Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 Diabetes
Oxidative stress and persistent inflammation are exaggerated through chronic over-nutrition and a sedentary lifestyle, resulting in insulin resistance. In type 2 diabetes (T2D), impaired insulin signaling leads to hyperglycemia and long-term complications, including metabolic liver dysfunction, resu...
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| Format: | Article |
| Language: | English |
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MDPI AG
2017-11-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/6/4/85 |
| _version_ | 1797708024321671168 |
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| author | Gina M. Coudriet Meghan M. Delmastro-Greenwood Dana M. Previte Meghan L. Marré Erin C. O’Connor Elizabeth A. Novak Garret Vincent Kevin P. Mollen Sojin Lee H. Henry Dong Jon D. Piganelli |
| author_facet | Gina M. Coudriet Meghan M. Delmastro-Greenwood Dana M. Previte Meghan L. Marré Erin C. O’Connor Elizabeth A. Novak Garret Vincent Kevin P. Mollen Sojin Lee H. Henry Dong Jon D. Piganelli |
| author_sort | Gina M. Coudriet |
| collection | DOAJ |
| description | Oxidative stress and persistent inflammation are exaggerated through chronic over-nutrition and a sedentary lifestyle, resulting in insulin resistance. In type 2 diabetes (T2D), impaired insulin signaling leads to hyperglycemia and long-term complications, including metabolic liver dysfunction, resulting in non-alcoholic fatty liver disease (NAFLD). The manganese metalloporphyrin superoxide dismustase (SOD) mimetic, manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnP), is an oxidoreductase known to scavenge reactive oxygen species (ROS) and decrease pro-inflammatory cytokine production, by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. We hypothesized that targeting oxidative stress-induced inflammation with MnP would assuage liver complications and enhance insulin sensitivity and glucose tolerance in a high-fat diet (HFD)-induced mouse model of T2D. During 12 weeks of feeding, we saw significant improvements in weight, hepatic steatosis, and biomarkers of liver dysfunction with redox modulation by MnP treatment in HFD-fed mice. Additionally, MnP treatment improved insulin sensitivity and glucose tolerance, while reducing serum insulin and leptin levels. We attribute these effects to redox modulation and inhibition of hepatic NF-κB activation, resulting in diminished ROS and pro-inflammatory cytokine production. This study highlights the importance of controlling oxidative stress and secondary inflammation in obesity-mediated insulin resistance and T2D. Our data confirm the role of NF-κB-mediated inflammation in the development of T2D, and demonstrate the efficacy of MnP in preventing the progression to disease by specifically improving liver pathology and hepatic insulin resistance in obesity. |
| first_indexed | 2024-03-12T06:16:15Z |
| format | Article |
| id | doaj.art-eb696c70a1ca4d40894bd21a08266ad0 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-12T06:16:15Z |
| publishDate | 2017-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-eb696c70a1ca4d40894bd21a08266ad02023-09-03T02:37:10ZengMDPI AGAntioxidants2076-39212017-11-01648510.3390/antiox6040085antiox6040085Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 DiabetesGina M. Coudriet0Meghan M. Delmastro-Greenwood1Dana M. Previte2Meghan L. Marré3Erin C. O’Connor4Elizabeth A. Novak5Garret Vincent6Kevin P. Mollen7Sojin Lee8H. Henry Dong9Jon D. Piganelli10Department of Surgery, Children’s Hospital of Pittsburgh of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USADepartment of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USADepartment of Surgery, Children’s Hospital of Pittsburgh of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USADepartment of Surgery, Children’s Hospital of Pittsburgh of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USADepartment of Surgery, Children’s Hospital of Pittsburgh of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USADepartment of Surgery, Children’s Hospital of Pittsburgh of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USADepartment of Surgery, Children’s Hospital of Pittsburgh of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USADepartment of Surgery, Children’s Hospital of Pittsburgh of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USADepartment of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USADepartment of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USADepartment of Surgery, Children’s Hospital of Pittsburgh of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USAOxidative stress and persistent inflammation are exaggerated through chronic over-nutrition and a sedentary lifestyle, resulting in insulin resistance. In type 2 diabetes (T2D), impaired insulin signaling leads to hyperglycemia and long-term complications, including metabolic liver dysfunction, resulting in non-alcoholic fatty liver disease (NAFLD). The manganese metalloporphyrin superoxide dismustase (SOD) mimetic, manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnP), is an oxidoreductase known to scavenge reactive oxygen species (ROS) and decrease pro-inflammatory cytokine production, by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. We hypothesized that targeting oxidative stress-induced inflammation with MnP would assuage liver complications and enhance insulin sensitivity and glucose tolerance in a high-fat diet (HFD)-induced mouse model of T2D. During 12 weeks of feeding, we saw significant improvements in weight, hepatic steatosis, and biomarkers of liver dysfunction with redox modulation by MnP treatment in HFD-fed mice. Additionally, MnP treatment improved insulin sensitivity and glucose tolerance, while reducing serum insulin and leptin levels. We attribute these effects to redox modulation and inhibition of hepatic NF-κB activation, resulting in diminished ROS and pro-inflammatory cytokine production. This study highlights the importance of controlling oxidative stress and secondary inflammation in obesity-mediated insulin resistance and T2D. Our data confirm the role of NF-κB-mediated inflammation in the development of T2D, and demonstrate the efficacy of MnP in preventing the progression to disease by specifically improving liver pathology and hepatic insulin resistance in obesity.https://www.mdpi.com/2076-3921/6/4/85SOD mimeticmetalloporphyrininflammationtype 2 diabetesNAFLDobesityinsulin resistance |
| spellingShingle | Gina M. Coudriet Meghan M. Delmastro-Greenwood Dana M. Previte Meghan L. Marré Erin C. O’Connor Elizabeth A. Novak Garret Vincent Kevin P. Mollen Sojin Lee H. Henry Dong Jon D. Piganelli Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 Diabetes Antioxidants SOD mimetic metalloporphyrin inflammation type 2 diabetes NAFLD obesity insulin resistance |
| title | Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 Diabetes |
| title_full | Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 Diabetes |
| title_fullStr | Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 Diabetes |
| title_full_unstemmed | Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 Diabetes |
| title_short | Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 Diabetes |
| title_sort | treatment with a catalytic superoxide dismutase sod mimetic improves liver steatosis insulin sensitivity and inflammation in obesity induced type 2 diabetes |
| topic | SOD mimetic metalloporphyrin inflammation type 2 diabetes NAFLD obesity insulin resistance |
| url | https://www.mdpi.com/2076-3921/6/4/85 |
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