Internet Archive Scholar

GDF15 and the beneficial actions of metformin in pre-diabetes [article]

Anthony P Coll, Michael Chen, Pranali Taskar, Debra Rimmington, Satish Patel, John Tadross, Irene Cimino, Ming Yang, Paul Welsh, Samuel Virtue, Deborah A Goldspink, Emily Miedzybrodzka (+16 others)
2019 bioRxiv   pre-print

Preserved Fulltext

Web Archive Capture PDF (2.3 MB)
https://web.archive.org/web/20200212202258/https://www.biorxiv.org/content/biorxiv/early/2019/06/21/677831.full.pdf

A copy of this work was available on the public web and has been preserved in the Wayback Machine. The capture dates from 2020; you can also visit the original URL. The file type is application/pdf.

Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing Type 2 diabetes in people at high risk, by lowering body weight, fat mass and circulating insulin levels through mechanisms that are incompletely understood. Recent observational studies reporting the association of metformin use and circulating levels of GDF15 led us to hypothesize that GDF15, which signals through a specific receptor complex in the hindbrain to reduce body weight, might mediate these
more » ... ects. We measured GDF15 in people without diabetes from a randomized placebo-controlled trial of metformin. Over 18 months, participants allocated metformin lost significant weight and levels of GDF15 were persistently elevated compared to placebo. The change in plasma GDF15 in this study correlated positively with weight loss. In wild-type mice, oral metformin increased circulating GDF15 with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to high fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GFRAL. In obese, high fat-fed mice, the effects of metformin to reduce body weight were reversed by a GFRAL antagonist antibody. Metformin had effects on both energy intake and energy expenditure that required GDF15. The insulin sensitising effects of metformin determined by insulin tolerance were abolished in mice lacking GDF15. Metformin significantly reduced fasting glucose and insulin levels in wild type but not in mice lacking GDF15. In summary, metformin increases the circulating levels of GDF15, which appears to be necessary for many of its actions as a metabolic chemopreventive agent.
doi:10.1101/677831 fatcat:eydkfrophvb5tn6ayc3jatps6y
Citation

Anthony P Coll, Michael Chen, Pranali Taskar, Debra Rimmington, Satish Patel, John Tadross, Irene Cimino, Ming Yang, Paul Welsh, Samuel Virtue, Deborah A Goldspink, Emily Miedzybrodzka, Y.C. Loraine Tung, Sergio Rodriguez-Cuenca, Rute A Tomaz, Heather P Harding, Audrey Melvin, Giles S.H. Yeo, David Preiss, Antonio Vidal-Puig, Ludovic Vallier, David Ron, Fiona M Gribble, Frank Reimann, Naveed Sattar, David B Savage, Bernard B Allan, Stephen O'Rahilly. "GDF15 and the beneficial actions of metformin in pre-diabetes." bioRxiv (2019)