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Kushwaha K, Garg SS, Mandal D, Khurana N, Gupta J. Screening of natural epigenetic modifiers for managing glycemic memory and diabetic nephropathy. J Drug Target 2024; 32:807-819. [PMID: 38749010 DOI: 10.1080/1061186x.2024.2356737] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 04/03/2024] [Accepted: 05/10/2024] [Indexed: 05/28/2024]
Abstract
Short hyperglycaemic episodes trigger metabolic memory (MM) in which managing hyperglycaemia alone is not enough to tackle the progression of Diabetic nephropathy on the epigenetic axis. We used a structural similarity search approach to identify phytochemicals similar to natural epigenetic modifiers and docked with SIRT1 protein and did ADME studies. We found that UMB was 84.3% similar to esculetin. Upon docking, we found that UMB had a binding energy of -9.2 kcal/mol while the standard ligand had -11.8 kcal/mol. ADME showed UMB to be a good lead. 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay showed it to be a good antioxidant with IC50 of 107 µg/mL and MTT stands for 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) showed that it does not promote cell death. Oxidative biomarkers in vitro showed UMB was able to ameliorate glycemic memory induced by high glucose. Western blot revealed decreased histone acetylation under hyperglycaemic conditions and upon treatment with UMB along with DR, its levels increased. This led us to check our hypothesis of whether concomitant diet reversal (DR) together with UMB can alleviate high-fat diet-induced metabolic memory and diabetic nephropathy (DN) in SD rats. UMB was able to decrease blood glucose, lipid, renal, and liver profile concluding UMB was able to ameliorate DN and MM by increasing the histone acetylation level.
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Affiliation(s)
- Kriti Kushwaha
- Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
| | - Sourbh Suren Garg
- Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
| | - Debojyoti Mandal
- Department of Botany, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
| | - Navneet Khurana
- Department of Pharmacology, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Jeena Gupta
- Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
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Xu W, Lai S, Zhao J, Wei S, Fang X, Liu Y, Rong X, Guo J. The blockade of the TGF-β pathway alleviates abnormal glucose and lipid metabolism of lipodystrophy not obesity. Pharmacol Res Perspect 2024; 12:e1160. [PMID: 38174807 PMCID: PMC10765454 DOI: 10.1002/prp2.1160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 11/21/2023] [Indexed: 01/05/2024] Open
Abstract
TGF-β is thought to be involved in the physiological functions of early organ development and pathological changes in substantial organ fibrosis, while studies around adipose tissue function and systemic disorders of glucolipid metabolism are still scarce. In this investigation, two animal models, aP2-SREBP-1c mice and ob/ob mice, were used. TGF-β pathway showed up-regulated in the inguinal white adipose tissue (iWAT) of the two models. SB431542, a TGF-β inhibitor, successfully increased inguinal white adipocyte size by more than 1.5 times and decreased the weight of Peripheral organs including liver, Spleen and Kidney to 73.05%/62.18%/73.23% of pre-administration weights. The iWAT showed elevated expression of GLUTs and lipases, followed by a recovery of circulation GLU, TG, NEFA, and GLYCEROL to the wild-type levels in aP2-SREBP-1c mice. In contrast, TGF-β inhibition did not have similar effects on that of ob/ob mice. In vitro, TGF-β blocker treated mature adipocytes had considerably higher levels of glycerol and triglycerides than the control group, whereas GLUTs and lipases expression levels were unchanged. These findings show that inhibiting the abnormally upregulated TGF-β pathway will only restore iWAT expansion and ameliorate the global metabolic malfunction of glucose and lipids in lipodystrophy, not obesity.
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Affiliation(s)
- Wen‐Dong Xu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Shui‐Zheng Lai
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Jia Zhao
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Shi‐Jie Wei
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Xue‐Ying Fang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Yi‐Yi Liu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Xiang‐Lu Rong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
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Speelman T, Dale L, Louw A, Verhoog NJD. The Association of Acute Phase Proteins in Stress and Inflammation-Induced T2D. Cells 2022; 11:2163. [PMID: 35883605 PMCID: PMC9321356 DOI: 10.3390/cells11142163] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/02/2022] [Accepted: 07/04/2022] [Indexed: 02/06/2023] Open
Abstract
Acute phase proteins (APPs), such as plasminogen activator inhibitor-1 (PAI-1), serum amyloid A (SAA), and C-reactive protein (CRP), are elevated in type-2 diabetes (T2D) and are routinely used as biomarkers for this disease. These APPs are regulated by the peripheral mediators of stress (i.e., endogenous glucocorticoids (GCs)) and inflammation (i.e., pro-inflammatory cytokines), with both implicated in the development of insulin resistance, the main risk factor for the development of T2D. In this review we propose that APPs, PAI-1, SAA, and CRP, could be the causative rather than only a correlative link between the physiological elements of risk (stress and inflammation) and the development of insulin resistance.
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Affiliation(s)
| | | | | | - Nicolette J. D. Verhoog
- Biochemistry Department, Stellenbosch University, Van der Byl Street, Stellenbosch 7200, South Africa; (T.S.); (L.D.); (A.L.)
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Pucelik B, Barzowska A, Dąbrowski JM, Czarna A. Diabetic Kinome Inhibitors-A New Opportunity for β-Cells Restoration. Int J Mol Sci 2021; 22:9083. [PMID: 34445786 PMCID: PMC8396662 DOI: 10.3390/ijms22169083] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/13/2021] [Accepted: 08/18/2021] [Indexed: 01/03/2023] Open
Abstract
Diabetes, and several diseases related to diabetes, including cancer, cardiovascular diseases and neurological disorders, represent one of the major ongoing threats to human life, becoming a true pandemic of the 21st century. Current treatment strategies for diabetes mainly involve promoting β-cell differentiation, and one of the most widely studied targets for β-cell regeneration is DYRK1A kinase, a member of the DYRK family. DYRK1A has been characterized as a key regulator of cell growth, differentiation, and signal transduction in various organisms, while further roles and substrates are the subjects of extensive investigation. The targets of interest in this review are implicated in the regulation of β-cells through DYRK1A inhibition-through driving their transition from highly inefficient and death-prone populations into efficient and sufficient precursors of islet regeneration. Increasing evidence for the role of DYRK1A in diabetes progression and β-cell proliferation expands the potential for pharmaceutical applications of DYRK1A inhibitors. The variety of new compounds and binding modes, determined by crystal structure and in vitro studies, may lead to new strategies for diabetes treatment. This review provides recent insights into the initial self-activation of DYRK1A by tyrosine autophosphorylation. Moreover, the importance of developing novel DYRK1A inhibitors and their implications for the treatment of diabetes are thoroughly discussed. The evolving understanding of DYRK kinase structure and function and emerging high-throughput screening technologies have been described. As a final point of this work, we intend to promote the term "diabetic kinome" as part of scientific terminology to emphasize the role of the synergistic action of multiple kinases in governing the molecular processes that underlie this particular group of diseases.
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Affiliation(s)
- Barbara Pucelik
- Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland; (B.P.); (A.B.)
| | - Agata Barzowska
- Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland; (B.P.); (A.B.)
| | - Janusz M. Dąbrowski
- Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland
| | - Anna Czarna
- Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland; (B.P.); (A.B.)
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Janssen JAMJL. Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer. Int J Mol Sci 2021; 22:ijms22157797. [PMID: 34360563 PMCID: PMC8345990 DOI: 10.3390/ijms22157797] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/11/2021] [Accepted: 07/13/2021] [Indexed: 01/10/2023] Open
Abstract
For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.
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Affiliation(s)
- Joseph A M J L Janssen
- Department of internal Medicine, Division of Endocrinology, Erasmus Medical Center, 40, 3015 GD Rotterdam, The Netherlands
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Azizi S, Mahdavi R, Mobasseri M, Aliasgharzadeh S, Abbaszadeh F, Ebrahimi-Mameghani M. The impact of L-citrulline supplementation on glucose homeostasis, lipid profile, and some inflammatory factors in overweight and obese patients with type 2 diabetes: A double-blind randomized placebo-controlled trial. Phytother Res 2021; 35:3157-3166. [PMID: 33876875 DOI: 10.1002/ptr.6997] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 11/24/2020] [Accepted: 12/13/2020] [Indexed: 12/17/2022]
Abstract
This study investigated the impact of L-citrulline on glucose homeostasis, lipid profile, and inflammatory factors in overweight and obese patients with type 2 diabetes (T2D). In total, 54 participants with T2D were assigned to L-citrulline (3 g/day L-citrulline) or placebo groups and tested for 8 weeks. Serum levels of insulin, fasting glucose, hemoglobin A1c (HbA1c), lipid profile, tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), and L-citrulline were measured pre- and post-intervention. Totally, 45 patients were enrolled in the research. L-citrulline supplementation decreased serum levels of insulin (p = .025), glucose (p = .032), HbA1c (p = .001), HOMA-IR (p = .037), TNF-α (p = .036), and hs-CRP (p = .027) significantly. At the end of the study, despite the significant decrease in serum levels of triglyceride (p = .027) and the increase in high-density lipoprotein cholesterol levels (p < .001) in the L-citrulline group, no significant differences were found for these parameters between the groups. Moreover, no significant inter- and intra-group changes were observed for dietary intakes, anthropometric indices, total and low-density lipoprotein cholesterol levels (p > .05). In conclusion, L-citrulline supplementation might improve glucose homeostasis, some lipid factors and inflammatory markers in overweight and obese patients with T2D.
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Affiliation(s)
- Samaneh Azizi
- Student Research Committee, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Mahdavi
- Nutrition Research Center, Department of Biochemistry and Diet Therapy, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Mobasseri
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soghra Aliasgharzadeh
- Student Research Committee, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Abbaszadeh
- Student Research Committee, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehrangiz Ebrahimi-Mameghani
- Nutrition Research Center, Department of Biochemistry and Diet Therapy, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Galmiche M, Achamrah N, Déchelotte P, Ribet D, Breton J. Role of microbiota-gut-brain axis dysfunctions induced by infections in the onset of anorexia nervosa. Nutr Rev 2021; 80:381-391. [PMID: 34010427 DOI: 10.1093/nutrit/nuab030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Anorexia nervosa (AN) is an eating disorder characterized by low food intake, severe body weight loss, intense fear of gaining weight, and dysmorphophobia. This chronic disease is associated with both psychiatric and somatic comorbidities. Over the years, clinical studies have accumulated evidence that viral or bacterial infections may promote the onset of eating disorders such as AN. This review aims to describe how infections and the subsequent immune responses affect food intake regulation in the short term and also how these processes may lead to long-term intestinal disorders, including gut barrier disruption and gut microbiota dysbiosis, even after the clearance of the pathogens. We discuss in particular how infection-mediated intestinal dysbiosis may promote the onset of several AN symptoms and comorbidities, including appetite dysregulation, functional gastrointestinal disorders, and mood disorders.
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Affiliation(s)
- Marie Galmiche
- M. Galmiche, N. Achamrah, P. Déchelotte, and J. Breton are with Nutrition Department, CHU Rouen, F-76000 Rouen, France. N. Achamrah, P. Déchelotte, D. Ribet, and J. Breton are with the UNIROUEN, INSERM UMR 1073, Nutrition, Gut and Brain Laboratory, Rouen, France. N. Achamrah, P. Déchelotte, D. Ribet, and J. Breton are with the UNIROUEN, Institute for Research and Innovation in Biomedicine, Normandie University, Rouen, France
| | - Najate Achamrah
- M. Galmiche, N. Achamrah, P. Déchelotte, and J. Breton are with Nutrition Department, CHU Rouen, F-76000 Rouen, France. N. Achamrah, P. Déchelotte, D. Ribet, and J. Breton are with the UNIROUEN, INSERM UMR 1073, Nutrition, Gut and Brain Laboratory, Rouen, France. N. Achamrah, P. Déchelotte, D. Ribet, and J. Breton are with the UNIROUEN, Institute for Research and Innovation in Biomedicine, Normandie University, Rouen, France
| | - Pierre Déchelotte
- M. Galmiche, N. Achamrah, P. Déchelotte, and J. Breton are with Nutrition Department, CHU Rouen, F-76000 Rouen, France. N. Achamrah, P. Déchelotte, D. Ribet, and J. Breton are with the UNIROUEN, INSERM UMR 1073, Nutrition, Gut and Brain Laboratory, Rouen, France. N. Achamrah, P. Déchelotte, D. Ribet, and J. Breton are with the UNIROUEN, Institute for Research and Innovation in Biomedicine, Normandie University, Rouen, France
| | - David Ribet
- M. Galmiche, N. Achamrah, P. Déchelotte, and J. Breton are with Nutrition Department, CHU Rouen, F-76000 Rouen, France. N. Achamrah, P. Déchelotte, D. Ribet, and J. Breton are with the UNIROUEN, INSERM UMR 1073, Nutrition, Gut and Brain Laboratory, Rouen, France. N. Achamrah, P. Déchelotte, D. Ribet, and J. Breton are with the UNIROUEN, Institute for Research and Innovation in Biomedicine, Normandie University, Rouen, France
| | - Jonathan Breton
- M. Galmiche, N. Achamrah, P. Déchelotte, and J. Breton are with Nutrition Department, CHU Rouen, F-76000 Rouen, France. N. Achamrah, P. Déchelotte, D. Ribet, and J. Breton are with the UNIROUEN, INSERM UMR 1073, Nutrition, Gut and Brain Laboratory, Rouen, France. N. Achamrah, P. Déchelotte, D. Ribet, and J. Breton are with the UNIROUEN, Institute for Research and Innovation in Biomedicine, Normandie University, Rouen, France
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Abu-Farha M, Al-Mulla F, Thanaraj TA, Kavalakatt S, Ali H, Abdul Ghani M, Abubaker J. Impact of Diabetes in Patients Diagnosed With COVID-19. Front Immunol 2020; 11:576818. [PMID: 33335527 PMCID: PMC7736089 DOI: 10.3389/fimmu.2020.576818] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 11/02/2020] [Indexed: 01/08/2023] Open
Abstract
COVID-19 is a disease caused by the coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2), known as a highly contagious disease, currently affecting more than 200 countries worldwide. The main feature of SARS-CoV-2 that distinguishes it from other viruses is the speed of transmission combined with higher risk of mortality from acute respiratory distress syndrome (ARDS). People with diabetes mellitus (DM), severe obesity, cardiovascular disease, and hypertension are more likely to get infected and are at a higher risk of mortality from COVID-19. Among elderly patients who are at higher risk of death from COVID-19, 26.8% have DM. Although the reasons for this increased risk are yet to be determined, several factors may contribute to type-2 DM patients' increased susceptibility to infections. A possible factor that may play a role in increasing the risk in people affected by diabetes and/or obesity is the impaired innate and adaptive immune response, characterized by a state of chronic and low-grade inflammation that can lead to abrupt systemic metabolic alteration. SARS patients previously diagnosed with diabetes or hyperglycemia had higher mortality and morbidity rates when compared with patients who were under metabolic control. Similarly, obese individuals are at higher risk of developing complications from SARS-CoV-2. In this review, we will explore the current and evolving insights pertinent to the metabolic impact of coronavirus infections with special attention to the main pathways and mechanisms that are linked to the pathophysiology and treatment of diabetes.
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Affiliation(s)
- Mohamed Abu-Farha
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman, Kuwait
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait
| | | | - Sina Kavalakatt
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman, Kuwait
| | - Hamad Ali
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait
- Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Health Sciences Center, Kuwait University, Jabriya, Kuwait
| | - Mohammed Abdul Ghani
- Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Jehad Abubaker
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman, Kuwait
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Perrone MA, Babu Dasari J, Intorcia A, Gualtieri P, Marche M, Di Luozzo M, Merra G, Bernardini S, Romeo F, Sergi D. Phenotypic classification and biochemical profile of obesity for cardiovascular prevention. GAZZETTA MEDICA ITALIANA ARCHIVIO PER LE SCIENZE MEDICHE 2020. [DOI: 10.23736/s0393-3660.20.04259-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Zhao J, Wu Y, Rong X, Zheng C, Guo J. Anti-Lipolysis Induced by Insulin in Diverse Pathophysiologic Conditions of Adipose Tissue. Diabetes Metab Syndr Obes 2020; 13:1575-1585. [PMID: 32494174 PMCID: PMC7227813 DOI: 10.2147/dmso.s250699] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 04/19/2020] [Indexed: 12/13/2022] Open
Abstract
As an important energy reservoir, adipose tissue maintains lipid balance and regulates energy metabolism. When the body requires energy, adipocytes provide fatty acids to peripheral tissues through lipolysis. Insulin plays an important role in regulating normal fatty acid levels by inhibiting lipolysis. When the morphology of adipose tissue is abnormal, its microenvironment changes and the lipid metabolic balance is disrupted, which seriously impairs insulin sensitivity. As the most sensitive organ to respond to insulin, lipolysis levels in adipose tissue are affected by impaired insulin function, which results in serious metabolic diseases. However, the specific underlying mechanisms of this process have not yet been fully elucidated, and further study is required. The purpose of this review is to discuss the effects of adipose tissue on the anti-lipolysis process triggered by insulin under different conditions. In particular, the functional changes of this process respond to inconsonantly morphological changes of adipose tissue.
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Affiliation(s)
- Jia Zhao
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangdong, People's Republic of China
| | - YaYun Wu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangdong, People's Republic of China
| | - XiangLu Rong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangdong, People's Republic of China
- Guangdong TCM Key Laboratory for the Prevention and Treatment of Metabolic Diseases, Guangdong, People's Republic of China
- Joint Laboratory of Guangdong Province and Hong Kong and Macao Regions on Metabolic Diseases, Guangdong, People's Republic of China
| | - CuiWen Zheng
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangdong, People's Republic of China
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangdong, People's Republic of China
- Guangdong TCM Key Laboratory for the Prevention and Treatment of Metabolic Diseases, Guangdong, People's Republic of China
- Joint Laboratory of Guangdong Province and Hong Kong and Macao Regions on Metabolic Diseases, Guangdong, People's Republic of China
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Clemenzi MN, Wellhauser L, Aljghami ME, Belsham DD. Tumour necrosis factor α induces neuroinflammation and insulin resistance in immortalised hypothalamic neurones through independent pathways. J Neuroendocrinol 2019; 31:e12678. [PMID: 30582235 DOI: 10.1111/jne.12678] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 11/26/2018] [Accepted: 12/05/2018] [Indexed: 12/27/2022]
Abstract
The links between obesity, inflammation and insulin resistance, which are all key characteristics of type 2 diabetes mellitus, are yet to be delineated in the brain. One of the key neuroinflammatory proteins detected in the hypothalamus with over-nutrition is tumour necrosis factor (TNF)α. Using immortalised embryonic rat and mouse hypothalamic cell lines (rHypoE-7 and mHypoE-46) that express orexigenic neuropeptide Y and agouti-related peptide, we investigated changes in insulin signalling and inflammatory gene marker mRNA expression after TNFα exposure. A quantitative polymerase chain reaction array of 84 inflammatory markers (cytokines, chemokines and receptors) demonstrated an increase in the expression of multiple genes encoding inflammatory markers upon exposure to 100 ng mL-1 TNFα for 4 hours. Furthermore, neurones pre-exposed to TNFα (50 ng mL-1 ) for 6 or 16 hours exhibited a significant reduction in phosphorylated Akt compared to control after insulin treatment, indicating the attenuation of insulin signalling. mRNA expression of insulin signalling-related genes was also decreased with exposure to TNFα. TNFα significantly increased mRNA expression of IκBα, Tnfrsf1a and IL6 at 4 and 24 hours, activating a pro-inflammatory state. An inhibitor study using an inhibitor of nuclear factor kappa B kinase subunit β (IKK-β) inhibitor, PS1145, demonstrated that TNFα-induced neuroinflammatory marker expression occurs through the IKK-β/nuclear factor-kappa B pathway, whereas oleate, a monounsaturated fatty acid, had no effect on inflammatory markers. To test the efficacy of anti-inflammatory treatment to reverse insulin resistance, neurones were treated with TNFα and PS1145, which did not significantly restore the TNFα-induced changes in cellular insulin sensitivity, indicating that an alternative pathway may be involved. In conclusion, exposure to the inflammatory cytokine TNFα causes cellular insulin resistance and inflammation marker expression in the rHypoE-7 and mHypoE-46 neurones, consistent with effects seen with TNFα in peripheral tissues. It also mimics insulin- and palmitate-induced insulin resistance in hypothalamic neurones. The present study provides further evidence that altered central energy metabolism may be caused by obesity-induced cytokine expression.
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Affiliation(s)
| | - Leigh Wellhauser
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Makram E Aljghami
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Denise D Belsham
- Department of Physiology, University of Toronto, Toronto, ON, Canada
- Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada
- Department of Medicine, University of Toronto, Toronto, ON, Canada
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12
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Abstract
The mammalian Sirtuins (SIRT1-7) are an evolutionarily conserved family of NAD+-dependent deacylase and mono-ADP-ribosyltransferase. Sirtuins display distinct subcellular localizations and functions and are involved in cell survival, senescence, metabolism and genome stability. Among the mammalian Sirtuins, SIRT1 and SIRT6 have been thoroughly investigated and have prominent metabolic regulatory roles. Moreover, SIRT1 and SIRT6 have been implicated in obesity, insulin resistance, type 2 diabetes mellitus (T2DM), fatty liver disease and cardiovascular diseases. However, the roles of other Sirtuins are not fully understood. Recent studies have shown that these Sirtuins also play important roles in inflammation, mitochondrial dysfunction, and energy metabolism. Insulin resistance is the critical pathological trait of obesity and metabolic syndrome as well as the core defect in T2DM. Accumulating clinical and experimental animal evidence suggests the potential roles of the remaining Sirtuins in the regulation of insulin resistance through diverse biological mechanisms. In this review, we summarize recent advances in the understanding of the functions of Sirtuins in various insulin resistance-associated physiological processes, including inflammation, mitochondrial dysfunction, the insulin signaling pathway, glucose, and lipid metabolism. In addition, we highlight the important gaps that must be addressed in this field.
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Affiliation(s)
- Shuang Zhou
- Internal Medicine, Peking Union Medical College Hospital, Beijing, China
| | - Xiaoqiang Tang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
- *Correspondence: Xiaoqiang Tang
| | - Hou-Zao Chen
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Hou-Zao Chen ;
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13
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Hamza SM, Sung MM, Gao F, Soltys CLM, Smith NP, MacDonald PE, Light PE, Dyck JRB. Chronic insulin infusion induces reversible glucose intolerance in lean rats yet ameliorates glucose intolerance in obese rats. Biochim Biophys Acta Gen Subj 2016; 1861:313-322. [PMID: 27871838 DOI: 10.1016/j.bbagen.2016.11.029] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 11/10/2016] [Accepted: 11/17/2016] [Indexed: 01/19/2023]
Abstract
BACKGROUND Although insulin resistance (IR) is a key factor in the pathogenesis of type 2 diabetes (T2D), the precise role of insulin in the development of IR remains unclear. Therefore, we investigated whether chronic basal insulin infusion is causative in the development of glucose intolerance. METHODS Normoglycemic lean rats surgically instrumented with i.v. catheters were infused with insulin (3mU/kg/min) or physiological saline for 6weeks. At infusion-end, plasma insulin levels along with glucose tolerance were assessed. RESULTS Six weeks of insulin infusion induced glucose intolerance and impaired insulin response in healthy rats. Interestingly, the effects of chronic insulin infusion were completely normalized following 24h withdrawal of exogenous insulin and plasma insulin response to glucose challenge was enhanced, suggesting improved insulin secretory capacity. As a result of this finding, we assessed whether the effects of insulin therapy followed by a washout could ameliorate established glucose intolerance in obese rats. Obese rats were similarly instrumented and infused with insulin or physiological saline for 7days followed by 24h washout. Seven day-insulin therapy in obese rats significantly improved glucose tolerance, which was attributed to improved insulin secretory capacity and improved insulin signaling in liver and skeletal muscle. CONCLUSION Moderate infusion of insulin alone is sufficient to cause glucose intolerance and impair endogenous insulin secretory capacity, whereas short-term, intensive insulin therapy followed by insulin removal effectively improves glucose tolerance, insulin response and peripheral insulin sensitivity in obese rats. GENERAL SIGNIFICANCE New insight into the link between insulin and glucose intolerance may optimize T2D management.
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Affiliation(s)
- Shereen M Hamza
- Department of Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada
| | - Miranda M Sung
- Department of Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada
| | - Fei Gao
- Department of Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada
| | - Carrie-Lynn M Soltys
- Department of Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada
| | - Nancy P Smith
- Department of Pharmacology, University of Alberta, Edmonton, AB, Canada
| | - Patrick E MacDonald
- Department of Pharmacology, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Peter E Light
- Department of Pharmacology, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Jason R B Dyck
- Department of Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada; Department of Pharmacology, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
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14
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Tikoo K, Sharma E, Amara VR, Pamulapati H, Dhawale VS. Metformin Improves Metabolic Memory in High Fat Diet (HFD)-induced Renal Dysfunction. J Biol Chem 2016; 291:21848-21856. [PMID: 27551045 DOI: 10.1074/jbc.c116.732990] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 08/04/2016] [Indexed: 12/14/2022] Open
Abstract
Recently, we have shown that high fat diet (HFD) in vivo and in vitro generates metabolic memory by altering H3K36me2 and H3K27me3 on the promoter of FOXO1 (transcription factor of gluconeogenic genes) (Kumar, S., Pamulapati, H., and Tikoo, K. (2016) Mol. Cell. Endocrinol. 422, 233-242). Here we checked the hypothesis whether concomitant diet reversal and metformin could overcome HFD-induced metabolic memory and renal damage. Male adult Sprague-Dawley rats were rendered insulin-resistant by feeding high fat diet for 16 weeks. Then the rats were subjected to diet reversal alone and along with metformin for 8 weeks. Biochemical and histological markers of insulin resistance and kidney function were measured. Blood pressure and in vivo vascular reactivity to angiotensin II (200 ng kg-1) were also checked. Diet reversal could improve lipid profile but could not prevent renal complications induced by HFD. Interestingly, metformin along with diet reversal restored the levels of blood glucose, triglycerides, cholesterol, blood urea nitrogen, and creatinine. In kidney, metformin increased the activation of AMP-activated protein kinase (AMPK) and decreased inflammatory markers (COX-2 and IL-1β) and apoptotic markers (poly(ADP-ribose) polymerase (PARP) and caspase 3). Metformin was effective in lowering elevated basal blood pressure and acute change in mean arterial pressure in response to angiotensin II (Ang II). It also attenuated tubulointerstitial fibrosis and glomerulosclerosis induced by HFD feeding in kidney. Here we report, for the first time, that metformin treatment overcomes metabolic memory and prevents HFD-induced renal damage.
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Affiliation(s)
- Kulbhushan Tikoo
- From the Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab-160062, India
| | - Ekta Sharma
- From the Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab-160062, India
| | - Venkateswara Rao Amara
- From the Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab-160062, India
| | - Himani Pamulapati
- From the Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab-160062, India
| | - Vaibhav Shrirang Dhawale
- From the Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab-160062, India
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15
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White MF, Copps KD. The Mechanisms of Insulin Action. ENDOCRINOLOGY: ADULT AND PEDIATRIC 2016:556-585.e13. [DOI: 10.1016/b978-0-323-18907-1.00033-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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16
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Yoshitomi H, Momoo M, Ma X, Huang Y, Suguro S, Yamagishi Y, Gao M. L-Citrulline increases hepatic sensitivity to insulin by reducing the phosphorylation of serine 1101 in insulin receptor substrate-1. Altern Ther Health Med 2015; 15:188. [PMID: 26084330 PMCID: PMC4472399 DOI: 10.1186/s12906-015-0706-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 06/01/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND Insulin resistance is characterized by deficient responses to insulin in its target tissues. In the present study, we examined the effects of L-Citrulline (L-Cit) on insulin sensitivity and signaling cascades in rat hepatoma H4IIE cells and SHRSP.Z-Leprfa/IzmDmcr rats. METHODS H4IIE cells were pretreated in the presence or absence of 250 μM L-Cit in serum-free medium and then incubated in the presence or absence of 0.1 nM insulin. Rats were allocated into 2 groups; a control group (not treated) and L-Cit group (2 g/kg/day, L-Cit) and treated for 8 weeks. RESULTS L-Cit enhanced the insulin-induced phosphorylation of Akt in H4IIE cells. Moreover, the inhibited expression of Dex/cAMP-induced PEPCK mRNA by insulin was enhanced by the L-Cit treatment. The phosphorylation of tyrosine, which is upstream of Akt, in insulin receptor substrate-1 (IRS-1) was increased by the L-Cit treatment. The L-Cit-induced enhancement in insulin signaling was not related to the binding affinity of insulin to the insulin receptor or to the expression of the insulin receptor, but to a decrease in the phosphorylation of serine 1101 in IRS-1. These results were also confirmed in animal experiments. In the livers of L-Cit-treated rats, PI3K/Akt signaling was improved by decreases in the phosphorylation of serine 1101. CONCLUSIONS We herein demonstrated for the first time the beneficial effects of L-Cit on improved insulin resistance associated with enhanced insulin sensitivity. These results may have clinical applications for insulin resistance and the treatment of type-2 diabetes.
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Beretta M, Bauer M, Hirsch E. PI3K signaling in the pathogenesis of obesity: The cause and the cure. Adv Biol Regul 2015; 58:1-15. [PMID: 25512233 DOI: 10.1016/j.jbior.2014.11.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 11/21/2014] [Accepted: 11/21/2014] [Indexed: 06/04/2023]
Abstract
With the steady rise in the incidence of obesity and its associated comorbidities, in the last decades research aimed at understanding molecular mechanisms that control body weight has gained new interest. Fat gain is frequently associated with chronic adipose tissue inflammation and with peripheral as well as central metabolic derangements, resulting in an impaired hypothalamic regulation of energy homeostasis. Recent attention has focused on the role of phosphatidylinositol 3-kinase (PI3K) in both immune and metabolic response pathways, being involved in the pathophysiology of obesity and its associated metabolic diseases. In this review, we focus on distinct PI3K isoforms, especially class I PI3Ks, mediating inflammatory cells recruitment to the enlarged fat as well as intracellular responses to key hormonal regulators of fat storage, both in adipocytes and in the central nervous system. This integrated view of PI3K functions may ultimately help to develop new therapeutic interventions for the treatment of obesity.
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Affiliation(s)
- Martina Beretta
- Molecular Biotechnology Center, University of Torino, Torino, Italy; Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Michael Bauer
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Emilio Hirsch
- Molecular Biotechnology Center, University of Torino, Torino, Italy.
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Hajiaghaalipour F, Khalilpourfarshbafi M, Arya A. Modulation of glucose transporter protein by dietary flavonoids in type 2 diabetes mellitus. Int J Biol Sci 2015; 11:508-24. [PMID: 25892959 PMCID: PMC4400383 DOI: 10.7150/ijbs.11241] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 02/08/2015] [Indexed: 12/23/2022] Open
Abstract
Diabetes mellitus (DM) is a metabolic diseases characterized by hyperglycemia due to insufficient or inefficient insulin secretory response. This chronic disease is a global problem and there is a need for greater emphasis on therapeutic strategies in the health system. Phytochemicals such as flavonoids have recently attracted attention as source materials for the development of new antidiabetic drugs or alternative therapy for the management of diabetes and its related complications. The antidiabetic potential of flavonoids are mainly through their modulatory effects on glucose transporter by enhancing GLUT-2 expression in pancreatic β cells and increasing expression and promoting translocation of GLUT-4 via PI3K/AKT, CAP/Cb1/TC10 and AMPK pathways. This review highlights the recent findings on beneficial effects of flavonoids in the management of diabetes with particular emphasis on the investigations that explore the role of these compounds in modulating glucose transporter proteins at cellular and molecular level.
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Affiliation(s)
- Fatemeh Hajiaghaalipour
- 1. Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Manizheh Khalilpourfarshbafi
- 2. Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia
| | - Aditya Arya
- 1. Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
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Ceppo F, Jager J, Berthou F, Giorgetti-Peraldi S, Cormont M, Bost F, Tanti JF. [Implication of MAP kinases in obesity-induced inflammation and insulin resistance]. Biol Aujourdhui 2014; 208:97-107. [PMID: 25190570 DOI: 10.1051/jbio/2014014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Indexed: 12/16/2022]
Abstract
Insulin resistance is often associated with obesity and is a major risk factor for development of type 2 diabetes as well as cardiovascular and hepatic diseases. Insulin resistance may also increase the incidence or the aggressiveness of some cancers. Insulin resistance occurs owing to defects in insulin signaling in target tissues of this hormone. During the last ten years, it became evident that the chronic low-grade inflammatory state that develops during obesity plays an important role in insulin resistance development. Indeed, inflammatory cytokines activate several signaling pathways that impinge on the insulin signaling pathway. Among them, this review will focus on the implication of the MAP kinases JNK and ERK1/2 signaling in the development of insulin signaling alterations and will discuss the possibility to target these pathways in order to fight insulin resistance.
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Affiliation(s)
- Franck Ceppo
- INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Route de Saint-Antoine de Ginestière, 06204 Nice Cedex 3, France
| | - Jennifer Jager
- INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Route de Saint-Antoine de Ginestière, 06204 Nice Cedex 3, France - Adresse actuelle : Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, PA 19104, Philadelphia, USA
| | - Flavien Berthou
- INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Route de Saint-Antoine de Ginestière, 06204 Nice Cedex 3, France
| | - Sophie Giorgetti-Peraldi
- INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Route de Saint-Antoine de Ginestière, 06204 Nice Cedex 3, France
| | - Mireille Cormont
- INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Route de Saint-Antoine de Ginestière, 06204 Nice Cedex 3, France
| | - Fréderic Bost
- INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Route de Saint-Antoine de Ginestière, 06204 Nice Cedex 3, France
| | - Jean-François Tanti
- INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Route de Saint-Antoine de Ginestière, 06204 Nice Cedex 3, France
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Riondino S, Roselli M, Palmirotta R, Della-Morte D, Ferroni P, Guadagni F. Obesity and colorectal cancer: role of adipokines in tumor initiation and progression. World J Gastroenterol 2014; 20:5177-5190. [PMID: 24833848 PMCID: PMC4017033 DOI: 10.3748/wjg.v20.i18.5177] [Citation(s) in RCA: 146] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 01/20/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
Obesity-associated diseases account for a large portion of public health challenges. Among obesity-related disorders, a direct and independent relationship has been ascertained for colorectal cancer (CRC). The evidence that adipocyte hypertrophy and excessive adipose tissue accumulation (mainly visceral) can promote pathogenic adipocyte and adipose tissue-related diseases, has led to formulate the concept of "adiposopathy", defined as adipocyte and adipose tissue dysfunction that contributes to metabolic syndrome. Adipose tissue can, indeed, be regarded as an important and highly active player of the innate immune response, in which cytokine/adipokine secretion is responsible for a paracrine loop between adipocytes and macrophages, thus contributing to the systemic chronic low-grade inflammation associated with visceral obesity, which represents a favorable niche for tumor development. The adipocyte itself participates as a central mediator of this inflammatory response in obese individuals by secreting hormones, growth factors and proinflammatory cytokines, which are of particular relevance for the pathogenesis of CRC. Among adipocyte-secreted hormones, the most relevant to colorectal tumorigenesis are adiponectin, leptin, resistin and ghrelin. All these molecules have been involved in cell growth and proliferation, as well as tumor angiogenesis and it has been demonstrated that their expression changes from normal colonic mucosa to adenoma and adenocarcinoma, suggesting their involvement in multistep colorectal carcinogenesis. These findings have led to the hypothesis that an unfavorable adipokine profile, with a reduction of those with an anti-inflammatory and anti-cancerous activity, might serve as a prognostic factor in CRC patients and that adipokines or their analogues/antagonists might become useful agents in the management or chemoprevention of CRC.
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Wu D, Yang M, Chen Y, Jia Y, Ma ZA, Boden G, Li L, Yang G. Hypothalamic nesfatin-1/NUCB2 knockdown augments hepatic gluconeogenesis that is correlated with inhibition of mTOR-STAT3 signaling pathway in rats. Diabetes 2014; 63:1234-47. [PMID: 24478398 DOI: 10.2337/db13-0899] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Nesfatin-1, an 82-amino acid neuropeptide, has recently been characterized as a potent metabolic regulator. However, the metabolic mechanisms and signaling steps directly associated with the action of nesfatin-1 have not been well delineated. We established a loss-of-function model of hypothalamic nesfatin-1/NUCB2 signaling in rats through an adenoviral-mediated RNA interference. With this model, we found that inhibition of central nesfatin-1/NUCB2 activity markedly increased food intake and hepatic glucose flux and decreased glucose uptake in peripheral tissue in rats fed either a normal chow diet (NCD) or a high-fat diet (HFD). The change of hepatic glucose fluxes in the hypothalamic nesfatin-1/NUCB2 knockdown rats was accompanied by increased hepatic levels of glucose-6-phosphatase and PEPCK and decreased insulin receptor, insulin receptor substrate 1, and AKT kinase phosphorylation. Furthermore, knockdown of hypothalamic nesfatin-1 led to decreased phosphorylation of mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) and the subsequent suppressor of cytokine signaling 3 levels. These results demonstrate that hypothalamic nesfatin-1/NUCB2 plays an important role in glucose homeostasis and hepatic insulin sensitivity, which is, at least in part, associated with the activation of the mTOR-STAT3 signaling pathway.
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Affiliation(s)
- Dandong Wu
- Department of Endocrinology, Second Affiliated Hospital, and Key Laboratory of Laboratory Medical Diagnostics (Ministry of Education), Chongqing Medical University, Chongqing, China
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Yang R, Chang L, Wang M, Zhang H, Liu J, Wang Y, Jin X, Xu L, Li Y. MAPK pathway mediates the induction of visfatin in neonatal SD rat cardiomyocytes pretreated with glucose. Biomed Rep 2014; 2:282-286. [PMID: 24649111 DOI: 10.3892/br.2014.221] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 01/02/2014] [Indexed: 01/16/2023] Open
Abstract
The protein visfatin is an insulin mimetic that has been shown to reduce plasma glucose levels, increase cytokine production and induce angiogenesis. However, few studies have focused on visfatin expression in cardiomyocytes at the cellular level. Therefore, the aim of the present study was to investigate visfatin expression and its potential mechanisms in cultured neonatal rat cardiomyocytes exposed to high-glucose concentrations. Primary cultures of 2-to 3-day-old Sprague Dawley (SD) rat cardiomyocytes were pretreated with increasing concentrations of glucose. P38 mitogen-activated protein kinase (MAPK) pathway inhibitor SB203580, extra cellular signal-regulated kinase (ERK1/2) pathway inhibitor PD098059 and c-Jun NH 2-terminal kinase (JNK) pathway inhibitor SP600125 were used to block the effect of glucose on visfatin expression. Cell viability following each glucose treatment was determined using the MTT assay. Expression of visfatin was detected using RT-PCR and western blot analysis. Increased glucose concentration directly correlated with an increased expression of visfatin mRNA and protein in neonatal rat cardiomyocytes. Following high doses of glucose, visfatin mRNA and protein expression peaked after 24 h with no significant change thereafter. Increased visfatin expression was blocked by the P38 MAPK inhibitor SB203580, suggesting a potential mechanism not yet identified. Expression of visfatin in cardiomyocytes was increased through the P38 MAPK pathway in the presence of high-glucose concentrations.
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Affiliation(s)
- Rong Yang
- Department of Cardiology, Second Hospital of Hebei Medical University; The Hebei Institute of Cardiovascular and Cerebrovascular Diseases, Shijiazhuang, Hebei 050000, P.R. China
| | - Liang Chang
- Department of Cardiology, Second Hospital of Hebei Medical University; The Hebei Institute of Cardiovascular and Cerebrovascular Diseases, Shijiazhuang, Hebei 050000, P.R. China
| | - Mei Wang
- Department of Cardiology, Second Hospital of Hebei Medical University; The Hebei Institute of Cardiovascular and Cerebrovascular Diseases, Shijiazhuang, Hebei 050000, P.R. China
| | - Hui Zhang
- Department of Cardiology, Second Hospital of Hebei Medical University; The Hebei Institute of Cardiovascular and Cerebrovascular Diseases, Shijiazhuang, Hebei 050000, P.R. China
| | - Jinming Liu
- Department of Cardiology, Second Hospital of Hebei Medical University; The Hebei Institute of Cardiovascular and Cerebrovascular Diseases, Shijiazhuang, Hebei 050000, P.R. China
| | - Yaling Wang
- Department of Cardiology, Second Hospital of Hebei Medical University; The Hebei Institute of Cardiovascular and Cerebrovascular Diseases, Shijiazhuang, Hebei 050000, P.R. China
| | - Xin Jin
- Department of Cardiology, Second Hospital of Hebei Medical University; The Hebei Institute of Cardiovascular and Cerebrovascular Diseases, Shijiazhuang, Hebei 050000, P.R. China
| | - Lu Xu
- Department of Cardiology, Second Hospital of Hebei Medical University; The Hebei Institute of Cardiovascular and Cerebrovascular Diseases, Shijiazhuang, Hebei 050000, P.R. China
| | - Yongjun Li
- Department of Cardiology, Second Hospital of Hebei Medical University; The Hebei Institute of Cardiovascular and Cerebrovascular Diseases, Shijiazhuang, Hebei 050000, P.R. China
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Prevention of hyperglycemic signal pathways in metabolic syndrome carotid artery of rats. Transl Stroke Res 2013; 3:466-72. [PMID: 24323833 DOI: 10.1007/s12975-012-0205-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2012] [Revised: 07/10/2012] [Accepted: 07/30/2012] [Indexed: 10/28/2022]
Abstract
Obesity is the major risk factor for metabolic syndrome and atherosclerotic cardiocerebrovascular diseases and induces insulin resistance characterized by a dysfunction of insulin to activate insulin receptor /insulin receptor substrate 1(IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt pathway. Zucker fatty rats (8 weeks) were treated with vehicle (0.5 % methyl cellulose in physiological saline, p.o.), amlodipine (3 mg/kg/day, p.o.), atorvastatin (10 mg/kg/day, p.o.), or the combination of amlodipine plus atorvastatin (3 + 10 mg/kg/day, p.o.) for 28 days, and anti-insulin-like growth factor 1 (IGF-1)/IRS-1/PI3K/Akt pathways were evaluated. Our present immunohistochemical study first demonstrated that a combination of amlodipine plus atorvastatin treatment prevented an arteriosclerotic process compared to the single treatment with amlodipine or atorvastatin with strong recoveries of pTyr IRS-1, pPI3K, and pAkt expressions and with remarkable restraints of IGF-1 and pSer IRS-1. As a result, combination therapy with amlodipine plus atorvastatin showed a strong synergistic effect to prevent atherosclerotic processes. The present study newly suggests a synergistic benefit of combination therapy with amlodipine plus atorvastatin for strong prevention of atherosclerotic processes, which could reduce the clinical risk of cerebrovascular events for obesity patients.
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Immunomodulatory Role of an Ayurvedic Formulation on Imbalanced Immunometabolics during Inflammatory Responses of Obesity and Prediabetic Disease. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:795072. [PMID: 24302970 PMCID: PMC3835817 DOI: 10.1155/2013/795072] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Accepted: 08/13/2013] [Indexed: 12/15/2022]
Abstract
Kal-1 is a polyherbal decoction of seven different natural ingredients, traditionally used in controlling sugar levels, inflammatory conditions particularly regulating metabolic and immunoinflammatory balance which are the major factors involved in obesity and related diseases. In the present study, we aimed to investigate the effect of Kal-1 (an abbreviation derived from the procuring source) on diet-induced obesity and type II diabetes using C57BL/6J mice as a model. The present study was performed with two experimental groups involving obese and prediabetic mice as study animals. In one, the mice were fed on high-fat with increased sucrose diet, and different amounts (5, 20, and 75 μL) of Kal-1 were administered with monitoring of disease progression over a period of 21 weeks whereas in the second group the mice were first put on the same diet for 21 weeks and then treated with the same amounts of Kal-1. A significant reduction in body weight, fat pads, fasting blood glucose levels, insulin levels, biochemical parameters, immunological parameters, and an array of pro- and anticytokines was observed in obese and diabetic mice plus Kal-1 than control (lean) mice fed on normal diet. In conclusion, Kal-1 has immunomodulatory potential for diet-induced obesity and associated metabolic disorders.
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Roth J, Qiang X, Marbán SL, Redelt H, Lowell BC. The Obesity Pandemic: Where Have We Been and Where Are We Going? ACTA ACUST UNITED AC 2012; 12 Suppl 2:88S-101S. [PMID: 15601956 DOI: 10.1038/oby.2004.273] [Citation(s) in RCA: 149] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Obesity, a new pandemic, is associated with an increased risk of death, morbidity, and accelerated aging. The multiple therapeutic modalities used to promote weight loss are outlined with caution, especially for patients who are very young or old. Except for very rare single gene defects, the inheritance of obesity is complex and still poorly understood, despite active investigations. Recent advances that have shed light on the pathophysiology of obesity are the recognition that 1) excess fat is deposited in liver, muscle, and pancreatic islets; 2) fat tissue secretes a large number of active signaling molecules including leptin, adiponectin, and resistin, as well as free fatty acids; and 3) activated macrophages colonize the adipose tissue. Other candidates for key roles in the causes and consequences of obesity include 1) metabolic programming, where food acts as a developmental regulator; 2) the constellation of defects known as the "metabolic syndrome;" 3) cortisol overproduction in the adipose tissue; and especially, 4) insulin resistance. The possible etiologies of insulin resistance include cytokine excess, elevated free fatty acids, and hyperinsulinemia itself, as with transgenic overproduction of insulin in mice.
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Affiliation(s)
- Jesse Roth
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
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mTOR kinase inhibitors as a treatment strategy in hematological malignancies. Future Med Chem 2012; 4:487-504. [PMID: 22416776 DOI: 10.4155/fmc.12.14] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The mammalian target of rapamycin (mTOR) kinase is a key element of intracellular signal transduction, responsible for the regulation of cell growth and proliferation. Since abnormal activation of the mTOR pathway was found in several tumors, including human malignancies, it may be an attractive target for antineoplastic treatment. The first identified mTOR inhibitor was rapamycin (sirolimus). Subsequently, the most potent rapamycin analogues (rapalogues), such as everolimus, temsirolimus and deforolimus, have been developed. After encouraging preclinical experiments, several clinical trials testing the rapalogues in monotherapy or in combinations with other cytotoxic agents have been conducted in patients with hematological malignancies. Results of these studies, described in this review, indicate that inhibition of the mTOR pathway may be a very promising strategy of anti-tumor treatment in several types of lymphomas and leukemias. Recently, a second generation of more effective mTOR inhibitors has been developed. These are currently being assessed in preclinical, Phase I or I/II clinical studies.
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Andrews M, Arredondo M. Hepatic and adipocyte cells respond differentially to iron overload, hypoxic and inflammatory challenge. Biometals 2012; 25:749-59. [PMID: 22476617 DOI: 10.1007/s10534-012-9543-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Accepted: 03/19/2012] [Indexed: 12/19/2022]
Abstract
Adipose tissue secretes numerous pro-inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α that can lead to insulin resistance (IR). In the liver, both IL-6 and TNF-α induce IR by inhibiting phosphorylation or ubiquitination of IRS1. In IR development, Fe is a risk factor in type-2 diabetes development. We studied the expression of genes related to inflammation, hypoxia, and mitochondrial function in hepatic (HepG2) and adipose (3T3-L1) cells. HepG2 and 3T3-L1 cells were incubated with 20 μM Fe, 40 μM Fe, or 40 μM Fe/20 mM glucose for 7 days and then challenged with 20 ng/ml IL-6 and/or 100 μM CoCl(2) for 20 h. We measured intracellular Fe levels and the relative expression of hepcidin, NF-κB, IL-6, TNF-α, hypoxia inducible factor 1α (HIF-1α), and mitofusin 2 (Mfn-2) mRNA using qRT-PCR. The intracellular Fe concentration in HepG2 cells did not change with 20 or 40 μM Fe. However, levels were decreased with Fe/glucose and IL-6 and/or CoCl(2). 3T3-L1 cells showed an increase in intracellular Fe with high Fe plus either IL-6 or CoCl(2). HepG2 cells incubated with 40 μM Fe alone or Fe/glucose and challenged with IL-6 and/or CoCl(2) showed increased IL-6, NF-κB, and TNF-α mRNA expression and decreased mRNA expression of Mfn-2 in all experimental conditions. 3T3-L1 cells incubated with 40 μM Fe alone or Fe/glucose and challenged with IL-6 showed increased NF-κB mRNA expression and decreased Mfn-2 expression in all experimental conditions. Thus, high Fe, inflammation, and hypoxia trigger the expression of genes related to inflammation and Fe metabolism in HepG2 cells, in 3T3-L1 cells the same stimuli increased NF-kB and hepcidin expression.
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Affiliation(s)
- M Andrews
- Micronutrient Laboratory, Nutrition Institute and Food Technology, University of Chile, El Líbano 5524, Macul, Santiago, Chile
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Langlais P, Yi Z, Finlayson J, Luo M, Mapes R, De Filippis E, Meyer C, Plummer E, Tongchinsub P, Mattern M, Mandarino LJ. Global IRS-1 phosphorylation analysis in insulin resistance. Diabetologia 2011; 54:2878-89. [PMID: 21850561 PMCID: PMC3882165 DOI: 10.1007/s00125-011-2271-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Accepted: 07/08/2011] [Indexed: 01/25/2023]
Abstract
AIMS/HYPOTHESIS IRS-1 serine phosphorylation is often elevated in insulin resistance models, but confirmation in vivo in humans is lacking. We therefore analysed IRS-1 phosphorylation in human muscle in vivo. METHODS We used HPLC-electrospray ionisation (ESI)-MS/MS to quantify IRS-1 phosphorylation basally and after insulin infusion in vastus lateralis muscle from lean healthy, obese non-diabetic and type 2 diabetic volunteers. RESULTS Basal Ser323 phosphorylation was increased in type 2 diabetic patients (2.1 ± 0.43, p ≤ 0.05, fold change vs lean controls). Thr495 phosphorylation was decreased in type 2 diabetic patients (p ≤ 0.05). Insulin increased IRS-1 phosphorylation at Ser527 (1.4 ± 0.17, p ≤ 0.01, fold change, 60 min after insulin infusion vs basal) and Ser531 (1.3 ± 0.16, p ≤ 0.01, fold change, 60 min after insulin infusion vs basal) in the lean controls and suppressed phosphorylation at Ser348 (0.56 ± 0.11, p ≤ 0.01, fold change, 240 min after insulin infusion vs basal), Thr446 (0.64 ± 0.16, p ≤ 0.05, fold change, 60 min after insulin infusion vs basal), Ser1100 (0.77 ± 0.22, p ≤ 0.05, fold change, 240 min after insulin infusion vs basal) and Ser1142 (1.3 ± 0.2, p ≤ 0.05, fold change, 60 min after insulin infusion vs basal). CONCLUSIONS/INTERPRETATION We conclude that, unlike some aspects of insulin signalling, the ability of insulin to increase or suppress certain IRS-1 phosphorylation sites is intact in insulin resistance. However, some IRS-1 phosphorylation sites do not respond to insulin, whereas other Ser/Thr phosphorylation sites are either increased or decreased in insulin resistance.
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Affiliation(s)
- P. Langlais
- Center for Metabolic and Vascular Biology, School of Life Science, Arizona State University, ISTB1, 550 E. Orange St, Tempe, AZ 85287, USA
| | - Z. Yi
- Center for Metabolic and Vascular Biology, School of Life Science, Arizona State University, ISTB1, 550 E. Orange St, Tempe, AZ 85287, USA; Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy/Health Sciences, Wayne State University, Detroit, MI, USA
| | - J. Finlayson
- Center for Metabolic and Vascular Biology, School of Life Science, Arizona State wwUniversity, ISTB1, 550 E. Orange St, Tempe, AZ 85287, USA
| | - M. Luo
- Center for Metabolic and Vascular Biology, School of Life Science, Arizona State University, ISTB1, 550 E. Orange St, Tempe, AZ 85287, USA
| | - R. Mapes
- Center for Metabolic and Vascular Biology, School of Life Science, Arizona State University, ISTB1, 550 E. Orange St, Tempe, AZ 85287, USA
| | - E. De Filippis
- Center for Metabolic and Vascular Biology, School of Life Science, Arizona State University, ISTB1, 550 E. Orange St, Tempe, AZ 85287, USA
| | - C. Meyer
- Center for Metabolic and Vascular Biology, School of Life Science, Arizona State University, ISTB1, 550 E. Orange St, Tempe, AZ 85287, USA; Division of Endocrinology, Carl T. Hayden VA Medical Center, Mayo Clinic in Arizona, Phoenix, AZ, USA
| | - E. Plummer
- Division of Endocrinology, Carl T. Hayden VA Medical Center, Mayo Clinic in Arizona, Phoenix, AZ, USA
| | - P. Tongchinsub
- Center for Metabolic and Vascular Biology, School of Life Science, Arizona State University, ISTB1, 550 E. Orange St, Tempe, AZ 85287, USA
| | - M. Mattern
- Center for Metabolic and Vascular Biology, School of Life Science, Arizona State University, ISTB1, 550 E. Orange St, Tempe, AZ 85287, USA
| | - L. J. Mandarino
- Center for Metabolic and Vascular Biology, School of Life Science, Arizona State University, ISTB1, 550 E. Orange St, Tempe, AZ 85287, USA; Department of Medicine, Mayo Clinic in Arizona, Scottsdale, AZ, USA
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Kewalramani G, Fink LN, Asadi F, Klip A. Palmitate-activated macrophages confer insulin resistance to muscle cells by a mechanism involving protein kinase C θ and ε. PLoS One 2011; 6:e26947. [PMID: 22046423 PMCID: PMC3202600 DOI: 10.1371/journal.pone.0026947] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Accepted: 10/06/2011] [Indexed: 12/16/2022] Open
Abstract
Background Macrophage-derived factors contribute to whole-body insulin resistance, partly by impinging on metabolically active tissues. As proof of principle for this interaction, conditioned medium from macrophages treated with palmitate (CM-PA) reduces insulin action and glucose uptake in muscle cells. However, the mechanism whereby CM-PA confers this negative response onto muscle cells remains unknown. Methodology/Principal Findings L6-GLUT4myc myoblasts were exposed for 24 h to palmitate-free conditioned medium from RAW 264.7 macrophages pre-treated with 0.5 mM palmitate for 6 h. This palmitate-free CM-PA, containing selective cytokines and chemokines, inhibited myoblast insulin-stimulated insulin receptor substrate 1 (IRS1) tyrosine phosphorylation, AS160 phosphorylation, GLUT4 translocation and glucose uptake. These effects were accompanied by a rise in c-Jun N-terminal kinase (JNK) activation, degradation of Inhibitor of κBα (IκBα), and elevated expression of proinflammatory cytokines in myoblasts. Notably, CM-PA caused IRS1 phosphorylation on Ser1101, and phosphorylation of novel PKCθ and ε. Co-incubation of myoblasts with CM-PA and the novel and conventional PKC inhibitor Gö6983 (but not with the conventional PKC inhibitor Gö6976) prevented PKCθ and ε activation, JNK phosphorylation, restored IκBα mass and reduced proinflammatory cytokine production. Gö6983 also restored insulin signalling and glucose uptake in myoblasts. Moreover, co-silencing both novel PKC θ and ε isoforms in myoblasts by RNA interference, but not their individual silencing, prevented the inflammatory response and restored insulin sensitivity to CM-PA-treated myoblasts. Conclusions/Clinical Significance The results suggest that the block in muscle insulin action caused by CM-PA is mediated by novel PKCθ and PKCε. This study re-establishes the participation of macrophages as a relay in the action of fatty acids on muscle cells, and further identifies PKCθ and PKCε as key elements in the inflammatory and insulin resistance responses of muscle cells to macrophage products. Furthermore, it portrays these PKC isoforms as potential targets for the treatment of fatty acid-induced, inflammation-linked insulin resistance.
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Affiliation(s)
| | - Lisbeth Nielsen Fink
- Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
- Hagedorn Research Institute, Novo Nordisk A/S, Gentofte, Denmark
| | - Farzad Asadi
- Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
- Department of Biochemistry, School of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Amira Klip
- Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
- * E-mail:
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Picardi PK, Caricilli AM, de Abreu LLF, Carvalheira JBC, Velloso LA, Saad MJA. Modulation of hypothalamic PTP1B in the TNF-alpha-induced insulin and leptin resistance. FEBS Lett 2010; 584:3179-3184. [PMID: 20576518 DOI: 10.1016/j.febslet.2010.05.064] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Revised: 04/30/2010] [Accepted: 05/29/2010] [Indexed: 12/25/2022]
Abstract
We have associated functional and molecular studies of insulin and leptin to investigate the effect of TNF-alpha on central insulin and leptin signaling in rats pre-treated with PTP1B-ASO. The icv infusion of TNF-alpha-induced an increase in PTP1B protein expression and activity, and attenuated insulin and leptin sensitivity and signaling in the hypothalamus. However, TNF-alpha was able to completely blunt the leptin and insulin effect in rats treated with PTP1B-ASO, suggesting that TNF-alpha does not require PTP1B to fully attenuate the leptin and insulin effects. In addition, our data also show that other mechanisms of insulin and leptin resistance are activated in the hypothalamus by TNF-alpha.
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Affiliation(s)
- Paty Karoll Picardi
- Departamento de Clínica Médica, FCM, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil
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Király MA, Campbell J, Park E, Bates HE, Yue JTY, Rao V, Matthews SG, Bikopoulos G, Rozakis-Adcock M, Giacca A, Vranic M, Riddell MC. Exercise maintains euglycemia in association with decreased activation of c-Jun NH2-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats. Am J Physiol Endocrinol Metab 2010; 298:E671-82. [PMID: 19996384 DOI: 10.1152/ajpendo.90575.2008] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Stress-activated systems and oxidative stress are involved in insulin resistance, which, along with beta-cell failure, contribute to the development of type 2 diabetes mellitus (T2DM). Exercise improves insulin resistance and glucose tolerance, and these adaptations may, in part, be related to reductions in inflammation and oxidative stress. We investigated circulating and tissue-specific markers of inflammation and oxidative stress and insulin-signaling pathways in a rodent model of T2DM, the Zucker diabetic fatty rat, with and without voluntary exercise. At 5 wk of age, Zucker diabetic fatty rats (n = 8-9/group) were divided into basal (B), voluntary exercise (E), and sedentary control (S) groups. B rats were euthanized at 6 wk of age, and S and E rats were euthanized 10 wk later. E rats ran approximately 5 km/day, which improved insulin sensitivity and maintained fed and fasted glucose levels and glucose tolerance. Ten weeks of exercise also decreased whole body markers of inflammation and oxidative stress in plasma and liver, including lowered circulating IL-6, haptoglobin, and malondialdehyde levels, hepatic protein oxidation, and phosphorylated JNK, the latter indicating decreased JNK activity. Hepatic phosphoenolpyruvate carboxykinase levels and Ser(307)-phosphorylated insulin receptor substrate-1 were also reduced in E compared with S rats. In summary, we show that, in a rodent model of T2DM, voluntary exercise decreases circulating markers of inflammation and oxidative stress and lowers hepatic JNK activation and Ser(307)-phosphorylated insulin receptor substrate-1. These changes in oxidative stress markers and inflammation are associated with decreased hyperglycemia and insulin resistance and reduced expression of the main gluconeogenic enzyme phosphoenolpyruvate carboxykinase.
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The Mechanisms of Insulin Action. Endocrinology 2010. [DOI: 10.1016/b978-1-4160-5583-9.00034-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Cejkova P, Fojtikova M, Cerna M. Immunomodulatory role of prolactin in diabetes development. Autoimmun Rev 2009; 9:23-7. [DOI: 10.1016/j.autrev.2009.02.031] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2009] [Accepted: 02/17/2009] [Indexed: 02/01/2023]
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Alonso A, Ordóñez P, Fernández R, Moreno M, Llaneza P, Patterson AM, González C. 17beta-estradiol treatment is unable to reproduce p85 alpha redistribution associated with gestational insulin resistance in rats. J Steroid Biochem Mol Biol 2009; 116:160-70. [PMID: 19467325 DOI: 10.1016/j.jsbmb.2009.05.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2009] [Revised: 05/13/2009] [Accepted: 05/15/2009] [Indexed: 11/18/2022]
Abstract
Maternal metabolic adaptations are essential to ensure proper fetal development. According to changes in insulin sensitivity, pregnancy can be divided into two periods: early pregnancy, characterized by an increase in maternal insulin sensitivity, and late pregnancy, in which there is a significant increase in insulin resistance. The aims of the present work were two-fold: firstly, the molecular mechanisms associated with the development of pregnancy-related insulin resistance in peripheral tissues, mainly retroperitoneal adipose tissue and skeletal muscle, were studied in pregnant rats at 6, 11, and 16 days gestation. Secondly, the role of 17beta-estradiol in this process was elucidated in an animal model consisting of ovariectomized rats treated with 17beta-estradiol to mimic plasma gestational levels. The results support the conclusion that retroperitoneal adipose tissue plays a pivotal role in the decrease in insulin sensitivity during pregnancy, through a mechanism that involves p85 alpha redistribution to the insulin receptor and impairment of Glut4 translocation to the plasma membrane. Treatment with 17beta-estradiol did not reproduce the molecular adaptations that occur during pregnancy, suggesting that other hormonal factors presents in gestation but absent in our experimental model are responsible for p85 alpha redistribution to the insulin receptor.
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Affiliation(s)
- Ana Alonso
- Physiology Area, Department of Functional Biology, University of Oviedo, Spain
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35
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Blumenthal A, Isovski F, Rhee KY. Tuberculosis and host metabolism: ancient associations, fresh insights. Transl Res 2009; 154:7-14. [PMID: 19524868 DOI: 10.1016/j.trsl.2009.04.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2007] [Revised: 04/21/2009] [Accepted: 04/21/2009] [Indexed: 12/22/2022]
Abstract
Epidemiologic studies have repeatedly identified malnutrition as a risk factor for tuberculosis (TB), which is the leading bacterial cause of deaths worldwide. The biologic basis for this association, however, remains unclear. Recent work has uncovered a large array of signaling molecules lying at the intersection of metabolic and immune signaling, among which nuclear hormone receptors (NHRs) and the insulin receptor have emerged as 2 prototypic examples. Existing knowledge indicates that the physiologic functions of many NHRs overlap with known epidemiologic risk factors for TB and that diabetes, itself, predisposes to TB. Here, we assimilate these data and identify a potential mechanism that may help to explain the long-standing clinical association between TB and host metabolism. Together, these data emphasize the underused potential of interdisciplinary dialog in current TB research efforts.
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Varma V, Yao-Borengasser A, Rasouli N, Nolen GT, Phanavanh B, Starks T, Gurley C, Simpson P, McGehee RE, Kern PA, Peterson CA. Muscle inflammatory response and insulin resistance: synergistic interaction between macrophages and fatty acids leads to impaired insulin action. Am J Physiol Endocrinol Metab 2009; 296:E1300-10. [PMID: 19336660 PMCID: PMC2692398 DOI: 10.1152/ajpendo.90885.2008] [Citation(s) in RCA: 169] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2008] [Accepted: 03/18/2009] [Indexed: 12/12/2022]
Abstract
Obesity is characterized by adipose tissue expansion as well as macrophage infiltration of adipose tissue. This results in an increase in circulating inflammatory cytokines and nonesterified fatty acids, factors that cause skeletal muscle insulin resistance. Whether obesity also results in skeletal muscle inflammation is not known. In this study, we quantified macrophages immunohistochemically in vastus lateralis biopsies from eight obese and eight lean subjects. Our study demonstrates that macrophages infiltrate skeletal muscle in obesity, and we developed an in vitro system to study this mechanistically. Myoblasts were isolated from vastus lateralis biopsies and differentiated in culture. Coculture of differentiated human myotubes with macrophages in the presence of palmitic acid, to mimic an obese environment, revealed that macrophages in the presence of palmitic acid synergistically augment cytokine and chemokine expression in myotubes, decrease IkappaB-alpha protein expression, increase phosphorylated JNK, decrease phosphorylated Akt, and increase markers of muscle atrophy. These results suggest that macrophages alter the inflammatory state of muscle cells in an obese milieu, inhibiting insulin signaling. Thus in obesity both adipose tissue and skeletal muscle inflammation may contribute to insulin resistance.
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Affiliation(s)
- Vijayalakshmi Varma
- Division of Endocrinology, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
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Shafrir E, Ziv E. A useful list of spontaneously arising animal models of obesity and diabetes. Am J Physiol Endocrinol Metab 2009; 296:E1450-2. [PMID: 19468077 DOI: 10.1152/ajpendo.00113.2009] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Bruce CR, Hoy AJ, Turner N, Watt MJ, Allen TL, Carpenter K, Cooney GJ, Febbraio MA, Kraegen EW. Overexpression of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty acid oxidation and improve high-fat diet-induced insulin resistance. Diabetes 2009; 58:550-8. [PMID: 19073774 PMCID: PMC2646053 DOI: 10.2337/db08-1078] [Citation(s) in RCA: 274] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Skeletal muscle insulin resistance is associated with lipid accumulation, but whether insulin resistance is due to reduced or enhanced flux of long-chain fatty acids into the mitochondria is both controversial and unclear. We hypothesized that skeletal muscle-specific overexpression of the muscle isoform of carnitine palmitoyltransferase 1 (CPT1), the enzyme that controls the entry of long-chain fatty acyl CoA into mitochondria, would enhance rates of fatty acid oxidation and improve insulin action in muscle in high-fat diet insulin-resistant rats. RESEARCH DESIGN AND METHODS Rats were fed a standard (chow) or high-fat diet for 4 weeks. After 3 weeks, in vivo electrotransfer was used to overexpress the muscle isoform of CPT1 in the distal hindlimb muscles (tibialis anterior and extensor digitorum longus [EDL]). Skeletal muscle insulin action was examined in vivo during a hyperinsulinemic-euglycemic clamp. RESULTS In vivo electrotransfer produced a physiologically relevant increase of approximately 20% in enzyme activity; and although the high-fat diet produced insulin resistance in the sham-treated muscle, insulin action was improved in the CPT1-overexpressing muscle. This improvement was associated with a reduction in triacylglycerol content, the membrane-to-cytosolic ratio of diacylglycerol, and protein kinase C theta activity. Importantly, overexpression of CPT1 did not affect markers of mitochondrial capacity or function, nor did it alter skeletal muscle acylcarnitine profiles irrespective of diet. CONCLUSIONS Our data provide clear evidence that a physiological increase in the capacity of long-chain fatty acyl CoA entry into mitochondria is sufficient to ameliorate lipid-induced insulin resistance in muscle.
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Affiliation(s)
- Clinton R Bruce
- Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
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Boura-Halfon S, Zick Y. Serine kinases of insulin receptor substrate proteins. VITAMINS AND HORMONES 2009; 80:313-49. [PMID: 19251043 DOI: 10.1016/s0083-6729(08)00612-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Signaling of insulin and insulin-like growth factor-I (IGF-1) at target tissues is essential for growth, development and for normal homeostasis of glucose, fat, and protein metabolism. Control over this process is therefore tightly regulated. It can be achieved by a negative-feedback control mechanism, whereby downstream components inhibit upstream elements along the insulin and IGF-1 signaling pathway or by signals from other pathways that inhibit insulin/IGF-1 signaling thus leading to insulin/IGF-1 resistance. Phosphorylation of insulin receptor substrates (IRS) proteins on serine residues has emerged as a key step in these control processes both under physiological and pathological conditions. The list of IRS kinases is growing rapidly, concomitant with the list of potential Ser/Thr phosphorylation sites in IRS proteins. Here we review a range of conditions that activate IRS kinases to phosphorylate IRS proteins on selected domains. The specificity of this reaction is discussed and its characteristic as an "array" phosphorylation is suggested. Finally, its implications on insulin/IGF-1 signaling, insulin/IGF-1 resistance and diabetes, an emerging epidemic of the twenty-first century are outlined.
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Affiliation(s)
- Sigalit Boura-Halfon
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
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Friedman JE, Kirwan JP, Jing M, Presley L, Catalano PM. Increased skeletal muscle tumor necrosis factor-alpha and impaired insulin signaling persist in obese women with gestational diabetes mellitus 1 year postpartum. Diabetes 2008; 57:606-13. [PMID: 18083784 PMCID: PMC4697130 DOI: 10.2337/db07-1356] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Women with gestational diabetes mellitus (GDM) demonstrate chronic and progressive insulin resistance and a markedly increased risk of converting to type 2 diabetes after pregnancy. However, the cellular mechanisms underlying this insulin resistance are unknown. RESEARCH DESIGN AND METHODS We investigated the progression of insulin resistance in nine obese women with GDM during late pregnancy (30-36 weeks) and 1 year postpartum. Skeletal muscle biopsies were obtained at each visit, and insulin resistance was determined by the hyperinsulinemic-euglycemic clamp technique. RESULTS Insulin resistance was not significantly improved in GDM women (4.1 +/- 0.4 vs. 5.8 +/- 1.1 10(-2) mg x kg FFM x min(-1)/microU x ml(-1)). Subjects did not experience significant weight loss postpartum. Body weight, fat mass, fasting glucose, and plasma tumor necrosis factor (TNF)-alpha remained higher 1 year postpartum than seen in previously studied normal glucose-tolerant women. Skeletal muscle TNF-alpha mRNA was elevated five- to sixfold in GDM women and remained higher 1 year postpartum. While levels of insulin receptor (IR), IR substrate (IRS)-1, and p85 alpha improved postpartum, insulin-stimulated IR tyrosine phosphorylation and receptor tyrosine kinase activity did not significantly improve postpartum in GDM. The levels of (312)Ser-IRS-1 also did not improve postpartum and correlated with TNF-alpha mRNA (r(2) = 0.19, P < 0.03), consistent with a state of subclinical inflammation and chronic skeletal muscle insulin resistance. CONCLUSIONS These results suggest the mechanisms underlying chronic insulin resistance in GDM women may be driven by increased inflammation that impinges on the IR and IRS-1 signaling cascade in skeletal muscle. These findings have important implications for the health of GDM women during subsequent pregnancies and their risk for progression to type 2 diabetes.
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Affiliation(s)
- Jacob E Friedman
- Department of Pediatrics, University of Colorado Denver, P.O. Box 6511, MS-8106, Aurora, CO 80045, USA.
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Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J. Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care 2008; 31 Suppl 2:S262-8. [PMID: 18227495 DOI: 10.2337/dc08-s264] [Citation(s) in RCA: 547] [Impact Index Per Article: 32.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Insulin resistance, recently recognized as a strong predictor of disease in adults, has become the leading element of the metabolic syndrome and renewed as a focus of research. The condition exists when insulin levels are higher than expected relative to the level of glucose. Thus, insulin resistance is by definition tethered to hyperinsulinemia. The rising prevalence of medical conditions where insulin resistance is common has energized research into the causes. Many causes and consequences have been identified, but the direct contributions of insulin itself in causing or sustaining insulin resistance have received little sustained attention. We examine situations where insulin itself appears to be a proximate and important quantitative contributor to insulin resistance. 1) Mice transfected with extra copies of the insulin gene produce basal and stimulated insulin levels that are two to four times elevated. The mice are of normal weight but show insulin resistance, hyperglycemia, and hypertriglyceridemia. 2) Somogyi described patients with unusually high doses of insulin and hyperglycemia. Episodes of hypoglycemia with release of glucose-raising hormones, postulated as the culprits in early studies, have largely been excluded by studies including continuous glucose monitoring. 3) Rats and humans treated with escalating doses of insulin show both hyperinsulinemia and insulin resistance. 4) The pulsatile administration of insulin (rather than continuous) results in reduced requirements for insulin. 5) Many patients with insulinoma who have elevated basal levels of insulin have reduced (but not absent) responsiveness to administered insulin. In summary, hyperinsulinemia is often both a result and a driver of insulin resistance.
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Affiliation(s)
- Michael H Shanik
- Division of Endocrinology, North Shore-Long Island Jewish Health System, Lake Success, New York, USA
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Maraldi NM, Capanni C, Lattanzi G, Camozzi D, Facchini A, Manzoli FA. SREBP1 interaction with prelamin A forms: A pathogenic mechanism for lipodystrophic laminopathies. ACTA ACUST UNITED AC 2008; 48:209-23. [DOI: 10.1016/j.advenzreg.2007.11.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Ndumele CE, Pradhan AD, Ridker PM. Interrelationships between inflammation, C-reactive protein, and insulin resistance. ACTA ACUST UNITED AC 2007; 1:190-6. [PMID: 17679826 DOI: 10.1111/j.1559-4564.2006.05538.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The recognition that inflammation plays a fundamental role in atherothrombosis has led to the measurement of circulating inflammatory biomarkers such as high-sensitivity C-reactive protein (hs-CRP) as a means of improving cardiovascular disease detection and prevention. Clinically, levels of hs-CRP >3 mg/L indicate elevated risk for myocardial infarction and stroke, even among apparently healthy individuals with low-to-normal lipid levels. Emerging laboratory and epidemiologic data now link inflammation and hs-CRP to insulin resistance in that hs-CRP levels have been associated with impaired insulin sensitivity and the development of dysglycemic conditions, including the cardiometabolic syndrome and incident type 2 diabetes. hs-CRP has also been associated with each of the individual components of the cardiometabolic syndrome. Furthermore, in large prospective studies, hs-CRP adds prognostic information about cardiovascular risk beyond that provided by the cardiometabolic syndrome. These findings have led to discussion about the addition of hs-CRP measurement to the current definition of the cardiometabolic syndrome to improve detection of risk for both diabetes and cardiovascular events in patients. Multiple clinical studies are now underway that are evaluating whether agents traditionally used to improve glycemic control may also significantly reduce hs-CRP.
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Affiliation(s)
- Chiadi E Ndumele
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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Giraud J, Haas M, Feener EP, Copps KD, Dong X, Dunn SL, White MF. Phosphorylation of Irs1 at SER-522 inhibits insulin signaling. Mol Endocrinol 2007; 21:2294-302. [PMID: 17579213 DOI: 10.1210/me.2007-0159] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Multisite phosphorylation of Irs1 on serine and threonine residues regulates insulin signaling that can contribute to insulin resistance. We identified by mass spectrometry the phosphorylation of Ser522 in rat Irs1 (S522(Irs1)). The functional effects of this phosphorylation site were investigated in cultured cells using a sequence-specific phosphoserine antibody. Insulin stimulated the phosphorylation of S522(Irs1) in L6 myoblasts and myotubes. S522(Irs1) phosphorylation was inhibited by wortmannin, whereas PD98059, rapamycin, or glucose-starvation had no effect. Reducing Akt expression with small interfering RNA inhibited insulin-stimulated phosphorylation of S522(Irs1), suggesting the involvement of the phosphatidylinositol 3-kinase--> Akt cascade. A S522(Irs1)-->A522(Irs1) substitution increased insulin-stimulated tyrosine phosphorylation of Irs1 and signaling, whereas a S522(Irs1)-->E522(Irs1) substitution reduced insulin-stimulated Irs1 tyrosine phosphorylation. Together, these results suggest the phosphatidylinositol 3-kinase-->Akt cascade can inhibit insulin signaling through the phosphorylation of S522(Irs1).
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Affiliation(s)
- Jodel Giraud
- Howard Hughes Medical Institute, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA
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Romanatto T, Cesquini M, Amaral ME, Roman EA, Moraes JC, Torsoni MA, Cruz-Neto AP, Velloso LA. TNF-alpha acts in the hypothalamus inhibiting food intake and increasing the respiratory quotient--effects on leptin and insulin signaling pathways. Peptides 2007; 28:1050-8. [PMID: 17459524 DOI: 10.1016/j.peptides.2007.03.006] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2006] [Revised: 03/14/2007] [Accepted: 03/16/2007] [Indexed: 11/21/2022]
Abstract
Acting in the hypothalamus, tumor necrosis factor-alpha (TNF-alpha) produces a potent anorexigenic effect. However, the molecular mechanisms involved in this phenomenon are poorly characterized. In this study, we investigate the capacity of TNF-alpha to activate signal transduction in the hypothalamus through elements of the pathways employed by the anorexigenic hormones insulin and leptin. High dose TNF-alpha promotes a reduction of 25% in 12h food intake, which is an inhibitory effect that is marginally inferior to that produced by insulin and leptin. In addition, high dose TNF-alpha increases body temperature and respiratory quotient, effects not reproduced by insulin or leptin. TNF-alpha, predominantly at the high dose, is also capable of activating canonical pro-inflammatory signal transduction in the hypothalamus, inducing JNK, p38, and NFkappaB, which results in the transcription of early responsive genes and expression of proteins of the SOCS family. Also, TNF-alpha activates signal transduction through JAK-2 and STAT-3, but does not activate signal transduction through early and intermediary elements of the insulin/leptin signaling pathways such as IRS-2, Akt, ERK and FOXO1. When co-injected with insulin or leptin, TNF-alpha, at both high and low doses, partially impairs signal transduction through IRS-2, Akt, ERK and FOXO1 but not through JAK-2 and STAT-3. This effect is accompanied by the partial inhibition of the anorexigenic effects of insulin and leptin, when the low, but not the high dose of TNF-alpha is employed. In conclusion, TNF-alpha, on a dose-dependent way, modulates insulin and leptin signaling and action in the hypothalamus.
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Affiliation(s)
- Talita Romanatto
- Department of Internal Medicine, State University of Campinas, Brazil
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White MF. Regulating insulin signaling and beta-cell function through IRS proteins. Can J Physiol Pharmacol 2007; 84:725-37. [PMID: 16998536 DOI: 10.1139/y06-008] [Citation(s) in RCA: 125] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Diabetes mellitus is a complex disorder that arises from various causes, including dysregulated glucose sensing and impaired insulin secretion (maturity onset diabetes of youth, MODY), autoimmune-mediated beta-cell destruction (type 1), or insufficient compensation for peripheral insulin resistance (type 2). Type 2 diabetes is the most prevalent form that usually occurs at middle age; it afflicts more than 30 million people over the age of 65, but is appearing with greater frequency in children and adolescents. Dysregulated insulin signaling exacerbated by chronic hyperglycemia promotes a cohort of systemic disorders--including dyslipidemia, hypertension, cardiovascular disease, and female infertility. Understanding the molecular basis of insulin resistance can prevent these disorders and their inevitable progression to type 2 diabetes.
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Affiliation(s)
- Morris F White
- Howard Hughes Medical Institute, Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Karp Family Research Laboratories, Room 4210, 300 Longwood Avenue, Boston, MA 02115, USA.
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Igarashi M, Hirata A, Nozaki H, Kadomoto-Antsuki Y, Tominaga M. Role of angiotensin II type-1 and type-2 receptors on vascular smooth muscle cell growth and glucose metabolism in diabetic rats. Diabetes Res Clin Pract 2007; 75:267-77. [PMID: 16934905 DOI: 10.1016/j.diabres.2006.06.032] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2006] [Revised: 06/07/2006] [Accepted: 06/26/2006] [Indexed: 12/31/2022]
Abstract
This study investigates the mechanisms whereby angiotensin II (Ang II) signaling contributes to cell growth and glucose metabolism in cultured vascular smooth muscle cells (VSMCs) from male Wistar fatty rats (WF) and their littermates (Wistar lean rats, WL). The levels of the medial outgrowth rate of VSMCs and Ang II type-1 receptors (AT1R) in aortae from WF were more enhanced than those in aortae from WL, but the level of Ang II type-2 receptors (AT2R) was not different. A mixture of insulin and Ang II additively increased the values of [(3)H]-thymidine incorporation in WF and WL, which was inhibited by olmesartan, an AT1 receptor blockade (ARB), but not by PD123,319, an AT2 receptor blockade. Similarly, insulin and Ang II phosphorylated extracellular-regulated protein kinase 1/2, retinoblastoma tumor suppressor protein, and cyclic AMP response element binding protein, and these levels were higher in WF than in WL. In contrast, the phosphorylation was suppressed by olmesartan but not PD123,319. Insulin-stimulated Akt phosphorylation and 2-deoxy-d-glucose uptake in WF were significantly reduced by Ang II, and the reduction was ameliorated by olmesartan but not PD123,319. Differently from the result of Akt, the phosphorylation of the insulin-stimulated insulin receptor beta-subunit was not affected by Ang II, olmesartan, or PD123,319. However, the phosphorylation of insulin-stimulated insulin-related substrate (IRS)-1 was suppressed by Ang II, and the suppression was ameliorated by olmesartan, but not PD123,319, in both WF and WL. In contrast, the phosphorylation of IRS-1 on Ser(307) was elevated by the Ang II, and the elevation was suppressed by olmesartan, but not by PD123,319, in both WF and WL. These findings demonstrated that Ang II signaling contributes to cell proliferation and inhibition of the insulin signaling pathways through AT1R, but not trough AT2R, in both non-diabetic and diabetic VSMCs.
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MESH Headings
- Angiotensin II Type 1 Receptor Blockers/pharmacology
- Angiotensin II Type 2 Receptor Blockers
- Animals
- Aorta/physiopathology
- Blood Glucose/metabolism
- Cells, Cultured
- DNA Replication
- Deoxyglucose/metabolism
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/physiopathology
- Imidazoles/pharmacology
- Male
- Muscle, Smooth, Vascular/growth & development
- Muscle, Smooth, Vascular/physiopathology
- Nuclear Proteins/metabolism
- Obesity
- Rats
- Rats, Wistar
- Receptor, Angiotensin, Type 1/drug effects
- Receptor, Angiotensin, Type 1/physiology
- Receptor, Angiotensin, Type 2/drug effects
- Receptor, Angiotensin, Type 2/physiology
- Tetrazoles/pharmacology
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Affiliation(s)
- Masahiko Igarashi
- Department of Laboratory Medicine, Yamagata University School of Medicine, 2-2-2, Iida-nishi, Yamagata 990-9585, Japan.
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John BJ, Irukulla S, Abulafi AM, Kumar D, Mendall MA. Systematic review: adipose tissue, obesity and gastrointestinal diseases. Aliment Pharmacol Ther 2006; 23:1511-23. [PMID: 16696799 DOI: 10.1111/j.1365-2036.2006.02915.x] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Obesity is increasingly being recognized as a risk factor for a number of benign and malignant gastrointestinal conditions. However, literature on the underlying pathophysiological mechanisms is sparse and ambiguous. Insulin resistance is the most widely accepted link between obesity and disease, particularly colorectal cancer. The recognition that intra-abdominal fat is immunologically active sheds new light not only on the pathogenesis of obesity-related gastrointestinal conditions, but also on inflammatory conditions such as Crohn's disease. AIM To describe the biology of adipose tissue, its impact on the immune system and explores the possible underlying mechanisms linking obesity to gastrointestinal diseases. It also looks at the role of mesenteric fat in determining severity and course of Crohn's disease. METHODS Relevant English-language literature and abstracts cited on MEDLINE database were reviewed. RESULTS Our recent finding of an association between obesity and subclinical bowel inflammation suggests that, apart from promoting generalized immune activation, fat also evokes local immune responses. We propose that the proinflammatory milieu promoted by obesity could underlie many of these associations and that the mechanism implicating insulin resistance may merely represent an epiphenomenon. In Crohn's disease, on the other hand, intra-abdominal fat may provide a protective mechanism. CONCLUSION The potential of adipose tissue as a therapeutic target is vast and needs exploration.
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Affiliation(s)
- B J John
- Department of Colorectal Surgery, Mayday University Hospital, Croydon, UK
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