|
1
|
Molonia MS, Speciale A, Muscarà C, Salamone FL, Saija A, Cimino F. Low concentrations of α-lipoic acid reduce palmitic acid-induced alterations in murine hypertrophic adipocytes. Nat Prod Res 2024; 38:916-925. [PMID: 37129014 DOI: 10.1080/14786419.2023.2207137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 04/14/2023] [Indexed: 05/03/2023]
Abstract
Obesity is a metabolic disorder with excessive body fat accumulation, increasing incidence of chronic metabolic diseases. Hypertrophic obesity is associated with local oxidative stress and inflammation. Herein, we evaluated the in vitro activity of micromolar concentrations of α-lipoic acid (ALA) on palmitic acid (PA)-exposed murine hypertrophic 3T3-L1 adipocytes, focussing on the main molecular pathways involved in adipogenesis, inflammation, and insulin resistance. ALA, starting from 1 µM, decreased adipocytes hypertrophy, reducing PA-triggered intracellular lipid accumulation, PPAR-γ levels, and FABP4 gene expression, and counteracted PA-induced intracellular ROS levels and NF-κB activation. ALA reverted PA-induced insulin resistance, restoring PI3K/Akt axis and inducing GLUT-1 and glucose uptake, showing insulin sensitizing properties since it increased their basal levels. In conclusion, this study supports the potential effects of low micromolar ALA against hypertrophy, inflammation, and insulin resistance in adipose tissue, suggesting its important role as pharmacological supplement in the prevention of conditions linked to obesity and metabolic syndrome.
Collapse
Affiliation(s)
- Maria Sofia Molonia
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
- "Prof. Antonio Imbesi" Foundation, University of Messina,Messina, Italy
| | - Antonio Speciale
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Claudia Muscarà
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Federica Lina Salamone
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Antonella Saija
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Francesco Cimino
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| |
Collapse
|
|
2
|
Mazumdar D, Singh S. Diabetic Encephalopathy: Role of Oxidative and Nitrosative Factors in Type 2 Diabetes. Indian J Clin Biochem 2024; 39:3-17. [PMID: 38223005 PMCID: PMC10784252 DOI: 10.1007/s12291-022-01107-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022]
Abstract
Diabetes mellitus is a set of complex metabolic disorders characterized by chronic hyperglycaemic condition due to defective insulin secretion (Type 1) and action (Type 2), which leads to serious micro and macro-vascular damage, inflammation, oxidative and nitrosative stress and a deranged energy homeostasis due to imbalance in the glucose and lipid metabolism. Moreover, patient with diabetes mellitus often showed the nervous system disorders known as diabetic encephalopathy. The precise pathological mechanism of diabetic encephalopathy by which it effects the central nervous system directly or indirectly causing the cognitive and motor impairment, is not completely understood. However, it has been speculated that like other extracerebellar tissues, oxidative and nitrosative stress may play significant role in the pathogenesis of diabetic encephalopathy. Therefore, the present review aimed to explain the possible association of the oxidative and nitrosative stress caused by the chronic hyperglycaemic condition with the central nervous system complications of the type 2 diabetes mellitus induced diabetic encephalopathy.
Collapse
Affiliation(s)
- Debashree Mazumdar
- Biochemistry and Molecular Biology Laboratory, Department of Zoology, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, Chhattisgarh 495009 India
| | - Santosh Singh
- Biochemistry and Molecular Biology Laboratory, Department of Zoology, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, Chhattisgarh 495009 India
| |
Collapse
|
|
3
|
Handy RM, Holloway GP. Insights into the development of insulin resistance: Unraveling the interaction of physical inactivity, lipid metabolism and mitochondrial biology. Front Physiol 2023; 14:1151389. [PMID: 37153211 PMCID: PMC10157178 DOI: 10.3389/fphys.2023.1151389] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 04/07/2023] [Indexed: 05/09/2023] Open
Abstract
While impairments in peripheral tissue insulin signalling have a well-characterized role in the development of insulin resistance and type 2 diabetes (T2D), the specific mechanisms that contribute to these impairments remain debatable. Nonetheless, a prominent hypothesis implicates the presence of a high-lipid environment, resulting in both reactive lipid accumulation and increased mitochondrial reactive oxygen species (ROS) production in the induction of peripheral tissue insulin resistance. While the etiology of insulin resistance in a high lipid environment is rapid and well documented, physical inactivity promotes insulin resistance in the absence of redox stress/lipid-mediated mechanisms, suggesting alternative mechanisms-of-action. One possible mechanism is a reduction in protein synthesis and the resultant decrease in key metabolic proteins, including canonical insulin signaling and mitochondrial proteins. While reductions in mitochondrial content associated with physical inactivity are not required for the induction of insulin resistance, this could predispose individuals to the detrimental effects of a high-lipid environment. Conversely, exercise-training induced mitochondrial biogenesis has been implicated in the protective effects of exercise. Given mitochondrial biology may represent a point of convergence linking impaired insulin sensitivity in both scenarios of chronic overfeeding and physical inactivity, this review aims to describe the interaction between mitochondrial biology, physical (in)activity and lipid metabolism within the context of insulin signalling.
Collapse
|
|
4
|
Bhatti JS, Sehrawat A, Mishra J, Sidhu IS, Navik U, Khullar N, Kumar S, Bhatti GK, Reddy PH. Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives. Free Radic Biol Med 2022; 184:114-134. [PMID: 35398495 DOI: 10.1016/j.freeradbiomed.2022.03.019] [Citation(s) in RCA: 223] [Impact Index Per Article: 74.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 03/20/2022] [Accepted: 03/22/2022] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes (T2DM) is a persistent metabolic disorder rising rapidly worldwide. It is characterized by pancreatic insulin resistance and β-cell dysfunction. Hyperglycemia induced reactive oxygen species (ROS) production and oxidative stress are correlated with the pathogenesis and progression of this metabolic disease. To counteract the harmful effects of ROS, endogenous antioxidants of the body or exogenous antioxidants neutralise it and maintain bodily homeostasis. Under hyperglycemic conditions, the imbalance between the cellular antioxidant system and ROS production results in oxidative stress, which subsequently results in the development of diabetes. These ROS are produced in the endoplasmic reticulum, phagocytic cells and peroxisomes, with the mitochondrial electron transport chain (ETC) playing a pivotal role. The exacerbated ROS production can directly cause structural and functional modifications in proteins, lipids and nucleic acids. It also modulates several intracellular signaling pathways that lead to insulin resistance and impairment of β-cell function. In addition, the hyperglycemia-induced ROS production contributes to micro- and macro-vascular diabetic complications. Various in-vivo and in-vitro studies have demonstrated the anti-oxidative effects of natural products and their derived bioactive compounds. However, there is conflicting clinical evidence on the beneficial effects of these antioxidant therapies in diabetes prevention. This review article focused on the multifaceted role of oxidative stress caused by ROS overproduction in diabetes and related complications and possible antioxidative therapeutic strategies targeting ROS in this disease.
Collapse
Affiliation(s)
- Jasvinder Singh Bhatti
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
| | - Abhishek Sehrawat
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
| | - Jayapriya Mishra
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
| | - Inderpal Singh Sidhu
- Department of Zoology, Sri Guru Gobind Singh College, Sector 26, Chandigarh, India.
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Bathinda, India.
| | - Naina Khullar
- Department of Zoology, Mata Gujri College, Fatehgarh Sahib, Punjab, India.
| | - Shashank Kumar
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Bathinda, India.
| | - Gurjit Kaur Bhatti
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, India.
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA; Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA; Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA; Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
| |
Collapse
|
|
5
|
Posa DK, Baba SP. Intracellular pH Regulation of Skeletal Muscle in the Milieu of Insulin Signaling. Nutrients 2020; 12:nu12102910. [PMID: 32977552 PMCID: PMC7598285 DOI: 10.3390/nu12102910] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/24/2020] [Accepted: 08/31/2020] [Indexed: 12/18/2022] Open
Abstract
Type 2 diabetes (T2D), along with obesity, is one of the leading health problems in the world which causes other systemic diseases, such as cardiovascular diseases and kidney failure. Impairments in glycemic control and insulin resistance plays a pivotal role in the development of diabetes and its complications. Since skeletal muscle constitutes a significant tissue mass of the body, insulin resistance within the muscle is considered to initiate the onset of diet-induced metabolic syndrome. Insulin resistance is associated with impaired glucose uptake, resulting from defective post-receptor insulin responses, decreased glucose transport, impaired glucose phosphorylation, oxidation and glycogen synthesis in the muscle. Although defects in the insulin signaling pathway have been widely studied, the effects of cellular mechanisms activated during metabolic syndrome that cross-talk with insulin responses are not fully elucidated. Numerous reports suggest that pathways such as inflammation, lipid peroxidation products, acidosis and autophagy could cross-talk with insulin-signaling pathway and contribute to diminished insulin responses. Here, we review and discuss the literature about the defects in glycolytic pathway, shift in glucose utilization toward anaerobic glycolysis and change in intracellular pH [pH]i within the skeletal muscle and their contribution towards insulin resistance. We will discuss whether the derangements in pathways, which maintain [pH]i within the skeletal muscle, such as transporters (monocarboxylate transporters 1 and 4) and depletion of intracellular buffers, such as histidyl dipeptides, could lead to decrease in [pH]i and the onset of insulin resistance. Further we will discuss, whether the changes in [pH]i within the skeletal muscle of patients with T2D, could enhance the formation of protein aggregates and activate autophagy. Understanding the mechanisms by which changes in the glycolytic pathway and [pH]i within the muscle, contribute to insulin resistance might help explain the onset of obesity-linked metabolic syndrome. Finally, we will conclude whether correcting the pathways which maintain [pH]i within the skeletal muscle could, in turn, be effective to maintain or restore insulin responses during metabolic syndrome.
Collapse
Affiliation(s)
- Dheeraj Kumar Posa
- Diabetes and Obesity Center, University of Louisville, Louisville, KY 40202, USA
- Christina Lee Brown Envirome Institute, University of Louisville, Louisville, KY 40202, USA
| | - Shahid P Baba
- Diabetes and Obesity Center, University of Louisville, Louisville, KY 40202, USA
- Christina Lee Brown Envirome Institute, University of Louisville, Louisville, KY 40202, USA
| |
Collapse
|
|
6
|
Liu G, Liu J, Pian L, Gui S, Lu B. α‑lipoic acid protects against carbon tetrachloride‑induced liver cirrhosis through the suppression of the TGF‑β/Smad3 pathway and autophagy. Mol Med Rep 2018; 19:841-850. [PMID: 30535447 PMCID: PMC6323260 DOI: 10.3892/mmr.2018.9719] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 09/28/2018] [Indexed: 12/21/2022] Open
Abstract
α-lipoic acid (ALA) is a naturally occurring antioxidant with protective effects against various hepatic injuries. The aim of the present study was to investigate the mechanisms by which ALA protects the liver from carbon tetrachloride (CCl4)-induced liver cirrhosis. The widely used liver cirrhosis rat model was established via an intraperitoneal injection of 2 mg/kg 50% CCl4, three times/week for 8 weeks. Simultaneously, 50 or 100 mg/kg ALA was orally administrated to the rats every day for 8 weeks. The activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was detected in the serum. The pathological liver injuries were analyzed using hematoxylin and eosin and Masson's trichrome staining. The principal factors involved in the transforming growth factor-β (TGF-β)/mothers against decapentaplegic homolog 9 (Smad3) and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways and in autophagy were examined using reverse transcription-quantitative polymerase chain reaction or western blot analysis. The results demonstrated that the administration of ALA alleviated CCl4-induced liver injury, as demonstrated by decreased ALT and AST activity, improved pathological injuries and reduced collagen deposition. The CCl4-induced increase in TGF-β and phosphorylated-Smad3 expression levels was additionally inhibited by treatment with ALA. Furthermore, the administration of ALA reversed the CCl4-induced upregulation of light chain 3II and Beclin-1, and downregulation of p62. The CCl4-induced suppression of the AKT/mTOR pathway was additionally restored following treatment with ALA. In combination, the results of the present study demonstrated that ALA was able to protect CCl4-induced liver cirrhosis, an effect that may be associated with inactivation of the TGF-β/Smad3 pathway and suppression of autophagy.
Collapse
Affiliation(s)
- Guangwei Liu
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital, Henan University of Chinese Medicine, Zhengzhou, Henan 450004, P.R. China
| | - Jiangkai Liu
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital, Henan University of Chinese Medicine, Zhengzhou, Henan 450004, P.R. China
| | - Linping Pian
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital, Henan University of Chinese Medicine, Zhengzhou, Henan 450004, P.R. China
| | - Songlin Gui
- Department of Emergency Medicine, Zhengzhou Chinese Medicine Hospital, Zhengzhou, Henan 450007, P.R. China
| | - Baoping Lu
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital, Henan University of Chinese Medicine, Zhengzhou, Henan 450004, P.R. China
| |
Collapse
|
|
7
|
Ighodaro OM. Molecular pathways associated with oxidative stress in diabetes mellitus. Biomed Pharmacother 2018; 108:656-662. [PMID: 30245465 DOI: 10.1016/j.biopha.2018.09.058] [Citation(s) in RCA: 301] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 09/10/2018] [Accepted: 09/11/2018] [Indexed: 12/31/2022] Open
Abstract
The role of oxidative stress in the occurrence and development of diabetes mellitus is both critical and pivotal. Several molecular event cascade in different metabolic pathways such as glycolytic, hexosamine, protein kinase C, polyol and advanced glycation end-product (AGE) pathways have been identified as pro-oxidative processes and are usually up-regulated in the diabetics. Inhibition of glyceraldehyde-3-P dehydrogenase by poly-ADP-ribose polymerase 1 and subsequent accumulation of the enzyme substrate (glyceraldehyde-3-P) appears to be central to diabetes-associated oxidative stress. Increased level of glyceraldehyde-3-P activates two major pro-oxidative pathways in diabetes: (i) It activates the AGE pathway, precisely the synthesis of methylglyoxal from non-enzymatic dephosphorylation of the triose phosphates (ii) It activates protein kinase C (PKC) pathway by promoting the synthesis of diacylglycerol. In addition, it causes the accumulation of glycolytic metabolites upstream, and this leads to excessive stimulation of other pro-oxidative pathways such as hexosamine and polyol pathways. This review tends to highlight the main oxidative processes associated with diabetes mellitus.
Collapse
|
|
8
|
Al-Lahham R, Deford JH, Papaconstantinou J. Mitochondrial-generated ROS down regulates insulin signaling via activation of the p38MAPK stress response pathway. Mol Cell Endocrinol 2016; 419:1-11. [PMID: 26454089 DOI: 10.1016/j.mce.2015.09.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 08/18/2015] [Accepted: 09/14/2015] [Indexed: 01/09/2023]
Abstract
Impairment of insulin signaling and hepatic insulin resistance has been attributed to ROS-mediated activation of p38MAPK stress response signaling. Our research focused on whether (a) ROS generated by mitochondrial electron transport chain complex I (ETC-CI) dysfunction, via the use of Rotenone, inactivates insulin signaling; and (b) the p38MAPK pathway is involved in the ROS-induced impairment of insulin signaling. Our results show that in primary mouse hepatocytes the CI inhibitor, Rotenone, (a) induces IRS-1 Ser(307) phosphorylation that is blocked by the anti-oxidant NAC or by the p38MAPK inhibitors, SB203580 and SB202190; (b) inhibits insulin-stimulated AKT-Ser(473) and GSK3β-Ser(9) phosphorylations, in a manner that is not responsive to reversal by the anti-oxidant NAC or by the p38MAPK inhibitors, SB203580 and SB202190. We conclude that rotenone-induced insulin resistance involves a p38MAPK-dependent mechanism for the inhibition of the proximal end of insulin signaling (IRS1), and a p38MAPK-independent mechanism for the inhibition of the distal end (AKT and GSK3β). Our study suggests that ROS generated by inhibition of ETC CI, promotes hepatic insulin resistance partly via activation of the p38MAPK stress-response pathway.
Collapse
Affiliation(s)
- Rabab Al-Lahham
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - James H Deford
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - John Papaconstantinou
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, 77555, USA.
| |
Collapse
|
|
9
|
Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 2015; 6:456-480. [PMID: 25897356 PMCID: PMC4398902 DOI: 10.4239/wjd.v6.i3.456] [Citation(s) in RCA: 738] [Impact Index Per Article: 73.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 11/21/2014] [Accepted: 01/12/2015] [Indexed: 02/05/2023] Open
Abstract
Oxidative stress is increased in metabolic syndrome and type 2 diabetes mellitus (T2DM) and this appears to underlie the development of cardiovascular disease, T2DM and diabetic complications. Increased oxidative stress appears to be a deleterious factor leading to insulin resistance, dyslipidemia, β-cell dysfunction, impaired glucose tolerance and ultimately leading to T2DM. Chronic oxidative stress, hyperglycemia and dyslipidemia are particularly dangerous for β-cells from lowest levels of antioxidant, have high oxidative energy requirements, decrease the gene expression of key β-cell genes and induce cell death. If β-cell functioning is impaired, it results in an under production of insulin, impairs glucose stimulated insulin secretion, fasting hyperglycemia and eventually the development of T2DM.
Collapse
|
|
10
|
Cordero-Herrera I, Martín MA, Goya L, Ramos S. Cocoa flavonoids protect hepatic cells against high-glucose-induced oxidative stress: relevance of MAPKs. Mol Nutr Food Res 2015; 59:597-609. [PMID: 25594685 DOI: 10.1002/mnfr.201400492] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Revised: 10/20/2014] [Accepted: 12/22/2014] [Indexed: 01/05/2023]
Abstract
SCOPE Oxidative stress plays a main role in the pathogenesis of type 2 diabetes mellitus. Cocoa and (-)-epicatechin (EC), a main cocoa flavanol, have been suggested to exert beneficial effects in type 2 diabetes mellitus because of their protective effects against oxidative stress and insulin-like properties. In this study, the protective effect of EC and a cocoa phenolic extract (CPE) against oxidative stress induced by a high-glucose challenge, which causes insulin resistance, was investigated on hepatic HepG2 cells. METHODS AND RESULTS Oxidative status, phosphorylated mitogen-activated protein kinases (MAPKs), nuclear factor E2 related factor 2 (Nrf2) and p-(Ser)-IRS-1 expression, and glucose uptake were evaluated. EC and CPE regulated antioxidant enzymes and activated extracellular-regulated kinase and Nrf2. EC and CPE pre-treatment prevented high-glucose-induced antioxidant defences and p-MAPKs, and maintained Nrf2 stimulation. The presence of selective MAPK inhibitors induced changes in redox status, glucose uptake, p-(Ser)- and total IRS-1 levels that were observed in CPE-mediated protection. CONCLUSION EC and CPE recovered redox status of insulin-resistant HepG2 cells, suggesting that the functionality in EC- and CPE-treated cells was protected against high-glucose-induced oxidative insult. CPE beneficial effects on redox balance and insulin resistance were mediated by targeting MAPKs.
Collapse
Affiliation(s)
- Isabel Cordero-Herrera
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), Ciudad Universitaria, Madrid, Spain
| | | | | | | |
Collapse
|
|
11
|
Demine S, Reddy N, Renard P, Raes M, Arnould T. Unraveling biochemical pathways affected by mitochondrial dysfunctions using metabolomic approaches. Metabolites 2014; 4:831-78. [PMID: 25257998 PMCID: PMC4192695 DOI: 10.3390/metabo4030831] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Revised: 09/02/2014] [Accepted: 09/18/2014] [Indexed: 02/06/2023] Open
Abstract
Mitochondrial dysfunction(s) (MDs) can be defined as alterations in the mitochondria, including mitochondrial uncoupling, mitochondrial depolarization, inhibition of the mitochondrial respiratory chain, mitochondrial network fragmentation, mitochondrial or nuclear DNA mutations and the mitochondrial accumulation of protein aggregates. All these MDs are known to alter the capacity of ATP production and are observed in several pathological states/diseases, including cancer, obesity, muscle and neurological disorders. The induction of MDs can also alter the secretion of several metabolites, reactive oxygen species production and modify several cell-signalling pathways to resolve the mitochondrial dysfunction or ultimately trigger cell death. Many metabolites, such as fatty acids and derived compounds, could be secreted into the blood stream by cells suffering from mitochondrial alterations. In this review, we summarize how a mitochondrial uncoupling can modify metabolites, the signalling pathways and transcription factors involved in this process. We describe how to identify the causes or consequences of mitochondrial dysfunction using metabolomics (liquid and gas chromatography associated with mass spectrometry analysis, NMR spectroscopy) in the obesity and insulin resistance thematic.
Collapse
Affiliation(s)
- Stéphane Demine
- Laboratory of Biochemistry and Cell Biology (URBC), NARILIS (Namur Research Institute for Life Sciences), University of Namur (UNamur), 61 rue de Bruxelles, Namur 5000, Belgium.
| | - Nagabushana Reddy
- Laboratory of Biochemistry and Cell Biology (URBC), NARILIS (Namur Research Institute for Life Sciences), University of Namur (UNamur), 61 rue de Bruxelles, Namur 5000, Belgium.
| | - Patricia Renard
- Laboratory of Biochemistry and Cell Biology (URBC), NARILIS (Namur Research Institute for Life Sciences), University of Namur (UNamur), 61 rue de Bruxelles, Namur 5000, Belgium.
| | - Martine Raes
- Laboratory of Biochemistry and Cell Biology (URBC), NARILIS (Namur Research Institute for Life Sciences), University of Namur (UNamur), 61 rue de Bruxelles, Namur 5000, Belgium.
| | - Thierry Arnould
- Laboratory of Biochemistry and Cell Biology (URBC), NARILIS (Namur Research Institute for Life Sciences), University of Namur (UNamur), 61 rue de Bruxelles, Namur 5000, Belgium.
| |
Collapse
|
|
12
|
Ruan Y, Zheng FP, Li L, Wang Z, Li H. Reactive oxygen species up-regulates SOCS-3 in 3T3-L1 adipocytes. Int J Diabetes Dev Ctries 2014. [DOI: 10.1007/s13410-014-0201-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
|
|
13
|
Kim DY, Kim J, Ham HJ, Choue R. Effects of d-α-tocopherol supplements on lipid metabolism in a high-fat diet-fed animal model. Nutr Res Pract 2013; 7:481-7. [PMID: 24353834 PMCID: PMC3865271 DOI: 10.4162/nrp.2013.7.6.481] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Revised: 08/02/2013] [Accepted: 08/12/2013] [Indexed: 11/12/2022] Open
Abstract
High-fat diet up-regulates either insulin resistance or triglycerides, which is assumed to be related to the expression of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ. The beneficial effects of vitamin E on insulin resistance are well known; however, it is not clear if vitamin E with a high-fat diet alters the expression of PPAR-α and PPAR-γ. We investigated the effects of d-α-tocopherol supplementation on insulin sensitivity, blood lipid profiles, lipid peroxidation, and the expression of PPAR-α and PPAR-γ in a high-fat (HF) diet-fed male C57BL/6J model of insulin resistance. The animals were given a regular diet (CON; 10% fat), a HF diet containing 45% fat, or a HF diet plus d-α-tocopherol (HF-E) for a period of 20 weeks. The results showed that the HF diet induced insulin resistance and altered the lipid profile, specifically the triglyceride (TG) and total cholesterol (TC) levels (P < 0.05). In this animal model, supplementation with d-α-tocopherol improved insulin resistance as well as the serum levels of TG and very-low-density lipoprotein-cholesterol (VLDL-C) (P < 0.05). Moreover, the treatment decreased the levels of malondialdehyde (MDA) in the serum and liver while increasing hepatic PPAR-α expression and decreasing PPAR-γ expression. In conclusion, the oral administration of d-α-tocopherol with a high-fat diet had positive effects on insulin resistance, lipid profiles, and oxidative stress through the expression of PPAR-α and PPAR-γ in a high-fat diet-fed male mice.
Collapse
Affiliation(s)
- Do Yeon Kim
- Department of Medical Nutrition, Graduate School of East-West Medical Science, Kyung Hee University, 1732 Deogyeong-daero, Giheung-gu, Yongin, Gyeonggi 446-701, Korea. ; Research Institute of Medical Nutrition, Kyung Hee University, Seoul 130-701, Korea
| | - Jinkyung Kim
- Department of Medical Nutrition, Graduate School of East-West Medical Science, Kyung Hee University, 1732 Deogyeong-daero, Giheung-gu, Yongin, Gyeonggi 446-701, Korea
| | - Hye Jin Ham
- Department of Medical Nutrition, Graduate School of East-West Medical Science, Kyung Hee University, 1732 Deogyeong-daero, Giheung-gu, Yongin, Gyeonggi 446-701, Korea
| | - Ryowon Choue
- Department of Medical Nutrition, Graduate School of East-West Medical Science, Kyung Hee University, 1732 Deogyeong-daero, Giheung-gu, Yongin, Gyeonggi 446-701, Korea. ; Research Institute of Medical Nutrition, Kyung Hee University, Seoul 130-701, Korea
| |
Collapse
|
|
14
|
Ishiki M, Nishida Y, Ishibashi H, Wada T, Fujisaka S, Takikawa A, Urakaze M, Sasaoka T, Usui I, Tobe K. Impact of divergent effects of astaxanthin on insulin signaling in L6 cells. Endocrinology 2013; 154:2600-12. [PMID: 23715867 DOI: 10.1210/en.2012-2198] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Because oxidative stress promotes insulin resistance in obesity and type 2 diabetes, it is crucial to find effective antioxidant for the purpose of decreasing this threat. In this study, we explored the effect of astaxanthin, a carotenoid antioxidant, on insulin signaling and investigated whether astaxanthin improves cytokine- and free fatty acid-induced insulin resistance in vitro. We examined the effect of astaxanthin on insulin-stimulated glucose transporter 4 (GLUT4) translocation, glucose uptake, and insulin signaling in cultured rat L6 muscle cells using plasma membrane lawn assay, 2-deoxyglucose uptake, and Western blot analysis. Next, we examined the effect of astaxanthin on TNFα- and palmitate-induced insulin resistance. The amount of reactive oxygen species generated by TNFα or palmitate with or without astaxanthin was evaluated by dichlorofluorescein staining. We also compared the effect of astaxanthin on insulin signaling with that of other antioxidants, α-lipoic acid and α-tocopherol. We observed astaxanthin enhanced insulin-stimulated GLUT4 translocation and glucose uptake, which was associated with an increase in insulin receptor substrate-1 tyrosine and Akt phosphorylation and a decrease in c-Jun N-terminal kinase (JNK) and insulin receptor substrate-1 serine 307 phosphorylation. Furthermore, astaxanthin restored TNFα- and palmitate-induced decreases in insulin-stimulated GLUT4 translocation or glucose uptake with a concomitant decrease in reactive oxygen species generation. α-Lipoic acid enhanced Akt phosphorylation and decreased ERK and JNK phosphorylation, whereas α-tocopherol enhanced ERK and JNK phosphorylation but had little effect on Akt phosphorylation. Collectively these findings indicate astaxanthin is a very effective antioxidant for ameliorating insulin resistance by protecting cells from oxidative stress generated by various stimuli including TNFα and palmitate.
Collapse
Affiliation(s)
- Manabu Ishiki
- The First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Ruskovska T, Bernlohr DA. Oxidative stress and protein carbonylation in adipose tissue - implications for insulin resistance and diabetes mellitus. J Proteomics 2013; 92:323-34. [PMID: 23584148 DOI: 10.1016/j.jprot.2013.04.002] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Revised: 03/15/2013] [Accepted: 04/03/2013] [Indexed: 12/18/2022]
Abstract
While historically considered simply as a depot for excess energy, white adipose tissue is a dynamically active endocrine organ capable of responding to a variety of efferent stimuli resulting in the synthesis and secretion of peptides, proteins and metabolites that serve as signal transducers to the peripheral and central circulation. Such regulation controls a variety of physiological processes including energy expenditure, food intake, reproductive capacity and responsiveness to insulin. Indeed, the accumulation of inflammatory cells in white adipose tissue is considered to be causative in the development of insulin resistance and eventually type 2 diabetes mellitus. A large body of evidence suggests that oxidative stress in adipose tissue not only correlates with insulin resistance but is also causative in its development. Moreover, using the available plasma oxidative stress biomarkers, many clinical studies have shown the presence of systemic oxidative stress in obese insulin resistant subjects, and its decrease after the successful treatment of obesity. In this review we emphasize the role of protein carbonylation in dysfunctional obese white adipose tissue and its metabolic implications. We focus on glutathione S-transferase A4 as the key enzyme for trans-4-hydroxy-2-nonenal and trans-4-oxo-2-nonenal removal from the cell, thus preventing protein carbonylation. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine.
Collapse
Affiliation(s)
- Tatjana Ruskovska
- Faculty of Medical Sciences, Goce Delcev University, Stip, Former Yugolav Republic of Macedonia.
| | | |
Collapse
|
|
16
|
Nierenberg AA, Kansky C, Brennan BP, Shelton RC, Perlis R, Iosifescu DV. Mitochondrial modulators for bipolar disorder: a pathophysiologically informed paradigm for new drug development. Aust N Z J Psychiatry 2013; 47:26-42. [PMID: 22711881 DOI: 10.1177/0004867412449303] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Bipolar patients frequently relapse within 12 months of their previous mood episode, even in the context of adequate treatment, suggesting that better continuation and maintenance treatments are needed. Based on recent research of the pathophysiology of bipolar disorder, we review the evidence for mitochondrial dysregulation and selected mitochondrial modulators (MM) as potential treatments. METHODS We reviewed the literature about mitochondrial dysfunction and potential MMs worthy of study that could improve the course of bipolar disorder, reduce subsyndromal symptoms, and prevent subsequent mood episodes. RESULTS MM treatment targets mitochondrial dysfunction, oxidative stress, altered brain energy metabolism and the dysregulation of multiple mitochondrial genes in patients with bipolar disorder. Several tolerable and readily available candidates include N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q(10) (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin. The specific metabolic pathways by which these MMs may improve the symptoms of bipolar disorder are discussed and combinations of selected MMs could be of interest as well. CONCLUSIONS Convergent data implicate mitochondrial dysfunction as an important component of the pathophysiology of bipolar disorder. Clinical trials of individual MMs as well as combinations are warranted.
Collapse
|
|
17
|
Henriksen EJ. Effects of H2O2 on insulin signaling the glucose transport system in mammalian skeletal muscle. Methods Enzymol 2013; 528:269-78. [PMID: 23849871 DOI: 10.1016/b978-0-12-405881-1.00016-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hydrogen peroxide (H2O2) is an important regulator of cellular events leading to glucose transport activation in mammalian skeletal muscle. In the absence of insulin, H2O2 in the low micromolar range engages the canonical IRS-1/PI3K/Akt-dependent insulin signaling pathway, as well as other signaling elements (AMPK and p38 MAPK), to increase basal glucose transport activity. In contrast, in the presence of insulin, H2O2 antagonizes insulin signaling by recruitment of various deleterious serine/threonine kinases, producing a state of insulin resistance. Here, we describe the H2O2 enzymatic-generating system, utilizing glucose oxidase, that has been used to investigate the impact of H2O2 on cellular signaling mechanisms related to glucose transport activity in isolated rat skeletal muscle preparations, such as the soleus. By varying the glucose oxidase concentration in the medium, target ranges of steady-state H2O2 concentrations (30-90 μM) can be attained for up to 6h, with subsequent assessment of cellular signaling and glucose transport activity.
Collapse
Affiliation(s)
- Erik J Henriksen
- Department of Physiology, Muscle Metabolism Laboratory, University of Arizona College of Medicine, Tucson, Arizona, USA.
| |
Collapse
|
|
18
|
Wang Z, McMonagle C, Yoshimitsu S, Budhathoki S, Morita M, Toyomura K, Ohnaka K, Takayanagi R, Kono S. No effect modification of serum bilirubin or coffee consumption on the association of gamma-glutamyltransferase with glycated hemoglobin in a cross-sectional study of Japanese men and women. BMC Endocr Disord 2012; 12:24. [PMID: 23092212 PMCID: PMC3509408 DOI: 10.1186/1472-6823-12-24] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Accepted: 10/17/2012] [Indexed: 01/11/2023] Open
Abstract
UNLABELLED BACKGROUND Oxidative stress has been implicated in the development of type 2 diabetes mellitus. Bilirubin is a potent endogenous antioxidant, and coffee is a major source of exogenous antioxidants. Serum gamma-glutamyltransferase (GGT), a marker of oxidative stress, is a strong predictor of the risk of type 2 diabetes mellitus. This study evaluated the effect modification of bilirubin and coffee consumption on the association of serum GGT with glycated hemoglobin (HbA1c) and the combined effect of bilirubin and coffee on HbA1c concentrations. METHODS The subjects were 4492 men and 6242 women aged 49-76 years who participated in the baseline survey of an on-going cohort study on lifestyle-related diseases in Fukuoka, Japan. Geometric means of HbA1c were examined according to quartile categories of GGT, with stratification by serum total bilirubin (≥ 0.6 mg/dL versus less in men and ≥ 0.5 mg/dL versus less in women) and coffee consumption (< 1, 1-3 and ≥ 4 cups of per day). Statistical adjustment was made for age, smoking, alcohol use and body mass index by using analysis of covariance. RESULTS HbA1 concentrations increased progressively with increasing levels of GGT in both men and women. The increasing trend of HbA1c concentrations associated with GGT did not differ by either bilirubin status or coffee consumption. Both men and women with high bilirubin had consistently lower concentrations of HbA1c across the GGT quartiles. Higher coffee consumption was associated with lower concentrations of HbA1c in women with low bilirubin (trend P = 0.04), but not with high bilirubin (trend P = 0.37). There was no such association between coffee and HbA1c in men with either low or high bilirubin levels. CONCLUSIONS Bilirubin is possibly protective against deterioration of glucose metabolism. Further studies are needed regarding the combined effect of bilirubin and coffee on glucose metabolism.
Collapse
Affiliation(s)
- Zhenjie Wang
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Christopher McMonagle
- MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
| | - Shinichiro Yoshimitsu
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Sanjeev Budhathoki
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Makiko Morita
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Kengo Toyomura
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Keizo Ohnaka
- Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryoichi Takayanagi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Suminori Kono
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| |
Collapse
|
|
19
|
α-Lipoic acid ameliorates impaired glucose uptake in LYRM1 overexpressing 3T3-L1 adipocytes through the IRS-1/Akt signaling pathway. J Bioenerg Biomembr 2012; 44:579-86. [DOI: 10.1007/s10863-012-9460-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2012] [Accepted: 07/03/2012] [Indexed: 10/28/2022]
|
|
20
|
Prieto-Hontoria PL, Pérez-Matute P, Fernández-Galilea M, Alfredo Martínez J, Moreno-Aliaga MJ. Effects of lipoic acid on AMPK and adiponectin in adipose tissue of low- and high-fat-fed rats. Eur J Nutr 2012; 52:779-87. [PMID: 22664981 DOI: 10.1007/s00394-012-0384-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Accepted: 05/17/2012] [Indexed: 12/20/2022]
Abstract
BACKGROUND Lipoic acid (LA) is an antioxidant with antiobesity and antidiabetic properties. Adiponectin is an adipokine with potent anti-inflammatory and insulin-sensitizing properties. AMP-activated protein kinase (AMPK) is a key enzyme involved in cellular energy homeostasis. Activation of AMPK has been considered as a target to reverse the metabolic abnormalities associated with obesity and type 2 diabetes. AIM OF THE STUDY The aim of this study was to determine the effects of LA on AMPK phosphorylation and adiponectin production in adipose tissue of low-fat (control diet) and high-fat diet-fed rats. RESULTS Dietary supplementation with LA reduced body weight and adiposity in control and high-fat-fed rats. LA also reduced basal hyperinsulinemia as well as the homeostasis model assessment (HOMA) levels, an index of insulin resistance, in high-fat-fed rats, which was in part independent of their food intake lowering actions. Furthermore, AMPK phosphorylation was increased in white adipose tissue (WAT) from LA-treated rats as compared with pair-fed animals. Dietary supplementation with LA also upregulated adiponectin gene expression in WAT, while a negative correlation between adiposity-corrected adiponectin levels and HOMA index was found. Our present data suggest that the ability of LA supplementation to prevent insulin resistance in high-fat diet-fed rats might be related in part to the stimulation of AMPK and adiponectin in WAT.
Collapse
Affiliation(s)
- Pedro L Prieto-Hontoria
- Department of Nutrition, Food Science, Physiology and Toxicology, University of Navarra, Pamplona, Spain
| | | | | | | | | |
Collapse
|
|
21
|
Croze ML, Vella RE, Pillon NJ, Soula HA, Hadji L, Guichardant M, Soulage CO. Chronic treatment with myo-inositol reduces white adipose tissue accretion and improves insulin sensitivity in female mice. J Nutr Biochem 2012; 24:457-66. [PMID: 22658648 DOI: 10.1016/j.jnutbio.2012.01.008] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2011] [Revised: 01/10/2012] [Accepted: 01/20/2012] [Indexed: 12/30/2022]
Abstract
Type 2 diabetes is a complex disease characterized by a state of insulin resistance in peripheral tissues such as skeletal muscle, adipose tissue or liver. Some inositol isomers have been reported to possess insulin-mimetic activity and to be efficient in lowering blood glucose level. The aim of the present study was to assess in mice the metabolic effects of a chronic treatment with myo-inositol, the most common stereoisomer of inositol. Mice given myo-inositol treatment (0.9 or 1.2 mg g(-1) day(-1), 15 days, orally or intraperitoneally) exhibited an improved glucose tolerance due to a greater insulin sensitivity. Mice treated with myo-inositol exhibited a decreased white adipose tissue accretion (-33%, P<.005) compared with controls. The decrease in white adipose tissue deposition was due to a decrease in adipose cell volume (-33%, P<.05), while no change was noticed in total adipocyte number. In skeletal muscle, in vivo as well as ex vivo myo-inositol treatment increased protein kinase B/Akt phosphorylation under baseline and insulin-stimulated conditions, suggesting a synergistic action of myo-inositol treatment and insulin on proteins of the insulin signalling pathway. Myo-inositol could therefore constitute a viable nutritional strategy for the prevention and/or treatment of insulin resistance and type 2 diabetes.
Collapse
|
|
22
|
Kotnik D, Šmidovnik A, Jazbec-Križman P, Križman M, Prošek M. Direct analysis of carbohydrates in animal plasma by ion chromatography coupled with mass spectrometry and pulsed amperometric detection for use as a non-invasive diagnostic tool. J Chromatogr B Analyt Technol Biomed Life Sci 2011; 879:3700-6. [DOI: 10.1016/j.jchromb.2011.10.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Revised: 10/04/2011] [Accepted: 10/06/2011] [Indexed: 11/25/2022]
|
|
23
|
Mansego ML, Redon J, Martinez-Hervas S, Real JT, Martinez F, Blesa S, Gonzalez-Albert V, Saez GT, Carmena R, Chaves FJ. Different impacts of cardiovascular risk factors on oxidative stress. Int J Mol Sci 2011; 12:6146-63. [PMID: 22016650 PMCID: PMC3189774 DOI: 10.3390/ijms12096146] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2011] [Revised: 09/01/2011] [Accepted: 09/07/2011] [Indexed: 02/07/2023] Open
Abstract
The objective of the study was to evaluate oxidative stress (OS) status in subjects with different cardiovascular risk factors. With this in mind, we have studied three models of high cardiovascular risk: hypertension (HT) with and without metabolic syndrome, familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) with and without insulin resistance. Oxidative stress markers (oxidized/reduced glutathione ratio, 8-oxo-deoxyguanosine and malondialdehide) together with the activity of antioxidant enzyme triad (superoxide dismutase, catalase, glutathione peroxidase) and activation of both pro-oxidant enzyme (NAPDH oxidase components) and AGTR1 genes, as well as antioxidant enzyme genes (CuZn-SOD, CAT, GPX1, GSR, GSS and TXN) were measured in mononuclear cells of controls (n = 20) and patients (n = 90) by assessing mRNA levels. Activity of some of these antioxidant enzymes was also tested. An increase in OS and pro-oxidant gene mRNA values was observed in patients compared to controls. The hypertensive group showed not only the highest OS values, but also the highest pro-oxidant activation compared to those observed in the other groups. In addition, in HT a significantly reduced antioxidant activity and mRNA induction of antioxidant genes were found when compared to controls and the other groups. In FH and FCH, the activation of pro-oxidant enzymes was also higher and antioxidant ones lower than in the control group, although it did not reach the values obtained in hypertensives. The thioredoxin system was more activated in patients as compared to controls, and the highest levels were in hypertensives. The increased oxidative status in the presence of cardiovascular risk factors is a consequence of both the activation of pro-oxidant mechanisms and the reduction of the antioxidant ones. The altered response of the main cytoplasmic antioxidant systems largely contributes to OS despite the apparent attempt of the thioredoxin system to control it.
Collapse
Affiliation(s)
- Maria L. Mansego
- Genotyping and Genetic Diagnosis Unit, Research Foundation of Hospital Clínico; Avenida Blasco Ibañez, 17, Valencia 46010, Spain; E-Mails: (S.B); (V.G.-A.); (F.J.C.)
- CIBER of obesity (CIBERob), Santiago de Compostela 15706, Spain; E-Mails: (J.R.); (F.M.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +34-963-983-916; Fax: +34-963-864-926
| | - Josep Redon
- CIBER of obesity (CIBERob), Santiago de Compostela 15706, Spain; E-Mails: (J.R.); (F.M.)
- Hypertension Unit, Hospital Clinico; Avenida Blasco Ibañez, 17, Valencia 46010, Spain
| | - Sergio Martinez-Hervas
- Service of Endocrinology and Nutrition, Hospital Clínico Universitario, Avenida Blasco Ibañez, 17, Valencia 46010, Spain; E-Mails: (S.M.-H.); (J.T.R.); (R.C.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08017, Spain
| | - Jose T. Real
- Service of Endocrinology and Nutrition, Hospital Clínico Universitario, Avenida Blasco Ibañez, 17, Valencia 46010, Spain; E-Mails: (S.M.-H.); (J.T.R.); (R.C.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08017, Spain
| | - Fernando Martinez
- CIBER of obesity (CIBERob), Santiago de Compostela 15706, Spain; E-Mails: (J.R.); (F.M.)
- Hypertension Unit, Hospital Clinico; Avenida Blasco Ibañez, 17, Valencia 46010, Spain
| | - Sebastian Blesa
- Genotyping and Genetic Diagnosis Unit, Research Foundation of Hospital Clínico; Avenida Blasco Ibañez, 17, Valencia 46010, Spain; E-Mails: (S.B); (V.G.-A.); (F.J.C.)
| | - Veronica Gonzalez-Albert
- Genotyping and Genetic Diagnosis Unit, Research Foundation of Hospital Clínico; Avenida Blasco Ibañez, 17, Valencia 46010, Spain; E-Mails: (S.B); (V.G.-A.); (F.J.C.)
| | - Guillermo T. Saez
- Department of Biochemistry and Molecular Biology, University of Valencia, Avenida Blasco Ibañez, 17, Valencia 46010, Spain; E-Mail:
| | - Rafael Carmena
- Service of Endocrinology and Nutrition, Hospital Clínico Universitario, Avenida Blasco Ibañez, 17, Valencia 46010, Spain; E-Mails: (S.M.-H.); (J.T.R.); (R.C.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08017, Spain
| | - Felipe J. Chaves
- Genotyping and Genetic Diagnosis Unit, Research Foundation of Hospital Clínico; Avenida Blasco Ibañez, 17, Valencia 46010, Spain; E-Mails: (S.B); (V.G.-A.); (F.J.C.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08017, Spain
| |
Collapse
|
|
24
|
Henriksen EJ, Diamond-Stanic MK, Marchionne EM. Oxidative stress and the etiology of insulin resistance and type 2 diabetes. Free Radic Biol Med 2011; 51:993-9. [PMID: 21163347 PMCID: PMC3071882 DOI: 10.1016/j.freeradbiomed.2010.12.005] [Citation(s) in RCA: 407] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2010] [Revised: 11/19/2010] [Accepted: 12/06/2010] [Indexed: 12/21/2022]
Abstract
The condition of oxidative stress arises when oxidant production exceeds antioxidant activity in cells and plasma. The overabundance of oxidants is mechanistically connected to the multifactorial etiology of insulin resistance, primarily in skeletal muscle tissue, and the subsequent development of type 2 diabetes. Two important mechanisms for this oxidant excess are (1) the mitochondrial overproduction of hydrogen peroxide and superoxide ion under conditions of energy surplus and (2) the enhanced activation of cellular NADPH oxidase via angiotensin II receptors. Several recent studies are reviewed that support the concept that direct exposure of mammalian skeletal muscle to an oxidant stress (including hydrogen peroxide) results in stimulation of the serine kinase p38 mitogen-activated protein kinase (p38 MAPK), and that the engagement of this stress-activated p38 MAPK signaling is mechanistically associated with diminished insulin-dependent stimulation of insulin signaling elements and glucose transport activity. The beneficial interactions between the antioxidant α-lipoic acid and the advanced glycation end-product inhibitor pyridoxamine that ameliorate oxidant stress-associated defects in whole-body and skeletal-muscle insulin action in the obese Zucker rat, a model of prediabetes, are also addressed. Overall, this review highlights the importance of oxidative stress in the development of insulin resistance in mammalian skeletal muscle tissue, at least in part via a p38-MAPK-dependent mechanism, and indicates that interventions that reduce this oxidative stress and oxidative damage can improve insulin action in insulin-resistant animal models. Strategies to prevent and ameliorate oxidative stress remain important in the overall treatment of insulin resistance and type 2 diabetes.
Collapse
Affiliation(s)
- Erik J Henriksen
- Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093, USA.
| | | | | |
Collapse
|
|
25
|
Ikeda N, Inoguchi T, Sonoda N, Fujii M, Takei R, Hirata E, Yokomizo H, Zheng J, Maeda Y, Kobayashi K, Takayanagi R. Biliverdin protects against the deterioration of glucose tolerance in db/db mice. Diabetologia 2011; 54:2183-91. [PMID: 21614569 DOI: 10.1007/s00125-011-2197-2] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2010] [Accepted: 04/12/2011] [Indexed: 01/11/2023]
Abstract
AIMS/HYPOTHESIS We have previously shown a negative correlation between serum bilirubin levels and prevalence of type 2 diabetes, suggesting that bilirubin inhibits development of this disease. To confirm this hypothesis, we investigated whether administration of biliverdin, the precursor of bilirubin, protects against the deterioration of glucose tolerance in db/db mice, a rodent model of type 2 diabetes. METHODS Biliverdin (20 mg/kg daily) was orally administered to 5-week-old db/db mice for 4 weeks. After 4 weeks of treatment, i.p. glucose tolerance and insulin tolerance tests were performed. Insulin content was evaluated by immunostaining and ELISA. Oxidative stress markers (8-hydroxy-2'-deoxyguansosine and dihydroethidium staining) and expression of NADPH oxidase components Pdx1 and Bax were also evaluated in isolated islets. RESULTS Treatment with biliverdin partially prevented worsening of hyperglycaemia and glucose intolerance in db/db mice. This effect was accompanied by a significant increase in insulin content and Pdx1 expression, and a significant decrease of apoptosis and Bax expression in pancreatic islets from db/db mice. At the same time, levels of oxidative stress markers and NADPH oxidase component production in islets were normalised. Biliverdin had little effect on HOMA of insulin resistance or insulin resistance evaluated by insulin tolerance tests. CONCLUSIONS/INTERPRETATION Biliverdin may protect against progressive worsening of glucose tolerance in db/db mice, mainly via inhibition of oxidative stress-induced beta cell damage.
Collapse
Affiliation(s)
- N Ikeda
- Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Carter EA, Bonab AA, Goverman J, Paul K, Yerxa J, Tompkins RG, Fischman AJ. Evaluation of the antioxidant peptide SS31 for treatment of burn-induced insulin resistance. Int J Mol Med 2011; 28:589-94. [PMID: 21805045 DOI: 10.3892/ijmm.2011.752] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Accepted: 06/06/2011] [Indexed: 12/28/2022] Open
Abstract
After severe burn injury and other major traumas, glucose tolerance tests demonstrate delayed glucose disposal. This 'diabetes of injury' could be explained by insulin deficiency, and several studies have shown that soon after trauma (ebb phase) insulin concentrations are reduced in the face of hyperglycemia. After resuscitation of trauma patients (flow phase), β-cell responsiveness normalizes and plasma insulin levels are appropriate or even higher than expected, however, glucose intolerance and hyperglycemia persist. In the acute care setting, several approaches have been used for treating insulin resistance, including insulin infusion, propranolol and glucagon-like-peptide-1 (GLP-1). Recently, it was demonstrated that a tetrapeptide with antioxidant properties D-Arg-Dmt-Lys-Phe-NH2 (SS31), but not its inactive analogue Phe-D-Arg-Phe-Lys-NH2 (SS20) attenuates insulin resistance in mice maintained on a high fat diet. In this report the effects of SS31 and SS20 on burn-induced insulin resistance was studied in mice. Oral glucose tolerance tests (OGTT) were performed in 4 groups of 6 mice with thermal injury with or without pre-treatment with SS31 or SS20 and sham controls. In addition, biodistribution of 18FDG was measured in burned mice with and without SS31 treatment and shams (subsets of these animals were also studied by µPET). For comparison purposes, groups of 6 cold-stressed mice with and without SS31 treatment were also studied. The results of these studies demonstrate that SS31 but not SS20 ameliorated burn-induced insulin resistance. In addition, SS31 treatment resulted in marked reduction in the increased 18FDG uptake by brown adipose tissue (BAT) in burned but not cold-stressed animals; suggesting that the stressors act by different mechanisms. Overall, these studies confirmed that SS31 can be used to reverse burn-induced insulin resistance and provide a firm pre-clinical basis for future clinical trials of SS31 for the treatment of insulin resistance in patients with burn injury.
Collapse
Affiliation(s)
- Edward A Carter
- Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA
| | | | | | | | | | | | | |
Collapse
|
|
27
|
Fernández-Galilea M, Pérez-Matute P, Prieto-Hontoria P, Martínez JA, Moreno-Aliaga MJ. Effects of lipoic acid on apelin in 3T3-L1 adipocytes and in high-fat fed rats. J Physiol Biochem 2011; 67:479-86. [DOI: 10.1007/s13105-011-0087-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2010] [Accepted: 03/14/2011] [Indexed: 11/24/2022]
|
|
28
|
Garcia-Bailo B, El-Sohemy A, Haddad PS, Arora P, Benzaied F, Karmali M, Badawi A. Vitamins D, C, and E in the prevention of type 2 diabetes mellitus: modulation of inflammation and oxidative stress. Biologics 2011; 5:7-19. [PMID: 21383912 PMCID: PMC3044790 DOI: 10.2147/btt.s14417] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Indexed: 12/15/2022]
Abstract
The incidence of type 2 diabetes mellitus (T2DM) is increasing worldwide, and certain population subgroups are especially vulnerable to the disease. To reduce T2DM risk and progression at the population level, preventative strategies are needed that can be implemented on a population-wide scale with minimal cost and effort. Chronic low-grade inflammation resulting from oxidative stress and imbalances in the innate immune system has been associated with obesity, metabolic syndrome, and insulin resistance – critical stages in the development and progression of T2DM. Therefore, inflammation may play a causal role in the pathogenesis of T2DM, and reducing it via modulation of oxidative stress and the innate immune response could lead to a status of improved insulin sensitivity and delayed disease onset. Dietary supplementation with anti-inflammatory and antioxidant nutritional factors, such as micronutrients, might present a novel strategy toward the prevention and control of T2DM at the population level. This review examines current knowledge linking oxidation, inflammatory signaling pathways, and vitamin supplementation or intake to the risk of T2DM. The concept that micronutrients, via attenuation of inflammation, could be employed as a novel preventive measure for T2DM is evaluated in the context of its relevance to public health.
Collapse
Affiliation(s)
- Bibiana Garcia-Bailo
- Office for Biotechnology, Genomics and Population Health, Public Health Agency of Canada, Toronto, ON, Canada
| | | | | | | | | | | | | |
Collapse
|
|
29
|
Diamond-Stanic MK, Marchionne EM, Teachey MK, Durazo DE, Kim JS, Henriksen EJ. Critical role of the transient activation of p38 MAPK in the etiology of skeletal muscle insulin resistance induced by low-level in vitro oxidant stress. Biochem Biophys Res Commun 2011; 405:439-44. [PMID: 21241662 DOI: 10.1016/j.bbrc.2011.01.049] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Accepted: 01/13/2011] [Indexed: 01/06/2023]
Abstract
Increased cellular exposure to oxidants may contribute to the development of insulin resistance and type 2 diabetes. Skeletal muscle is the primary site of insulin-dependent glucose disposal in the body; however, the effects of oxidative stress on insulin signaling and glucose transport activity in mammalian skeletal muscle are not well understood. We therefore studied the effects of a low-level in vitro oxidant stress (30-40 μM H2O2) on basal and insulin-stimulated (5 mU/ml) glucose transport activity and insulin signaling at 2, 4, and 6 h in isolated rat soleus muscle. H2O2 increased basal glucose transport activity at 2 and 4 h, but not at 6 h. This low-level oxidant stress significantly impaired insulin-stimulated glucose transport activity at all time points, and was associated with inhibition of insulin-stimulated phosphorylation of Akt Ser473 and GSK-3β Ser9. In the presence of insulin, H2O2 decreased total protein expression of IRS-1 at 6 h and IRS-2 at 4 and 6 h. Phosphorylation of p38 MAPK Thr180/Tyr182 was transiently increased by H2O2 in the presence and absence of insulin at 2 and 4 h, but not at 6 h. Selective inhibition of p38 MAPK with A304000 partially rescued the H2O2-induced reduction in insulin-stimulated glucose transport activity. These results indicate that direct in vitro exposure of isolated mammalian skeletal muscle to a low-level oxidant stress impairs distal insulin signaling and insulin-stimulated glucose transport activity, at least in part, due to a p38 MAPK-dependent mechanism.
Collapse
|
|
30
|
Ikemura M, Nishikawa M, Hyoudou K, Kobayashi Y, Yamashita F, Hashida M. Improvement of Insulin Resistance by Removal of Systemic Hydrogen Peroxide by PEGylated Catalase in Obese Mice. Mol Pharm 2010; 7:2069-76. [DOI: 10.1021/mp100110c] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Mai Ikemura
- Department of Drug Delivery Research and Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, and Institute for Integrated Cell-Material Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Makiya Nishikawa
- Department of Drug Delivery Research and Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, and Institute for Integrated Cell-Material Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Kenji Hyoudou
- Department of Drug Delivery Research and Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, and Institute for Integrated Cell-Material Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yuki Kobayashi
- Department of Drug Delivery Research and Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, and Institute for Integrated Cell-Material Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Fumiyoshi Yamashita
- Department of Drug Delivery Research and Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, and Institute for Integrated Cell-Material Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Mitsuru Hashida
- Department of Drug Delivery Research and Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, and Institute for Integrated Cell-Material Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| |
Collapse
|
|
31
|
Ohnaka K, Kono S, Inoguchi T, Yin G, Morita M, Adachi M, Kawate H, Takayanagi R. Inverse associations of serum bilirubin with high sensitivity C-reactive protein, glycated hemoglobin, and prevalence of type 2 diabetes in middle-aged and elderly Japanese men and women. Diabetes Res Clin Pract 2010; 88:103-10. [PMID: 20083320 DOI: 10.1016/j.diabres.2009.12.022] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2009] [Revised: 12/14/2009] [Accepted: 12/15/2009] [Indexed: 12/20/2022]
Abstract
AIM The aim of this study was to examine the association of serum bilirubin, an endogenous antioxidant, with serum high sensitivity C-reactive protein (hs-CRP) level, HbA(1c), and the prevalence of type 2 diabetes in middle-aged and elderly Japanese men and women (n=12,400). METHODS Analysis of covariance and logistic regression analysis were used to estimate geometric means of hs-CRP and HbA(1c) and odds ratios of prevalent diabetes according to bilirubin concentrations, respectively, with statistical adjustment for behavioral factors and liver enzymes. RESULTS Geometric means of hs-CRP and HbA(1c) were progressively lower with increasing concentrations of serum bilirubin in men and women each. An inverse association between serum bilirubin and HbA(1c) was slightly attenuated after adjustment for hs-CRP, but still remained highly significant (trend P=0.0004 in men and trend P=10(-5) in women). Multivariate-adjusted odds ratios of prevalent diabetes for the lowest to highest quintiles of serum total bilirubin were 1.00, 1.00, 0.73, 0.80, and 0.73 (trend P=0.002), without adjustment for hs-CRP, and 1.00, 1.04, 0.76, 0.86, and 0.79 (trend P=0.01), with adjustment for hs-CRP. CONCLUSIONS Higher concentrations of serum bilirubin probably confer protection against the development of type 2 diabetes.
Collapse
Affiliation(s)
- Keizo Ohnaka
- Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Archuleta TL, Lemieux AM, Saengsirisuwan V, Teachey MK, Lindborg KA, Kim JS, Henriksen EJ. Oxidant stress-induced loss of IRS-1 and IRS-2 proteins in rat skeletal muscle: role of p38 MAPK. Free Radic Biol Med 2009; 47:1486-93. [PMID: 19703555 PMCID: PMC2767452 DOI: 10.1016/j.freeradbiomed.2009.08.014] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2009] [Revised: 08/10/2009] [Accepted: 08/19/2009] [Indexed: 02/07/2023]
Abstract
Oxidative stress is characterized as an imbalance between the cellular production of oxidants and the cellular antioxidant defenses and contributes to the development of numerous cardiovascular and metabolic disorders, including hypertension and insulin resistance. The effects of prolonged oxidant stress in vitro on the insulin-dependent glucose transport system in mammalian skeletal muscle are not well understood. This study examined the in vitro effects of low-level oxidant stress (60-90 microM, H(2)O(2)) for 4 h on insulin-stimulated (5 mU/ml) glucose transport activity (2-deoxyglucose uptake) and on protein expression of critical insulin signaling factors (insulin receptor (IR), IR substrates IRS-1 and IRS-2, phosphatidylinositol 3-kinase, Akt, and glycogen synthase kinase-3 (GSK-3)) in isolated soleus muscle of lean Zucker rats. This oxidant stress exposure caused significant (50%, p<0.05) decreases in insulin-stimulated glucose transport activity that were associated with selective loss of IRS-1 (59%) and IRS-2 (33%) proteins, increased (64%) relative IRS-1 Ser(307) phosphorylation, and decreased phosphorylation of Akt Ser(473) (50%) and GSK-3beta Ser(9) (43%). Moreover, enhanced (37%) phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was observed. Selective inhibition of p38 MAPK (10 microM A304000) prevented a significant portion (29%) of the oxidant stress-induced loss of IRS-1 (but not IRS-2) protein and allowed partial recovery of the impaired insulin-stimulated glucose transport activity. These results indicate that in vitro oxidative stress in mammalian skeletal muscle leads to substantial insulin resistance of distal insulin signaling and glucose transport activity, associated with a selective loss of IRS-1 protein, in part due to a p38 MAPK-dependent mechanism.
Collapse
Affiliation(s)
- Tara L. Archuleta
- Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093
| | - Andrew M. Lemieux
- Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093
| | - Vitoon Saengsirisuwan
- Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093
- Department of Physiology, Faculty of Science, Mahidol University, Rama VI Road, 10400 Bangkok, Thailand
| | - Mary K. Teachey
- Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093
| | - Katherine A. Lindborg
- Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093
| | - John S. Kim
- Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093
| | - Erik J. Henriksen
- Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093
| |
Collapse
|
|
33
|
Reddy SS, Ramatholisamma P, Karuna R, Saralakumari D. Preventive effect of Tinospora cordifolia against high-fructose diet-induced insulin resistance and oxidative stress in male Wistar rats. Food Chem Toxicol 2009; 47:2224-9. [DOI: 10.1016/j.fct.2009.06.008] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2009] [Revised: 04/27/2009] [Accepted: 06/05/2009] [Indexed: 11/28/2022]
|
|
34
|
Ge X, Liu Z, Qi W, Shi X, Zhai Q. Chromium (VI) induces insulin resistance in 3T3-L1 adipocytes through elevated reactive oxygen species generation. Free Radic Res 2009; 42:554-63. [DOI: 10.1080/10715760802155113] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
35
|
Wang CT, Chang HH, Hsiao CH, Lee MJ, Ku HC, Hu YJ, Kao YH. The effects of green tea (-)-epigallocatechin-3-gallate on reactive oxygen species in 3T3-L1 preadipocytes and adipocytes depend on the glutathione and 67 kDa laminin receptor pathways. Mol Nutr Food Res 2009; 53:349-60. [PMID: 19065584 DOI: 10.1002/mnfr.200800013] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Green tea (-)-epigallocatechin-3-gallate (EGCG) is known as to regulate obesity and fat cell activity. However, little information is known about the effects of EGCG on oxidative reactive oxygen species (ROS) of fat cells. Using 3T3-L1 preadipocytes and adipocytes, we found that EGCG increased ROS production in dose- and time-dependent manners. The concentration of EGCG that increased ROS levels by 180-500% was approximately 50 muM for a range of 8-16 h of treatment. In contrast, EGCG dose- and time-dependently decreased the amount of intracellular glutathione (GSH) levels. EGCG was more effective than (-)-epicatechin, (-)-epicatechin-3-gallate, and (-)-epigallocatechin in changing ROS and GSH levels. This suggests a catechin-specific effect. To further examine the relation of GSH to ROS as altered by EGCG, we observed that exposure of preadipocytes and adipocytes to N-acetyl-L-cysteine (a GSH precursor) blocked the EGCG-induced increases in ROS levels and decreases in GSH levels. These observations suggest a GSH-dependent effect of EGCG on ROS production. While EGCG was demonstrated to alter levels of ROS and GSH, its signaling was altered by an EGCG receptor (the so-called 67 kDa laminin receptor(67LR)) antiserum, but not by normal rabbit serum. These data suggest that EGCG mediates GSH and ROS levels via the 67LR pathway.
Collapse
Affiliation(s)
- Chih-Ting Wang
- Department of Life Science, College of Science, National Central University, Chung-Li City, Taoyuan, Taiwan
| | | | | | | | | | | | | |
Collapse
|
|
36
|
Lee BW, Kwon SJ, Chae HY, Kang JG, Kim CS, Lee SJ, Yoo HJ, Kim JH, Park KS, Ihm SH. Dose-related cytoprotective effect of alpha-lipoic acid on hydrogen peroxide-induced oxidative stress to pancreatic beta cells. Free Radic Res 2009; 43:68-77. [PMID: 19358002 DOI: 10.1080/10715760802590400] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
alpha-Lipoic acid (alpha-LA), an antioxidant used for diabetic polyneuropathy, was reported to induce AMP-activated protein kinase activation and reductions in insulin secretion in pancreatic beta-cells at high concentrations (> or = 500 micromol/l). This study investigated whether alpha-LA has a protective role under oxidative stress in beta-cells and its effect is dose-related. In INS-1 cells treated with alpha-LA (150-1200 micromol/l) for 24 h, alpha-LA itself (> or = 300 micromol/l) induced apoptotic death dose-dependently. However, pre-treatment with 150 and 300 micromol/l alpha-LA reduced the hydrogen peroxide-induced apoptosis in INS-1 cells and isolated islets. alpha-LA alleviated hydrogen peroxide-induced reactive oxygen species production, mitochondrial membrane depolarization and c-JNK activation in beta-cells. alpha-LA induced phosphoinositide 3-kinase-dependent Akt phosphorylation in INS-1 cells. While alpha-LA is harmful to beta-cells at high concentrations in vitro, it has potential cytoprotective effects on beta-cells under oxidative stress as in diabetes by its antioxidant properties and possibly by Akt phosphorylation at clinically relevant concentrations.
Collapse
Affiliation(s)
- Byung Wan Lee
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Republic of Korea
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Bashan N, Kovsan J, Kachko I, Ovadia H, Rudich A. Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev 2009; 89:27-71. [PMID: 19126754 DOI: 10.1152/physrev.00014.2008] [Citation(s) in RCA: 363] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Regulated production of reactive oxygen species (ROS)/reactive nitrogen species (RNS) adequately balanced by antioxidant systems is a prerequisite for the participation of these active substances in physiological processes, including insulin action. Yet, increasing evidence implicates ROS and RNS as negative regulators of insulin signaling, rendering them putative mediators in the development of insulin resistance, a common endocrine abnormality that accompanies obesity and is a risk factor of type 2 diabetes. This review deals with this dual, seemingly contradictory, function of ROS and RNS in regulating insulin action: the major processes for ROS and RNS generation and detoxification are presented, and a critical review of the evidence that they participate in the positive and negative regulation of insulin action is provided. The cellular and molecular mechanisms by which ROS and RNS are thought to participate in normal insulin action and in the induction of insulin resistance are then described. Finally, we explore the potential usefulness and the challenges in modulating the oxidant-antioxidant balance as a potentially promising, but currently disappointing, means of improving insulin action in insulin resistance-associated conditions, leading causes of human morbidity and mortality of our era.
Collapse
Affiliation(s)
- Nava Bashan
- Department of Clinical Biochemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
| | | | | | | | | |
Collapse
|
|
38
|
Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin CT, Price JW, Kang L, Rabinovitch PS, Szeto HH, Houmard JA, Cortright RN, Wasserman DH, Neufer PD. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest 2009; 119:573-81. [PMID: 19188683 DOI: 10.1172/jci37048] [Citation(s) in RCA: 964] [Impact Index Per Article: 60.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2008] [Accepted: 12/10/2008] [Indexed: 12/11/2022] Open
Abstract
High dietary fat intake leads to insulin resistance in skeletal muscle, and this represents a major risk factor for type 2 diabetes and cardiovascular disease. Mitochondrial dysfunction and oxidative stress have been implicated in the disease process, but the underlying mechanisms are still unknown. Here we show that in skeletal muscle of both rodents and humans, a diet high in fat increases the H(2)O(2)-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function. Furthermore, we show that attenuating mitochondrial H(2)O(2) emission, either by treating rats with a mitochondrial-targeted antioxidant or by genetically engineering the overexpression of catalase in mitochondria of muscle in mice, completely preserves insulin sensitivity despite a high-fat diet. These findings place the etiology of insulin resistance in the context of mitochondrial bioenergetics by demonstrating that mitochondrial H(2)O(2) emission serves as both a gauge of energy balance and a regulator of cellular redox environment, linking intracellular metabolic balance to the control of insulin sensitivity.
Collapse
Affiliation(s)
- Ethan J Anderson
- Metabolic Institute for the Study of Diabetes and Obesity, East Carolina University, Greenville, North Carolina 27834, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Lin CL, Lin JK. Epigallocatechin gallate (EGCG) attenuates high glucose-induced insulin signaling blockade in human hepG2 hepatoma cells. Mol Nutr Food Res 2008; 52:930-9. [DOI: 10.1002/mnfr.200700437] [Citation(s) in RCA: 112] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
|
|
40
|
Manning PJ, Sutherland WHF, Walker RJ, Williams SM, de Jong SA, Berry EA. The effect of rosiglitazone on oxidative stress and insulin resistance in overweight individuals. Diabetes Res Clin Pract 2008; 81:209-15. [PMID: 18541328 DOI: 10.1016/j.diabres.2008.04.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2008] [Accepted: 04/19/2008] [Indexed: 01/11/2023]
Abstract
OBJECTIVE The purpose of this study was to examine the chronic effect of rosiglitazone on oxidative stress, inflammatory markers and hepatic risk factors for type 2 diabetes in overweight individuals. In addition we examined the effect of rosiglitazone on post-glucose challenge levels of glucose and insulin. RESEARCH DESIGN AND METHODS Forty overweight individuals (BMI>27kg/m(2)) were randomized in a double blind fashion to receive 6 months treatment with either rosiglitazone 4mg/day or placebo. Primary endpoints were markers of oxidative stress (plasma peroxides), inflammatory markers (IL-6, TNF-alpha and CRP) and postprandial glucose metabolism (glucose and insulin). Secondary endpoints were changes in insulin resistance as measured by HOMA, first and second phase insulin secretion, adiponectin and effects on lipid and hepatic parameters. RESULTS Plasma peroxides (-15%) decreased significantly during 6 months in the group that received rosiglitazone compared with placebo. Fasting plasma insulin concentrations decreased by 24% and HOMA increased by 35% in those receiving rosiglitazone. Plasma IL-6 (-25%), CRP (-55%) and GGT (-25%) concentrations declined significantly in the rosiglitazone group. Rosiglitazone increased plasma adiponectin by 81%. Treatment with rosiglitazone also resulted in significantly reduced first phase (-33%) and second phase (-20%) insulin release. CONCLUSIONS In overweight non-diabetic people rosiglitazone reduces oxidative stress and improves insulin sensitivity. Rosiglitazone also improves first and second phase insulin secretion and reduces markers of inflammation and GGT.
Collapse
Affiliation(s)
- Patrick J Manning
- Department of Medical and Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
| | | | | | | | | | | |
Collapse
|
|
41
|
Demozay D, Mas JC, Rocchi S, Van Obberghen E. FALDH reverses the deleterious action of oxidative stress induced by lipid peroxidation product 4-hydroxynonenal on insulin signaling in 3T3-L1 adipocytes. Diabetes 2008; 57:1216-26. [PMID: 18174527 DOI: 10.2337/db07-0389] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE Oxidative stress is associated with insulin resistance and is thought to contribute to progression toward type 2 diabetes. Oxidation induces cellular damages through increased amounts of reactive aldehydes from lipid peroxidation. The aim of our study was to investigate 1) the effect of the major lipid peroxidation end product, 4-hydroxynonenal (HNE), on insulin signaling in 3T3-L1 adipocytes, and 2) whether fatty aldehyde dehydrogenase (FALDH), which detoxifies HNE, protects cells and improves insulin action under oxidative stress conditions. RESEARCH DESIGN AND METHODS 3T3-L1 adipocytes were exposed to HNE and/or infected with control adenovirus or adenovirus expressing FALDH. RESULTS Treatment of 3T3-L1 adipocytes with HNE at nontoxic concentrations leads to a pronounced decrease in insulin receptor substrate (IRS)-1/-2 proteins and in insulin-induced IRS and insulin receptor beta (IR beta) tyrosine phosphorylation. Remarkably, we detect increased binding of HNE to IRS-1/-2-generating HNE-IRS adducts, which likely impair IRS function and favor their degradation. Phosphatidylinositol 3-kinase and protein kinase B activities are also downregulated upon HNE treatment, resulting in blunted metabolic responses. Moreover, FALDH, by reducing adduct formation, partially restores HNE-generated decrease in insulin-induced IRS-1 tyrosine phosphorylation and metabolic responses. Moreover, rosiglitazone could have an antioxidant effect because it blocks the noxious HNE action on IRS-1 by increasing FALDH gene expression. Collectively, our data show that FALDH improves insulin action in HNE-treated 3T3-L1 adipocytes. CONCLUSION Oxidative stress induced by reactive aldehydes, such as HNE, is implicated in the development of insulin resistance in 3T3-L1 adipocytes, which is alleviated by FALDH. Hence, detoxifying enzymes could play a crucial role in blocking progression of insulin resistance to diabetes.
Collapse
Affiliation(s)
- Damien Demozay
- Institut National de la Santé et de la Recherche Médicale (INSERM) U145 and U907, Institut Fédératif de Recherche 50, Faculté de Médecine, Université de Nice Sophia-Antipolis, Nice Cedex, France
| | | | | | | |
Collapse
|
|
42
|
Abstract
Insulin resistance is characteristic of obesity, type 2 diabetes, and components of the cardiometabolic syndrome, including hypertension and dyslipidemia, that collectively contribute to a substantial risk for cardiovascular disease. Metabolic actions of insulin in classic insulin target tissues (eg, skeletal muscle, fat, and liver), as well as actions in nonclassic targets (eg, cardiovascular tissue), help to explain why insulin resistance and metabolic dysregulation are central in the pathogenesis of the cardiometabolic syndrome and cardiovascular disease. Glucose and lipid metabolism are largely dependent on mitochondria to generate energy in cells. Thereby, when nutrient oxidation is inefficient, the ratio of ATP production/oxygen consumption is low, leading to an increased production of superoxide anions. Reactive oxygen species formation may have maladaptive consequences that increase the rate of mutagenesis and stimulate proinflammatory processes. In addition to reactive oxygen species formation, genetic factors, aging, and reduced mitochondrial biogenesis all contribute to mitochondrial dysfunction. These factors also contribute to insulin resistance in classic and nonclassic insulin target tissues. Insulin resistance emanating from mitochondrial dysfunction may contribute to metabolic and cardiovascular abnormalities and subsequent increases in cardiovascular disease. Furthermore, interventions that improve mitochondrial function also improve insulin resistance. Collectively, these observations suggest that mitochondrial dysfunction may be a central cause of insulin resistance and associated complications. In this review, we discuss mechanisms of mitochondrial dysfunction related to the pathophysiology of insulin resistance in classic insulin-responsive tissue, as well as cardiovascular tissue.
Collapse
Affiliation(s)
- Jeong-A Kim
- Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri, USA
| | | | | |
Collapse
|
|
43
|
Guo H, Ling W, Wang Q, Liu C, Hu Y, Xia M. Cyanidin 3-glucoside protects 3T3-L1 adipocytes against H2O2- or TNF-α-induced insulin resistance by inhibiting c-Jun NH2-terminal kinase activation. Biochem Pharmacol 2008; 75:1393-401. [DOI: 10.1016/j.bcp.2007.11.016] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2007] [Revised: 11/28/2007] [Accepted: 11/28/2007] [Indexed: 12/21/2022]
|
|
44
|
Wei Y, Chen K, Whaley-Connell AT, Stump CS, Ibdah JA, Sowers JR. Skeletal muscle insulin resistance: role of inflammatory cytokines and reactive oxygen species. Am J Physiol Regul Integr Comp Physiol 2007; 294:R673-80. [PMID: 18094066 DOI: 10.1152/ajpregu.00561.2007] [Citation(s) in RCA: 167] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The cardiometabolic syndrome (CMS), with its increased risk for cardiovascular disease (CVD), nonalcoholic fatty liver disease (NAFLD), and chronic kidney disease (CKD), has become a growing worldwide health problem. Insulin resistance is a key factor for the development of the CMS and is strongly related to obesity, hyperlipidemia, hypertension, type 2 diabetes mellitus (T2DM), CKD, and NAFLD. Insulin resistance in skeletal muscle is particularly important since it is normally responsible for more than 75% of all insulin-mediated glucose disposal. However, the molecular mechanisms responsible for skeletal muscle insulin resistance remain poorly defined. Accumulating evidence indicates that low-grade chronic inflammation and oxidative stress play fundamental roles in the development of insulin resistance, and inflammatory cytokines likely contribute to the link between inflammation, oxidative stress, and skeletal muscle insulin resistance. Understanding the mechanisms by which skeletal muscle tissue develops resistance to insulin will provide attractive targets for interventions, which may ultimately curb this serious problem. This review is focused on the effects of inflammatory cytokines and oxidative stress on insulin signaling in skeletal muscle and consequent development of insulin resistance.
Collapse
Affiliation(s)
- Yongzhong Wei
- Department of Internal Medicine, University of Missouri School of Medicine, Columbia, Missouri 65212, USA
| | | | | | | | | | | |
Collapse
|
|
45
|
Zhang WJ, Wei H, Hagen T, Frei B. Alpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. Proc Natl Acad Sci U S A 2007; 104:4077-82. [PMID: 17360480 PMCID: PMC1805485 DOI: 10.1073/pnas.0700305104] [Citation(s) in RCA: 211] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was recently shown to negatively regulate LPS-induced acute inflammatory responses. We previously observed that the metabolic thiol antioxidant alpha-lipoic acid (LA) inhibits LPS-induced expression of cellular adhesion molecules and adherence of monocytes to human aortic endothelial cells. Here we investigated the mechanism by which LA attenuates LPS-induced monocyte activation in vitro and acute inflammatory responses in vivo. Incubation of human monocytic THP-1 cells with LA induced phosphorylation of Akt in a time- and dose-dependent manner. In cells pretreated with LA followed by LPS, Akt phosphorylation was elevated initially and further increased during incubation with LPS. This LA-dependent increase in Akt phosphorylation was accompanied by inhibition of LPS-induced NF-kappaB DNA binding activity and up-regulation of TNFalpha and monocyte chemoattractant protein 1. Lipoic acid-dependent Akt phosphorylation and inhibition of NF-kappaB activity were abolished by the PI3K inhibitors LY294002 and wortmannin. Furthermore, LA treatment of LPS-exposed C57BL/6N mice strongly enhanced phosphorylation of Akt and glycogen synthase kinase 3beta in blood cells; inhibited the LPS-induced increase in serum concentrations and/or tissue expression of adhesion molecules, monocyte chemoattractant protein 1, and TNFalpha; and attenuated NF-kappaB activation in lung, heart, and aorta. Lipoic acid also improved survival of endotoxemic mice. All of these antiinflammatory effects of LA were abolished by treatment of the animals with wortmannin. We conclude that LA inhibits LPS-induced monocyte activation and acute inflammatory responses in vitro and in vivo by activating the PI3K/Akt pathway. Lipoic acid may be useful in the prevention of sepsis and inflammatory vascular diseases.
Collapse
Affiliation(s)
- Wei-Jian Zhang
- Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331-6512
- *To whom correspondence may be addressed. E-mail:
or
| | - Hao Wei
- Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331-6512
| | - Tory Hagen
- Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331-6512
| | - Balz Frei
- Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331-6512
- *To whom correspondence may be addressed. E-mail:
or
| |
Collapse
|
|
46
|
JeBailey L, Wanono O, Niu W, Roessler J, Rudich A, Klip A. Ceramide- and oxidant-induced insulin resistance involve loss of insulin-dependent Rac-activation and actin remodeling in muscle cells. Diabetes 2007; 56:394-403. [PMID: 17259384 DOI: 10.2337/db06-0823] [Citation(s) in RCA: 161] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
In muscle cells, insulin elicits recruitment of the glucose transporter GLUT4 to the plasma membrane. This process engages sequential signaling from insulin receptor substrate (IRS)-1 to phosphatidylinositol (PI) 3-kinase and the serine/threonine kinase Akt. GLUT4 translocation also requires an Akt-independent but PI 3-kinase-and Rac-dependent remodeling of filamentous actin. Although IRS-1 phosphorylation is often reduced in insulin-resistant states in vivo, several conditions eliciting insulin resistance in cell culture spare this early step. Here, we show that insulin-dependent Rac activation and its consequent actin remodeling were abolished upon exposure of L6 myotubes beginning at doses of C2-ceramide or oxidant-producing glucose oxidase as low as 12.5 micromol/l and 12.5 mU/ml, respectively. At 25 micromol/l and 25 mU/ml, glucose oxidase and C2-ceramide markedly reduced GLUT4 translocation and glucose uptake and lowered Akt phosphorylation on Ser473 and Thr308, yet they affected neither IRS-1 tyrosine phosphorylation nor its association with p85 and PI 3-kinase activity. Small interfering RNA-dependent Rac1 knockdown prevented actin remodeling and GLUT4 translocation but spared Akt phosphorylation, suggesting that Rac and actin remodeling do not contribute to overall Akt activation. We propose that ceramide and oxidative stress can each affect two independent arms of insulin signaling to GLUT4 at distinct steps, Rac-GTP loading and Akt phosphorylation.
Collapse
Affiliation(s)
- Lellean JeBailey
- Programme in Cell Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8
| | | | | | | | | | | |
Collapse
|
|
47
|
Biswas S, Gupta MK, Chattopadhyay D, Mukhopadhyay CK. Insulin-induced activation of hypoxia-inducible factor-1 requires generation of reactive oxygen species by NADPH oxidase. Am J Physiol Heart Circ Physiol 2007; 292:H758-66. [PMID: 17085541 DOI: 10.1152/ajpheart.00718.2006] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Hypoxia-inducible factor (HIF)-1 activation in response to hypoxia requires mitochondrial generation of reactive oxygen species (ROS). In contrast, the requirement of ROS for HIF-1 activation by growth factors like insulin remains unexplored. To explore that, insulin-sensitive hepatic cell HepG2 or cardiac muscle cell H9c2 cells were pretreated with NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) or apocynin and HIF-1 activation was tested by electrophoretic mobility shift and reporter gene assay. Antioxidants DPI or apocynin completely blocked insulin-stimulated HIF-1 activation. The restoration of HIF-1 activation by H2O2 in DPI-pretreated cells not only confirmed the role of ROS but also identified H2O2 as the responsible ROS. The role of NADPH oxidase was further confirmed by greater stimulation of HIF-1 during simultaneous treatment of suboptimal concentration of insulin along with NADPH but not by NADH. The role of oxidant generated by insulin is found to inhibit the protein tyrosine phosphatase as suggested by the following observations. First, tyrosine phosphatase-specific inhibitor sodium vanadate compensates DPI-inhibited HIF-1 activity. Second, sodium vanadate stimulates HIF-1 activation with suboptimal concentration of insulin. Third, DPI and pyrrolidene dithiocarbamate (PDTC) blocks insulin-receptor tyrosine kinase activation. The activity of phosphatidylinositol 3-kinase as evidenced by Akt phosphorylation, involved in HIF-1 activation, is also dependent on ROS generation by insulin. Finally, DPI pretreatment blocked insulin-stimulated expression of genes like VEGF, GLUT1, and ceruloplasmin. Overall, our data provide strong evidence for the essential role of NADPH oxidase-generated ROS in insulin-stimulated activation of HIF-1.
Collapse
Affiliation(s)
- Sudipta Biswas
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110-067, India
| | | | | | | |
Collapse
|
|
48
|
Huseini HF, Larijani B, Heshmat R, Fakhrzadeh H, Radjabipour B, Toliat T, Raza M. The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial. Phytother Res 2006; 20:1036-9. [PMID: 17072885 DOI: 10.1002/ptr.1988] [Citation(s) in RCA: 166] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Oxidative stresses are increasingly implicated in the pathogenesis of diabetic complications which may either cause direct pancreatic beta-cell damage or lead to metabolic abnormalities that can induce or aggravate diabetes. The valuable effect of antioxidant nutrients on the glycemic control of diabetic patients has been reported in experimental and clinical studies. The present study was designed to investigate the effects of the herbal medicine, Silybum marianum seed extract (silymarin), which is known to have antioxidant properties on the glycemic profile in diabetic patients. A 4-month randomized double-blind clinical trial was conducted in 51 type II diabetic patients in two well-matched groups. The first group (n = 25) received a silymarin (200 mg) tablet 3 times a day plus conventional therapy. The second group (n = 26) received the same therapy but a placebo tablet instead of silymarin. The patients were visited monthly and glycosylated hemoglobin (HbA(1)c), fasting blood glucose (FBS), insulin, total cholesterol, LDL and HDL, triglyceride, SGOT and SGPT levels were determined at the beginning and the end of the study. The results showed a significant decrease in HbA(1)c, FBS, total cholesterol, LDL, triglyceride SGOT and SGPT levels in silymarin treated patients compared with placebo as well as with values at the beginning of the study in each group. In conclusion, silymarin treatment in type II diabetic patients for 4 months has a beneficial effect on improving the glycemic profile.
Collapse
Affiliation(s)
- H Fallah Huseini
- Department of Pharmacology, Institute of Medicinal Plants, ACECR Tehran, Iran.
| | | | | | | | | | | | | |
Collapse
|
|
49
|
Shimoyama T, Yamaguchi S, Takahashi K, Katsuta H, Ito E, Seki H, Ushikawa K, Katahira H, Yoshimoto K, Ohno H, Nagamatsu S, Ishida H. Gliclazide protects 3T3L1 adipocytes against insulin resistance induced by hydrogen peroxide with restoration of GLUT4 translocation. Metabolism 2006; 55:722-30. [PMID: 16713429 DOI: 10.1016/j.metabol.2006.01.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2005] [Accepted: 01/08/2006] [Indexed: 12/13/2022]
Abstract
Increased oxidative stress under hyperglycemia may contribute to progressive deterioration of peripheral insulin sensitivity. In this study, we investigated whether gliclazide, a second-generation sulfonylurea, can protect 3T3L1 adipocytes from insulin resistance induced by oxidative stress, and whether gliclazide can restore insulin-stimulated glucose transporter 4 (GLUT4) translocation under oxidative stress. We incubated 3T3L1 adipocytes in hydrogen peroxide to produce oxidative stress, then administered various concentrations of gliclazide, N-acetylcystein (NAC), or glibenclamide. Cells treated with these drugs were next exposed to insulin, subsequent glucose uptake was measured, and the insulin-stimulated GLUT4 translocation was monitored in living cells. We found that hydrogen peroxide treatment alone suppressed glucose uptake by insulin stimulation to 65.9%+/-7.8% of the corresponding controls (P<.01). However, addition of 0.1 to 10 micromol/L gliclazide to hydrogen peroxide-treated cells dose-dependently restored glucose uptake, with 5 micromol/L gliclazide significantly restoring glucose uptake to 93.3+/-6.6% (P<.01) even under hydrogen peroxide. Treatment with the known anti-oxidant NAC also dose-dependently (0.1-10 mmol/L) restored insulin-induced glucose uptake in the presence of hydrogen peroxide. However, glibenclamide (0.1-10 micromol/L), another second-generation sulfonylurea, failed to improve glucose uptake. Similarly, treatment with 5 micromol/L gliclazide or 10 mmol/L NAC significantly overcome the reduction in insulin-stimulated GLUT4 translocation by hydrogen peroxide (P<.01), whereas 5 micromol/L glibenclamide did not. Therefore our data regarding gliclazide further characterize its mechanism of hypoglycemic effect: the observed improvements in insulin sensitivity and in GLUT4 translocation indicate that gliclazide counters the hydrogen peroxide-induced insulin resistance in 3T3L1 adipocytes and also would further augment the hypoglycemic effect of this drug as insulinotropic sulfonylurea.
Collapse
Affiliation(s)
- Tatsuhiro Shimoyama
- Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Pessler-Cohen D, Pekala PH, Kovsan J, Bloch-Damti A, Rudich A, Bashan N. GLUT4 repression in response to oxidative stress is associated with reciprocal alterations in C/EBP alpha and delta isoforms in 3T3-L1 adipocytes. Arch Physiol Biochem 2006; 112:3-12. [PMID: 16754198 DOI: 10.1080/13813450500500399] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Insulin responsiveness of adipocytes is acquired during normal adipogenesis, and is essential for maintaining whole-body insulin sensitivity. Differentiated adipocytes exposed to oxidative stress become insulin resistant, exhibiting decreased expression of genes like the insulin-responsive glucose transporter GLUT4. Here we assessed the effect of oxidative stress on DNA binding capacity of C/EBP isoforms known to participate in adipocyte differentiation, and determine the relevance for GLUT4 gene regulation. By electrophoretic mobility shift assay, nuclear proteins from oxidized adipocytes exhibited decreased binding of C/EBPalpha-containing dimers to a DNA oligonucleotide harboring the C/EBP binding sequence from the murine GLUT4 promoter. C/EBPdelta-containing dimers were increased, while C/EBPbeta-dimers were unchanged. These alterations were mirrored by a 50% decrease and a 2-fold increase in the protein content of C/EBPalpha and C/EBPdelta, respectively. In oxidized cells, GLUT4 protein and mRNA levels were decreased, and a GLUT4 promoter segment containing the C/EBP binding site partially mediated oxidative stress-induced repression of a reported gene. The antioxidant lipoic acid protected against oxidation-induced decrease in GLUT4 and C/EBPalpha mRNA, but did not prevent the increase in C/EBPdelta mRNA. We propose that oxidative stress induces adipocyte insulin resistance partially by affecting the expression of C/EBPalpha and delta, resulting in altered C/EBP-dimer composition potentially occupying the GLUT4 promoter.
Collapse
Affiliation(s)
- Dorit Pessler-Cohen
- Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | | | | | | | | | | |
Collapse
|