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Glyoxalase 1 modulation in obesity and diabetes
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Rabbani, Naila and Thornalley, Paul J. (2019) Glyoxalase 1 modulation in obesity and diabetes. Antioxidants & Redox Signaling, 30 (3). pp. 354-374. doi:10.1089/ars.2017.7424 ISSN 1523-0864.
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WRAP-glyoxalase-1-modulation-obesity-diabetes-Rabbani-2018.pdf - Accepted Version - Requires a PDF viewer. Download (1193Kb) | Preview |
Official URL: http://dx.doi.org/10.1089/ars.2017.7424
Abstract
Significance: Obesity and type 2 diabetes mellitus are increasing globally. There is also increasing associated complications, such as non-alcoholic fatty liver disease (NAFLD) and vascular complications of diabetes. There is currently no licensed treatment for NAFLD and no recent treatments for diabetic complications. New approaches are required, particularly those addressing mechanism-based risk factors for health decline and disease progression.
Recent Advances: Dicarbonyl stress is the abnormal accumulation of reactive dicarbonyl metabolites such as methylglyoxal (MG) leading to cell and tissue dysfunction. It is a potential driver of obesity, diabetes, and related complications that are unaddressed by current treatments. Increased formation of MG is linked to increased glyceroneogenesis and hyperglycemia in obesity and diabetes and also down-regulation of glyoxalase 1 (Glo1)—which provides the main enzymatic detoxification of MG. Glo1 functional genomics studies suggest that increasing Glo1 expression and activity alleviates dicarbonyl stress; slows development of obesity, related insulin resistance; and prevents development of diabetic nephropathy and other microvascular complications of diabetes. A new therapeutic approach constitutes small-molecule inducers of Glo1 expression—Glo1 inducers—exploiting a regulatory antioxidant response element in the GLO1 gene. A prototype Glo1 inducer, trans-resveratrol (tRES)-hesperetin (HESP) combination, in corrected insulin resistance, improved glycemic control and vascular inflammation in healthy overweight and obese subjects in clinical trial.
Critical Issues: tRES and HESP synergize pharmacologically, and HESP likely overcomes the low bioavailability of tRES by inhibition of intestinal glucuronosyltransferases.
Future Directions: Glo1 inducers may now be evaluated in Phase 2 clinical trials for treatment of NAFLD and vascular complications of diabetes.
Item Type: | Journal Article | ||||||||||||
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Subjects: | R Medicine > RC Internal medicine | ||||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Non-insulin-dependent diabetes, Obesity, Glyoxalase | ||||||||||||
Journal or Publication Title: | Antioxidants & Redox Signaling | ||||||||||||
Publisher: | Mary Ann Liebert, Inc. Publishers | ||||||||||||
ISSN: | 1523-0864 | ||||||||||||
Official Date: | January 2019 | ||||||||||||
Dates: |
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Volume: | 30 | ||||||||||||
Number: | 3 | ||||||||||||
Page Range: | pp. 354-374 | ||||||||||||
DOI: | 10.1089/ars.2017.7424 | ||||||||||||
Status: | Peer Reviewed | ||||||||||||
Publication Status: | Published | ||||||||||||
Access rights to Published version: | Restricted or Subscription Access | ||||||||||||
Date of first compliant deposit: | 10 January 2018 | ||||||||||||
Date of first compliant Open Access: | 2 January 2019 | ||||||||||||
RIOXX Funder/Project Grant: |
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