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      Drug Design, Development and Therapy (submit here)

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      Metformin Decreases Insulin Resistance in Type 1 Diabetes Through Regulating p53 and RAP2A in vitro and in vivo

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          Abstract

          Purpose

          Patients with type 1 diabetes (T1D) are associated with a high risk of multiple complications, so the development of T1D treatment is urgently needed. This study was set out to explore the molecular mechanism of metformin in the treatment of T1D insulin resistance.

          Patients and Methods

          Subcutaneous adipose tissues were collected from 68 T1D patients and 51 healthy controls. Insulin resistance model rats and cells were constructed and treated with metformin respectively. Western blot was used to detect p53 and RAP2A protein levels, and qPCR was utilized to measure p53 and RAP2A mRNA levels. SiRNA and RAP2A siRNA vectors were constructed to observe their effects on insulin resistance model cells.

          Results

          In T1D, p53 was up-regulated, while RAP2A was down-regulated. Metformin could effectively improve insulin resistance and inflammatory response while down-regulating p53 and up-regulating RAP2A. P53 induced insulin resistance and inflammatory response by inhibiting RAP2A and promoted apoptosis.

          Conclusion

          Metformin improves T1D insulin resistance and inflammatory response through p53/RAP2A pathway, and the regulation of p53/RAP2A pathway is conducive to improving the efficacy of metformin in the treatment of insulin resistance.

          Most cited references27

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          Type 1 diabetes

          Carmella Evans-Molina, Richard Oram, Linda A DiMeglio (2018)
          Type 1 diabetes is a chronic autoimmune disease characterised by insulin deficiency and resultant hyperglycaemia. Knowledge of type 1 diabetes has rapidly increased over the past 25 years, resulting in a broad understanding about many aspects of the disease, including its genetics, epidemiology, immune and β-cell phenotypes, and disease burden. Interventions to preserve β cells have been tested, and several methods to improve clinical disease management have been assessed. However, wide gaps still exist in our understanding of type 1 diabetes and our ability to standardise clinical care and decrease disease-associated complications and burden. This Seminar gives an overview of the current understanding of the disease and potential future directions for research and care.
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            A crucial role for adipose tissue p53 in the regulation of insulin resistance.

            Tohru Minamino, Masayuki Orimo, Ippei Shimizu … (2009)
            Various stimuli, such as telomere dysfunction and oxidative stress, can induce irreversible cell growth arrest, which is termed 'cellular senescence'. This response is controlled by tumor suppressor proteins such as p53 and pRb. There is also evidence that senescent cells promote changes related to aging or age-related diseases. Here we show that p53 expression in adipose tissue is crucially involved in the development of insulin resistance, which underlies age-related cardiovascular and metabolic disorders. We found that excessive calorie intake led to the accumulation of oxidative stress in the adipose tissue of mice with type 2 diabetes-like disease and promoted senescence-like changes, such as increased activity of senescence-associated beta-galactosidase, increased expression of p53 and increased production of proinflammatory cytokines. Inhibition of p53 activity in adipose tissue markedly ameliorated these senescence-like changes, decreased the expression of proinflammatory cytokines and improved insulin resistance in mice with type 2 diabetes-like disease. Conversely, upregulation of p53 in adipose tissue caused an inflammatory response that led to insulin resistance. Adipose tissue from individuals with diabetes also showed senescence-like features. Our results show a previously unappreciated role of adipose tissue p53 expression in the regulation of insulin resistance and suggest that cellular aging signals in adipose tissue could be a new target for the treatment of diabetes (pages 996-967).
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              p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression

              Sung-Hwan Moon, Chun-Hao Huang, Shauna Houlihan … (2019)
              There are still gaps in our understanding of the complex processes by which p53 suppresses tumorigenesis. Here we describe a novel role for p53 in suppressing the mevalonate pathway, which is responsible for biosynthesis of cholesterol and nonsterol isoprenoids. p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the ABCA1 cholesterol transporter gene. A mouse model of liver cancer reveals that downregulation of mevalonate pathway gene expression by p53 occurs in premalignant hepatocytes, when p53 is needed to actively suppress tumorigenesis. Furthermore, pharmacological or RNAi inhibition of the mevalonate pathway restricts the development of murine hepatocellular carcinomas driven by p53 loss. Like p53 loss, ablation of ABCA1 promotes murine liver tumorigenesis and is associated with increased SREBP-2 maturation. Our findings demonstrate that repression of the mevalonate pathway is a crucial component of p53-mediated liver tumor suppression and outline the mechanism by which this occurs.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Drug Des Devel Ther
                Journal ID (iso-abbrev): Drug Des Devel Ther
                Journal ID (publisher-id): DDDT
                Journal ID (pmc): dddt
                Title: Drug Design, Development and Therapy
                Publisher: Dove
                ISSN (Electronic): 1177-8881
                Publication date (Electronic): 17 June 2020
                Publication date Collection: 2020
                Volume: 14
                Pages: 2381-2392
                Affiliations
                [1 ]Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052, Henan Province, People’s Republic of China
                [2 ]Department of Cardiology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052, Henan Province, People’s Republic of China
                [3 ]Department of Respiratory, The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052, Henan Province, People’s Republic of China
                Author notes
                Correspondence: Peng-Fei Jiao Department of Respiratory,The First Affiliated Hospital of Zhengzhou University , No. 1, Jianshe East Road, Zhengzhou450052, Henan Province, People’s Republic of ChinaTel +86 371-66913257 Email 314761380@qq.com
                Article
                Publisher ID: 249557
                DOI: 10.2147/DDDT.S249557
                PMC ID: 7306576
                SO-VID: 4886e91a-a85b-40c9-9be8-708459748dbe
                Copyright © © 2020 Ren et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 13 February 2020
                Date accepted : 07 May 2020
                Page count
                Figures: 6, References: 28, Pages: 12
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: type 1 diabetes,p53,rap2a,insulin resistance,metformin
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: type 1 diabetes, p53, rap2a, insulin resistance, metformin

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