Mangiferin induces islet regeneration in aged mice through regulating p16INK4a

Wang,Hailian; He,Xia; Lei,Tiantian; Liu,Yilong; Huai,Guoli; Sun,Minghan; Deng,Shaoping; Yang,Hongji; Tong,Rongsheng; Wang,Yi

doi:10.3892/ijmm.2018.3524

Mangiferin induces islet regeneration in aged mice through regulating p16INK4a

Authors:
- Hailian Wang
- Xia He
- Tiantian Lei
- Yilong Liu
- Guoli Huai
- Minghan Sun
- Shaoping Deng
- Hongji Yang
- Rongsheng Tong
- Yi Wang
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Affiliations: Institute of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China, Personalized Drug Therapy Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, P.R. China, Department of Pharmacy, The People's Hospital of Leshan, Leshan, Sichuan 614000, P.R. China, Department of Gynecology, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
Published online on: March 1, 2018 https://doi.org/10.3892/ijmm.2018.3524
Pages: 3231-3242
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Previous studies by our group on mangiferin demonstrated that it exerts an anti‑hyperglycemic effect through the regulation of cell cycle proteins in 3‑month‑old, partially pancreatectomized (PPx) mice. However, β‑cell proliferation is known to become severely restricted with advanced age. Therefore, it is unknown whether mangiferin is able to reverse the diabetic condition and retain β‑cell regeneration capability in aged mice. In the present study, 12‑month‑old C57BL/6J mice that had undergone PPx were subjected to mangiferin treatment (90 mg/kg) for 28 days. Mangiferin‑treated aged mice exhibited decreased blood glucose levels and increased glucose tolerance, which was accompanied with higher serum insulin levels when compared with those in untreated PPx control mice. In addition, islet hyperplasia, elevated β‑cell proliferation and reduced β‑cell apoptosis were also identified in the mice that received mangiferin treatment. Further studies on the mRNA transcript and protein expression levels indicated comparatively increased levels of cyclins D1 and D2 and cyclin‑dependent kinase 4 in mangiferin‑treated mice, while the levels of p27Kip1 and p16INK4a were decreased relative to those in the untreated PPx controls. Of note, mangiferin treatment improved the proliferation rate of islet β‑cells in adult mice overexpressing p16INK4a, suggesting that mangiferin induced β‑cell proliferation via the regulation of p16INK4a. In addition, the mRNA transcription levels of critical genes associated with insulin secretion, including pancreatic and duodenal homeobox 1, glucose transporter 2 and glucokinase, were observed to be upregulated after mangiferin treatment. Taken together, it was indicated that mangiferin treatment significantly induced β‑cell proliferation and inhibited β‑cell apoptosis by regulating cell cycle checkpoint proteins. Furthermore, mangiferin was also demonstrated to regulate genes associated with insulin secretion. Collectively these, results suggest the therapeutic potential of mangiferin in the treatment of diabetes in aged individuals.

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