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Dean Pomerleau

Metformin Benefits May Result from "Crypto-CR"

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This new study [1] in Nature Metabolism (popular press account) seems to show that many of the benefits of metformin result from it raising levels of circulating GDF15, which in turn reduces appetite and induces weight loss in mice and humans. 

This pre-print [2] found very similar results - metformin increases GDF15, which in turn lowers food intake and induces weight loss in mice. In GDF15 knockout mice, metformin didn't result in reduced food intake or weight loss. Knocking out GDF15 in mice also abolished the improvement in insulin sensitivity that usually results from  metformin. Here are the graphs of food intake for normal mice (top) and GDF15 knockout mice (bottom) when given metformin vs. placebo.

Screenshot_20191209-171349_Foxit PDF.jpg

If these studies are correct, a large part of metformin benefits may result from its ability to suppress appetite (via GDF15), thereby reducing food intake and inducing a state of "crypto-CR". It would also suggest metformin may not do much for people who are already practicing CR.

--Dean

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[1] Nature Metabolism Published: 09 December 2019

Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss


Emily A. Day, Rebecca J. Ford, Brennan K. Smith, Pedrum Mohammadi-Shemirani, Marisa R. Morrow, Robert M. Gutgesell, Rachel Lu, Amogelang R. Raphenya, Mostafa Kabiri, Andrew G. McArthur, Natalia McInnes, Sibylle Hess, Guillaume Paré, Hertzel C. Gerstein & Gregory R. Steinberg

Abstract

Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs. 1,2,3). However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood1,2,3. Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system4. Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15.

 

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

Anthony P Coll, Michael Chen, Pranali Taskar, Debra Rimmington,  View ORCID ProfileSatish Patel, John Tadross, Irene Cimino, Ming Yang,  View ORCID ProfilePaul Welsh, Samuel Virtue, Deborah A. Goldspink, Emily Miedzybrodzka, Y. C. Loraine Tung, Sergio Rodriguez-Cuenca,  View ORCID ProfileRute A. Tomaz, Heather P. Harding, Audrey Melvin,  View ORCID ProfileGiles S.H. Yeo,  View ORCID ProfileDavid Preiss, Antonio Vidal-Puig, Ludovic Vallier,  View ORCID ProfileDavid Ron,  View ORCID ProfileFiona M. Gribble,  View ORCID ProfileFrank Reimann, Naveed Sattar, David B. Savage, Bernard B. Allan,  View ORCID ProfileStephen O’Rahilly

doi: https://doi.org/10.1101/677831

Summary

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.

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Thanks, Dean. Yep, that's definitely a downer. Insulin sensitising was certainly a major consideration for me. Now I have to re-think the utility of this. There are pleiotropic effects, but this one was a big one. Ouch.

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18 hours ago, Dean Pomerleau said:

... It would also suggest metformin may not do much for people who are already practicing CR.

--Dean

Yep, thanks for that. It makes sense.

An appetite suppressant would appear to be a miracle pleiotropic drug for those who are overweight and are experiencing weight-related issues.

Not so much so for the majority who lurk here.

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