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      Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway

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          Abstract

          Background

          Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor used in type 2 diabetes therapy, has demonstrated protective effects in diabetic chronic kidney disease, in part due to its pleiotropic actions. However, its potential direct effects on the kidney are still not completely defined. Here, by means of proteomics and miRNA profiling, we have further unveiled the role of sitagliptin in oxidative stress, as well as the underlying mechanisms.

          Methods

          Renal cortex samples from 9-month-old wild-type (Wistar), type II diabetic Goto-Kakizaki (GK) and sitagliptin-treated GK rats (GK+Sita) (10 mg kg −1 per day) were subjected to quantitative miRNA transcriptomic array, immunohistochemistry and Western blot studies. Renal GK and GK+Sita samples were also analyzed by differential in-gel electrophoresis. Bioinformatic tools were used to find out the relationships between altered proteins and related miRNA expression. Studies were also carried out in cultured tubular cells to confirm in vivo data.

          Results

          Diabetic GK rats exhibited proteinuria, renal interstitial inflammatory infiltrates and fibrosis, which improved by 20 weeks of sitagliptin treatment. Proteomic analysis of diabetic GK and Wistar rats showed a differential expression of 39 proteins mostly related to oxidative stress and catabolism. In addition, 15 miRNAs were also significantly altered in GK rats.

          Conclusion

          Treatment with sitagliptin was associated with modulation of antioxidant response in the diabetic kidney, involving a downregulation of miR-200a, a novel Keap-1 inhibitor and miR-21, coincidentally with the clinical and the morphological improvement. These data further support the concept that DPP-4 inhibitors could exert a direct reno-protective effect in patients with diabetic nephropathy.

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          Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.

          Sarah E Wild, Gojka Roglic, Anders Green … (2004)
          The goal of this study was to estimate the prevalence of diabetes and the number of people of all ages with diabetes for years 2000 and 2030. Data on diabetes prevalence by age and sex from a limited number of countries were extrapolated to all 191 World Health Organization member states and applied to United Nations' population estimates for 2000 and 2030. Urban and rural populations were considered separately for developing countries. The prevalence of diabetes for all age-groups worldwide was estimated to be 2.8% in 2000 and 4.4% in 2030. The total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. The prevalence of diabetes is higher in men than women, but there are more women with diabetes than men. The urban population in developing countries is projected to double between 2000 and 2030. The most important demographic change to diabetes prevalence across the world appears to be the increase in the proportion of people >65 years of age. These findings indicate that the "diabetes epidemic" will continue even if levels of obesity remain constant. Given the increasing prevalence of obesity, it is likely that these figures provide an underestimate of future diabetes prevalence.
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            Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial.

            Richard M. Bergenstal, Carol Wysham, Leigh MacConell … (2010)
            Most patients with type 2 diabetes begin pharmacotherapy with metformin, but eventually need additional treatment. We assessed the safety and efficacy of once weekly exenatide, a glucagon-like peptide 1 receptor agonist, versus maximum approved doses of the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the thiazolidinedione, pioglitazone, in patients treated with metformin. In this 26-week randomised, double-blind, double-dummy, superiority trial, patients with type 2 diabetes who had been treated with metformin, and at baseline had mean glycosylated haemoglobin (HbA(1c)) of 8.5% (SD 1.1), fasting plasma glucose of 9.1 mmol/L (2.6), and weight of 88.0 kg (20.1), were enrolled and treated at 72 sites in the USA, India, and Mexico. Patients were randomly assigned to receive: 2 mg injected exenatide once weekly plus oral placebo once daily; 100 mg oral sitagliptin once daily plus injected placebo once weekly; or 45 mg oral pioglitazone once daily plus injected placebo once weekly. Primary endpoint was change in HbA(1c) between baseline and week 26. Analysis was by intention to treat, for all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00637273. 170 patients were assigned to receive once weekly exenatide, 172 to receive sitagliptin, and 172 to receive pioglitazone. 491 patients received at least one dose of study drug and were included in the intention-to-treat analysis (160 on exenatide, 166 on sitagliptin, and 165 on pioglitazone). Treatment with exenatide reduced HbA(1c) (least square mean -1.5%, 95% CI -1.7 to -1.4) significantly more than did sitagliptin (-0.9%, -1.1 to -0.7) or pioglitazone (-1.2%, -1.4 to -1.0). Treatment differences were -0.6% (95% CI -0.9 to -0.4, p<0.0001) for exenatide versus sitagliptin, and -0.3% (-0.6 to -0.1, p=0.0165) for exenatide versus pioglitazone. Weight loss with exenatide (-2.3 kg, 95% CI-2.9 to -1.7) was significantly greater than with sitagliptin (difference -1.5 kg, 95% CI -2.4 to -0.7, p=0.0002) or pioglitazone (difference -5.1 kg, -5.9 to -4.3, p<0.0001). No episodes of major hypoglycaemia occurred. The most frequent adverse events with exenatide and sitagliptin were nausea (n=38, 24%, and n=16, 10%, respectively) and diarrhoea (n=29, 18%, and n=16, 10%, respectively); upper-respiratory-tract infection (n=17, 10%) and peripheral oedema (n=13, 8%) were the most frequent events with pioglitazone. The goal of many clinicians who manage diabetes is to achieve optimum glucose control alongside weight loss and a minimum number of hypoglycaemic episodes. Addition of exenatide once weekly to metformin achieved this goal more often than did addition of maximum daily doses of either sitagliptin or pioglitazone. Amylin Pharmaceuticals and Eli Lilly. Copyright 2010 Elsevier Ltd. All rights reserved.
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              Animal models in type 2 diabetes research: an overview.

              P Ramarao, K Srinivasan, John Kirby (2007)
              Type 2 diabetes is a complex and heterogeneous disorder presently affecting more than 100 million people worldwide and causing serious socio-economic problems. Appropriate experimental models are essential tools for understanding the pathogenesis, complications, and genetic or environmental influences that increase the risks of type 2 diabetes and testing of various therapeutic agents. The animal models of type 2 diabetes can be obtained either spontaneously or induced by chemicals or dietary or surgical manipulations and/or by combination thereof. In recent years, large number of new genetically modified animal models including transgenic, generalized knock-out and tissue-specific knockout mice have been engineered for the study of diabetes. This review gives an overview on the animal models of type 2 diabetes with reference to their origin/source, characteristic features, underlying causes/mechanism(s), advantages and disadvantages to the investigators in diabetes research. In addition, it especially describes the appropriate selection and usefulness of different animal models in preclinical testing of various new chemical entities (NCEs) for the treatment of type 2 diabetes.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes Metab Syndr Obes
                Journal ID (iso-abbrev): Diabetes Metab Syndr Obes
                Journal ID (publisher-id): Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
                Title: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
                Publisher: Dove Medical Press
                ISSN (Electronic): 1178-7007
                Publication date Collection: 2017
                Publication date (Electronic): 07 June 2017
                Volume: 10
                Pages: 207-222
                Affiliations
                [1 ]Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Autonoma University
                [2 ]CIBERDEM (Biomedical Research Centre in Diabetes and Associated Metabolic Disorders), Madrid, Spain
                Author notes
                Correspondence: Esther Civantos, Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Av. Reyes Católicos 2, 28040 Madrid, Spain, Email ecivantos@ 123456fjd.es
                Article
                Publisher ID: dmso-10-207
                DOI: 10.2147/DMSO.S132537
                PMC ID: 5473486
                PubMed ID: 28652790
                SO-VID: 5ed87bb6-a7eb-4718-899f-e0d66dd59391
                Copyright © © 2017 Civantos et al. This work is published and licensed by Dove Medical Press Limited
                License:

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Subject: Original Research

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: diabetes,sitagliptin,nrf2,keap-1,mirnas,gk rats
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: diabetes, sitagliptin, nrf2, keap-1, mirnas, gk rats

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