RT Journal Article
SR Electronic
T1 GDF15 and the beneficial actions of metformin in pre-diabetes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 677831
DO 10.1101/677831
A1 Anthony P Coll
A1 Michael Chen
A1 Pranali Taskar
A1 Debra Rimmington
A1 Satish Patel
A1 John Tadross
A1 Irene Cimino
A1 Ming Yang
A1 Paul Welsh
A1 Samuel Virtue
A1 Deborah A. Goldspink
A1 Emily Miedzybrodzka
A1 Y. C. Loraine Tung
A1 Sergio Rodriguez-Cuenca
A1 Rute A. Tomaz
A1 Heather P. Harding
A1 Audrey Melvin
A1 Giles S.H. Yeo
A1 David Preiss
A1 Antonio Vidal-Puig
A1 Ludovic Vallier
A1 David Ron
A1 Fiona M. Gribble
A1 Frank Reimann
A1 Naveed Sattar
A1 David B. Savage
A1 Bernard B. Allan
A1 Stephen O’Rahilly
YR 2019
UL http://biorxiv.org/content/early/2019/06/21/677831.abstract
AB 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 effects. 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.