC10118867 DOI: 10.1590/2359-3997000000242] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 10/10/2016] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To evaluate the effect of diacerein as an add-on to metformin in patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control. MATERIALS AND METHODS A randomized, double-blind, placebo-controlled clinical trial was carried out on 12 patients with T2DM and inadequate glycemic control [glycated hemoglobin A1c (A1C) ≥ 7%] with metformin as monotherapy (≥ 1500 mg per day) for at least the previous 90 days. Fasting and postprandial glucose were measured before and after the pharmacological intervention. A1C, lipid profile, creatinine and uric acid were also evaluated. After randomization, all patients continued with their dose of metformin. Six subjects received placebo and the other six volunteers took diacerein. Data were tested using the Wilcoxon signed-rank, Mann-Whitney U and chi-square tests. The Institutional Ethics Committee approved the study protocol. RESULTS After 90 days of diacerein as an add-on to metformin, there was a significant decrease in fasting glucose (196 ± 79 vs. 149 ± 70 mg/dL, p < 0.05), postprandial glucose (262 ± 99 vs. 187 ± 70 mg/dlL, p < 0.05) and A1C (8.4 ± 2.0 vs. 6.7 ± 1.7 %, p < 0.05). CONCLUSIONS Diacerein as an add-on to metformin in patients with T2DM improved their glycemic control.
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Dai Y, Ma BL, Zheng M, Shi R, Li YY, Wang TM, Ma YM. Identification of drug transporters involved in the uptake and efflux of rhein in hepatocytes. RSC Adv 2017. [DOI: 10.1039/c6ra28205a] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Rhein is an herbal medicine with various bioactivities and is derived from an anthraquinone compound. In this study, we aimed to identify drug transporters involved in the uptake and efflux of rhein in hepatocytes.
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Affiliation(s)
- Yan Dai
- Department of Pharmacology
- School of Pharmacy
- Shanghai University of Traditional Chinese Medicine
- Shanghai
- China
| | - Bing-Liang Ma
- Department of Pharmacology
- School of Pharmacy
- Shanghai University of Traditional Chinese Medicine
- Shanghai
- China
| | - Min Zheng
- Department of Pharmacology
- School of Pharmacy
- Shanghai University of Traditional Chinese Medicine
- Shanghai
- China
| | - Rong Shi
- Department of Pharmacology
- School of Pharmacy
- Shanghai University of Traditional Chinese Medicine
- Shanghai
- China
| | - Yuan-Yuan Li
- Department of Pharmacology
- School of Pharmacy
- Shanghai University of Traditional Chinese Medicine
- Shanghai
- China
| | - Tian-Ming Wang
- Department of Pharmacology
- School of Pharmacy
- Shanghai University of Traditional Chinese Medicine
- Shanghai
- China
| | - Yue-Ming Ma
- Department of Pharmacology
- School of Pharmacy
- Shanghai University of Traditional Chinese Medicine
- Shanghai
- China
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34
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Somatostatin receptor targeted liposomes with Diacerein inhibit IL-6 for breast cancer therapy. Cancer Lett 2016; 388:292-302. [PMID: 28025102 DOI: 10.1016/j.canlet.2016.12.021] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 11/24/2016] [Accepted: 12/16/2016] [Indexed: 01/13/2023]
Abstract
Selective targeting to the tumor niche remains a major challenge in successful cancer therapy. Somatostatin receptor 2 (SSTR2) is overexpressed in breast cancer cells thus making this receptor an attractive target for selective guidance of ligand-conjugated drug liposomes to the tumor site. In this study, a synthetic somatostatin analogue (SST) was used as SSTR2 targeting agent and Diacerein was employed as therapeutic molecule. Diacerein loaded liposomes (DNL) were prepared and they were further decorated with the synthetic and stable analogue of somatostatin (SST-DNL). Fabricated liposomes were nano-size in range and biocompatible. SST-DNL displayed significantly better anti-tumor efficacy as compared to free Diacerein (DN) and DNL in breast cancer models. Enhanced apoptosis in breast cancer cells was detected in SST-DNL treated groups as monitored by cell cycle analysis and changes in expression level of apoptotic/anti-apoptotic proteins Bcl-2, Bax, cleaved Caspase 3 and PARP. SST-DNL more effectively inhibited the oncogenic IL-6/IL-6R/STAT3/MAPK/Akt signalling pathways as compared to DN or DNL in cancer cells. In addition, SST-DNL effectively suppressed angiogenesis and cancer cell invasion. In vivo tumor growth in a MDA-MB-231 mouse xenograft model was significantly suppressed following SST-DNL treatment. In xenograft model, immunohistochemistry of Ki-67 and CD-31 indicated that SST-DNL improved the anti-proliferative and anti-angiogenic impacts of Diacerein. In vivo pharmacokinetic studies in rats showed enhanced circulation time in the DNL or SST-DNL treated groups as compared to free DN. Considering all of these findings, we conclude that SST-DNL provides a novel strategy with better efficacy for breast cancer therapy.
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35
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Pollack RM, Donath MY, LeRoith D, Leibowitz G. Anti-inflammatory Agents in the Treatment of Diabetes and Its Vascular Complications. Diabetes Care 2016; 39 Suppl 2:S244-52. [PMID: 27440839 DOI: 10.2337/dcs15-3015] [Citation(s) in RCA: 176] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The association between hyperglycemia and inflammation and vascular complications in diabetes is now well established. Antidiabetes drugs may alleviate inflammation by reducing hyperglycemia; however, the anti-inflammatory effects of these medications are inconsistent and it is unknown whether their beneficial metabolic effects are mediated via modulation of chronic inflammation. Recent data suggest that immunomodulatory treatments may have beneficial effects on glycemia, β-cell function, and insulin resistance. However, the mechanisms underlying their beneficial metabolic effects are not always clear, and there are concerns regarding the specificity, safety, and efficacy of immune-based therapies. Herein, we review the anti-inflammatory and metabolic effects of current antidiabetes drugs and of anti-inflammatory therapies that were studied in patients with type 2 diabetes. We discuss the potential benefit of using anti-inflammatory treatments in diabetes and important issues that should be addressed prior to implementation of such therapeutic approaches.
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Affiliation(s)
- Rena M Pollack
- Diabetes Unit, Hadassah University Hospital, Jerusalem, Israel
| | - Marc Y Donath
- Endocrinology, Diabetes, and Metabolism, Department of Biomedicine, University Hospital Basel, Basel, Switzerland
| | - Derek LeRoith
- Diabetes and Metabolism Clinical Research Center of Excellence, Rambam Health Care Campus, Haifa, Israel
| | - Gil Leibowitz
- Diabetes Unit, Hadassah University Hospital, Jerusalem, Israel Endocrine Service, Hadassah University Hospital, Jerusalem, Israel
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36
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Turner N, Zeng XY, Osborne B, Rogers S, Ye JM. Repurposing Drugs to Target the Diabetes Epidemic. Trends Pharmacol Sci 2016; 37:379-389. [PMID: 26900045 DOI: 10.1016/j.tips.2016.01.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 01/25/2016] [Accepted: 01/25/2016] [Indexed: 01/07/2023]
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37
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Rehman M, Madni A, Ihsan A, Khan WS, Khan MI, Mahmood MA, Ashfaq M, Bajwa SZ, Shakir I. Solid and liquid lipid-based binary solid lipid nanoparticles of diacerein: in vitro evaluation of sustained release, simultaneous loading of gold nanoparticles, and potential thermoresponsive behavior. Int J Nanomedicine 2015; 10:2805-14. [PMID: 25897224 PMCID: PMC4396646 DOI: 10.2147/ijn.s67147] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Binary fatty acid mixture-based solid lipid nanoparticles (SLNs) were prepared for delivery of diacerein, a novel disease-modifying osteoarthritis drug, with and without simultaneously loaded gold nanoparticles (GNPs). In order to optimize SLNs for temperature-responsive release, lipid mixtures were prepared using different ratios of solid (stearic acid or lauric acid) and liquid (oleic acid) fatty acids. SLNs were prepared by microemulsification (53 nm), hot melt encapsulation (10.4 nm), and a solvent emulsification-evaporation technique (7.8 nm). The physicochemical characteristics of SLNs were studied by Zetasizer, Fourier transform infrared, and X-ray diffraction analysis. High encapsulation of diacerein was achieved with diacerein-loaded and simultaneously GNP-diacerein-loaded SLNs. In vitro dissolution studies revealed a sustained release pattern for diacerein over 72 hours for diacerein-loaded SLNs and 12 hours for GNP-diacerein-loaded SLNs. An increase in diacerein payload increased the release time of diacerein while GNPs decreased it. In addition, rapid release of diacerein over 4 hours was observed at 40°C (melting point of optimized fatty acid mixture), demonstrating that these binary SLNs could be used for thermoresponsive drug delivery. Kinetic modeling indicated that drug release followed zero order and Higuchi diffusion models (R10>0.9), while the Korsmeyer-Peppas model predicted a diffusion release mechanism (n<0.5).
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Affiliation(s)
- Mubashar Rehman
- Department of Pharmacy, Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Pakistan
| | - Asadullah Madni
- Department of Pharmacy, Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Pakistan
| | - Ayesha Ihsan
- Nanobiotechnology Group, Industrial Biotechnology Division, National Institute of Biotechnology and Genetic Engineering, Faisalabad, Pakistan
| | - Waheed Samraiz Khan
- Nanobiotechnology Group, Industrial Biotechnology Division, National Institute of Biotechnology and Genetic Engineering, Faisalabad, Pakistan
| | - Muhammad Imran Khan
- Department of Pharmacy, Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Pakistan
| | - Muhammad Ahmad Mahmood
- Department of Pharmacy, Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Pakistan
| | - Muhammad Ashfaq
- Department of Pharmacy, Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Pakistan
| | - Sadia Zafar Bajwa
- Nanobiotechnology Group, Industrial Biotechnology Division, National Institute of Biotechnology and Genetic Engineering, Faisalabad, Pakistan
| | - Imran Shakir
- Sustainable Energy Technologies (SET) centre, College of Engineering, King Saud University, Riyadh, Saudi Arabia
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Litvinova L, Kirienkova E, Mazunin I, Vasilenko M, Fattakhov N. Insulin resistance pathogenesis in metabolic obesity. ACTA ACUST UNITED AC 2015; 61:70-82. [DOI: 10.18097/pbmc20156101070] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
In this review we discuss the molecular mechanisms of insulin resistance concomitant with metabolic inflammation. We also analyze the world results of experimental and clinical studies which aimed at identifying the molecular targets for the development of new prevention and treatment of insulin resistance.
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Affiliation(s)
- L.S. Litvinova
- Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - E.V. Kirienkova
- Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - I.O. Mazunin
- Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - M.A. Vasilenko
- Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - N.S. Fattakhov
- Immanuel Kant Baltic Federal University, Kaliningrad, Russia
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39
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Agrawal NK, Kant S. Targeting inflammation in diabetes: Newer therapeutic options. World J Diabetes 2014; 5:697-710. [PMID: 25317247 PMCID: PMC4138593 DOI: 10.4239/wjd.v5.i5.697] [Citation(s) in RCA: 137] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 04/24/2014] [Accepted: 05/29/2014] [Indexed: 02/05/2023] Open
Abstract
Inflammation has been recognised to both decrease beta cell insulin secretion and increase insulin resistance. Circulating cytokines can affect beta cell function directly leading to secretory dysfunction and increased apoptosis. These cytokines can also indirectly affect beta cell function by increasing adipocyte inflammation.The resulting glucotoxicity and lipotoxicity further enhance the inflammatory process resulting in a vicious cycle. Weight reduction and drugs such as metformin have been shown to decrease the levels of C-Reactive Protein by 31% and 13%, respectively. Pioglitazone, insulin and statins have anti-inflammatory effects. Interleukin 1 and tumor necrosis factor-α antagonists are in trials and NSAIDs such as salsalate have shown an improvement in insulin sensitivity. Inhibition of 12-lipo-oxygenase, histone de-acetylases, and activation of sirtuin-1 are upcoming molecular targets to reduce inflammation. These therapies have also been shown to decrease the conversion of pre-diabetes state to diabetes. Drugs like glicazide, troglitazone, N-acetylcysteine and selective COX-2 inhibitors have shown benefit in diabetic neuropathy by decreasing inflammatory markers. Retinopathy drugs are used to target vascular endothelial growth factor, angiopoietin-2, various proteinases and chemokines. Drugs targeting the proteinases and various chemokines are pentoxifylline, inhibitors of nuclear factor-kappa B and mammalian target of rapamycin and are in clinical trials for diabetic nephropathy. Commonly used drugs such as insulin, metformin, peroxisome proliferator-activated receptors, glucagon like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors also decrease inflammation. Anti-inflammatory therapies represent a potential approach for the therapy of diabetes and its complications.
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40
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Jung SJ, Park SH, Choi EK, Cha YS, Cho BH, Kim YG, Kim MG, Song WO, Park TS, Ko JK, So BO, Chae SW. Beneficial effects of Korean traditional diets in hypertensive and type 2 diabetic patients. J Med Food 2014; 17:161-71. [PMID: 24456367 DOI: 10.1089/jmf.2013.3042] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The prevalence of metabolic syndrome, hypertension, and diabetes has been increasing rapidly in Korea. The rate of increase has paralleled the replacement of Korean traditional diets (KTD), which emphasize vegetables and fermented foods, with western style dietary patterns that are rich in animal foods and saturated fat. We aimed to investigate the efficacy of the KTD in controlling fasting plasma glucose, blood pressure, and cardiovascular disease risk factors in hypertensive and type 2 diabetic (T2D) patients. Forty-one patients (61.8±1.5 years) who were taking medications prescribed for respective diseases were recruited from the Chonbuk National University Hospital for participation in a 12-week, parallel, controlled clinical trial. The control group (n=20) was advised to "eat as usual," whereas the experimental KTD diet group (n=21) was fed the KTD three times a day for 12 weeks. At the end of the trial, both groups had lower body mass index, % body fat, and waist-hip ratio compared to the baseline values (P<.05). Compared to the control group, the KTD group had a greater mean change (P<.05) from the baseline for glycated hemoglobin (HbA₁c) (-0.72% vs. -0.25%) and heart rate (-7.1 vs. +1.6). Regular consumption of the KTD for 12 weeks by hypertensive and T2D patients resulted in favorable changes in cardiovascular risk factors.
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Affiliation(s)
- Su-Jin Jung
- 1 Clinical Trial Center for Functional Foods, Chonbuk National University Hospital , Jeonju, Republic of Korea
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41
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Possible role of interleukin-1β in type 2 diabetes onset and implications for anti-inflammatory therapy strategies. PLoS Comput Biol 2014; 10:e1003798. [PMID: 25167060 PMCID: PMC4148195 DOI: 10.1371/journal.pcbi.1003798] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 07/08/2014] [Indexed: 12/31/2022] Open
Abstract
Increasing evidence of a role of chronic inflammation in type 2 diabetes progression has led to the development of therapies targeting the immune system. We develop a model of interleukin-1β dynamics in order to explain principles of disease onset. The parameters in the model are derived from in vitro experiments and patient data. In the framework of this model, an IL-1β switch is sufficient and necessary to account for type 2 diabetes onset. The model suggests that treatments targeting glucose bear the potential of stopping progression from pre-diabetes to overt type 2 diabetes. However, once in overt type 2 diabetes, these treatments have to be complemented by adjuvant anti-inflammatory therapies in order to stop or decelerate disease progression. Moreover, the model suggests that while glucose-lowering therapy needs to be continued all the way, dose and duration of the anti-inflammatory therapy needs to be specifically controlled. The model proposes a framework for the discussion of clinical trial outcomes.
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42
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Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov 2014; 13:465-76. [PMID: 24854413 DOI: 10.1038/nrd4275] [Citation(s) in RCA: 531] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The role of inflammation in the pathogenesis of type 2 diabetes and associated complications is now well established. Several conditions that are driven by inflammatory processes are also associated with diabetes, including rheumatoid arthritis, gout, psoriasis and Crohn's disease, and various anti-inflammatory drugs have been approved or are in late stages of development for the treatment of these conditions. This review discusses the rationale for the use of some of these anti-inflammatory treatments in patients with diabetes and what we could expect from their use. Future immunomodulatory treatments may not target a specific disease, but could instead act on a dysfunctional pathway that causes several conditions associated with the metabolic syndrome.
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Affiliation(s)
- Marc Y Donath
- Endocrinology, Diabetes & Metabolism, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland
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43
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Jaeckle Santos LJ, Li C, Doulias PT, Ischiropoulos H, Worthen GS, Simmons RA. Neutralizing Th2 inflammation in neonatal islets prevents β-cell failure in adult IUGR rats. Diabetes 2014; 63:1672-84. [PMID: 24408314 PMCID: PMC3994952 DOI: 10.2337/db13-1226] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Intrauterine growth restriction (IUGR) leads to development of type 2 diabetes (T2D) in adulthood. The mechanisms underlying this phenomenon have not been fully elucidated. Inflammation is associated with T2D; however, it is unknown whether inflammation is causal or secondary to the altered metabolic state. Here we show that the mechanism by which IUGR leads to the development of T2D in adulthood is via transient recruitment of T-helper 2 (Th) lymphocytes and macrophages in fetal islets resulting in localized inflammation. Although this immune response is short-lived, it results in a permanent reduction in islet vascularity and impaired insulin secretion. Neutralizing interleukin-4 antibody therapy given only in the newborn period ameliorates inflammation and restores vascularity and β-cell function into adulthood, demonstrating a novel role for Th2 immune responses in the induction and progression of T2D. In the neonatal stage, inflammation and vascular changes are reversible and may define an important developmental window for therapeutic intervention to prevent adult-onset diabetes.
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Affiliation(s)
- Lane J. Jaeckle Santos
- Division of Neonatology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Changhong Li
- Division of Neonatology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- The Children’s Hospital of Philadelphia, Philadelphia, PA
| | | | - Harry Ischiropoulos
- Division of Neonatology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - G. Scott Worthen
- Division of Neonatology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- The Children’s Hospital of Philadelphia, Philadelphia, PA
- Corresponding author: Rebecca A. Simmons, , or G. Scott Worthen,
| | - Rebecca A. Simmons
- Division of Neonatology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- The Children’s Hospital of Philadelphia, Philadelphia, PA
- Corresponding author: Rebecca A. Simmons, , or G. Scott Worthen,
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Martínez-Abundis E, González-Ortiz M, Mercado-Sesma AR, Reynoso-von-Drateln C, Moreno-Andrade A. Effect of avocado soybean unsaponifiables on insulin secretion and insulin sensitivity in patients with obesity. Obes Facts 2013; 6:443-8. [PMID: 24135894 PMCID: PMC5644760 DOI: 10.1159/000355720] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Accepted: 04/04/2013] [Indexed: 01/03/2023] Open
Abstract
AIM To evaluate the effect of avocado soybean unsaponifiables (ASU) on insulin secretion and insulin sensitivity in patients with obesity. METHODS A randomized, double-blind, placebo-controlled, clinical trial was carried out in 14 obese adult volunteers. After random allocation of the intervention, 7 patients received 300 mg of ASU or placebo during a fasting state for 3 months. A metabolic profile including IL-6 and high-sensitivity C-reactive protein (hs-CRP) levels was carried out prior to the intervention. A hyperglycemic-hyperinsulinemic clamp technique was used to assess insulin secretion and insulin sensitivity phases. Mann-Whitney U test and Wilcoxon test were performed for statistical analyses. The study was approved by the local ethics committee of our institution. RESULTS At baseline, both groups were similar according to clinical and laboratory characteristics. There was no significant difference in insulin secretion and insulin sensitivity with ASU. CONCLUSIONS ASU administration for 3 months did not modify insulin secretion and insulin sensitivity in patients with obesity.
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Affiliation(s)
- Esperanza Martínez-Abundis
- Medical Research Unit in Clinical Epidemiology, Specialties Hospital, Medical Unit of High Specialty, West National Medical Center, Mexican Institute of Social Security, Guadalajara, Mexico
- Cardiovascular Research Unit, Physiology Department, Health Science University Center, University of Guadalajara, Guadalajara, Mexico
| | - Manuel González-Ortiz
- Medical Research Unit in Clinical Epidemiology, Specialties Hospital, Medical Unit of High Specialty, West National Medical Center, Mexican Institute of Social Security, Guadalajara, Mexico
- Cardiovascular Research Unit, Physiology Department, Health Science University Center, University of Guadalajara, Guadalajara, Mexico
| | - Arieh R. Mercado-Sesma
- Cardiovascular Research Unit, Physiology Department, Health Science University Center, University of Guadalajara, Guadalajara, Mexico
| | - Claudia Reynoso-von-Drateln
- Medical Research Unit in Clinical Epidemiology, Specialties Hospital, Medical Unit of High Specialty, West National Medical Center, Mexican Institute of Social Security, Guadalajara, Mexico
| | - Aureliano Moreno-Andrade
- Medical Research Unit in Clinical Epidemiology, Specialties Hospital, Medical Unit of High Specialty, West National Medical Center, Mexican Institute of Social Security, Guadalajara, Mexico
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Imai Y, Dobrian AD, Morris MA, Nadler JL. Islet inflammation: a unifying target for diabetes treatment? Trends Endocrinol Metab 2013; 24:351-60. [PMID: 23484621 PMCID: PMC3686848 DOI: 10.1016/j.tem.2013.01.007] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Revised: 01/22/2013] [Accepted: 01/23/2013] [Indexed: 12/12/2022]
Abstract
In the past decade, islet inflammation has emerged as a contributor to the loss of functional β cell mass in both type 1 (T1D) and type 2 diabetes (T2D). Evidence supports the idea that overnutrition and insulin resistance result in the production of proinflammatory mediators by β cells. In addition to compromising β cell function and survival, cytokines may recruit macrophages into islets, thus augmenting inflammation. Limited but intriguing data imply a role of adaptive immune response in islet dysfunction in T2D. Clinical trials have validated anti-inflammatory therapies in T2D, whereas immune therapy for T1D remains challenging. Further research is required to improve our understanding of islet inflammatory pathways and to identify more effective therapeutic targets for T1D and T2D.
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Affiliation(s)
- Yumi Imai
- Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
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Donath MY, Dalmas É, Sauter NS, Böni-Schnetzler M. Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab 2013; 17:860-872. [PMID: 23747245 DOI: 10.1016/j.cmet.2013.05.001] [Citation(s) in RCA: 252] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 04/15/2013] [Accepted: 05/01/2013] [Indexed: 12/12/2022]
Abstract
The role of the immune system is to restore functionality in response to stress. Increasing evidence shows that this function is not limited to insults by infection or injury and plays a role in response to overnutrition. Initially, this metabolic activation of the immune system is a physiological response, but it may become deleterious with time. Therefore, therapeutic interventions should aim at modulating the immune system rather than simply damping it. In this article, we describe the physiology and pathology of the immune system during obesity and diabetes with a focus on islet inflammation, the IL-1β pathway, and clinical translation.
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Affiliation(s)
- Marc Y Donath
- Endocrinology, Diabetes, and Metabolism and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
| | - Élise Dalmas
- Endocrinology, Diabetes, and Metabolism and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland
| | - Nadine S Sauter
- Endocrinology, Diabetes, and Metabolism and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland
| | - Marianne Böni-Schnetzler
- Endocrinology, Diabetes, and Metabolism and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland
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Cuny T, Guerci B, Cariou B. New avenues for the pharmacological management of type 2 diabetes: An update. ANNALES D'ENDOCRINOLOGIE 2012; 73:459-68. [DOI: 10.1016/j.ando.2012.09.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Tobar N, Oliveira AG, Guadagnini D, Bagarolli RA, Rocha GZ, Araujo TG, Prada PO, Saad MJ. Comment on: Ramos-Zavala et al. Effect of diacerein on insulin secretion and metabolic control in drug-naïve patients with type 2 diabetes: a randomized clinical trial. Diabetes Care 2011;34:1591-1594. Diabetes Care 2012; 35:e13; author reply e14. [PMID: 22275450 PMCID: PMC3263872 DOI: 10.2337/dc11-1856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Natália Tobar
- Department of Internal Medicine, State University of Campinas, São Paolo, Brazil
| | | | - Dioze Guadagnini
- Department of Internal Medicine, State University of Campinas, São Paolo, Brazil
| | - Renata A. Bagarolli
- Department of Internal Medicine, State University of Campinas, São Paolo, Brazil
| | - Guilherme Z. Rocha
- Department of Internal Medicine, State University of Campinas, São Paolo, Brazil
| | - Tiago G. Araujo
- Department of Internal Medicine, State University of Campinas, São Paolo, Brazil
| | - Patrícia O. Prada
- Department of Internal Medicine, State University of Campinas, São Paolo, Brazil
| | - Mario J.A. Saad
- Department of Internal Medicine, State University of Campinas, São Paolo, Brazil
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Response to Comment on: Ramos-Zavala et al. Effect of Diacerein on Insulin Secretion and Metabolic Control in Drug-Naïve Patients With Type 2 Diabetes: A Randomized Clinical Trial. Diabetes Care 2011;34:1591–1594. Diabetes Care 2012. [PMCID: PMC3263891 DOI: 10.2337/dc11-2035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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