American Federation for Medical Research

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Metabolic and Gene Expression Changes with Metformin Treatment in Nondiabetic Older Adults
Erika F. Brutsaert1, Ameya Kulkarni2, Valentin Anghel2, Kehao Zhang2, Noah Bloomgarden1, Michael Pollak3, Jessica Mar2, Meredith Hawkins1, Jill Crandall1, Nir Barzilai2. 1Endocrinology, Montefiore Medical Center/ Albert Einstein College of Medicine, Hastings on Hudson, New York, United States, 2Albert Einstein College of Medicine, Bronx, New York, United States, 3McGill, Montreal, Quebec, Canada

Purpose of Study Recent findings suggest that metformin has pleotropic effects and may slow age-related disease by targeting processes disturbed by aging. However, human studies are lacking. This study investigated the effects of metformin on metabolic outcomes and on gene transcription in fat and muscle in older adults.
Methods Used We studied ~70-year-old participants (n=14), in a randomized, double-blind, placebo-controlled, crossover trial in which they were treated with 6 weeks each of metformin and placebo. Following each treatment period, skeletal muscle and subcutaneous adipose biopsies were obtained, and a mixedmeal challenge test was performed. Gene transcriptional changes of subcutaneous adipose tissue and skeletal muscle were assessed using RNAseq.
Summary of Results Metformin therapy lowered 2-hour glucose, insulin AUC, and insulin secretion compared with placebo. Using FDR<0.05, 647 genes were differentially expressed in muscle and 146 genes were differentially expressed in adipose tissue. Both metabolic and non-metabolic pathways were significantly influenced, including pyruvate metabolism and DNA repair in muscle and PPAR & SREBP signaling, mitochondrial fatty acid oxidation and collagen trimerization in adipose.
Conclusions This study provides the first evidence that, in older adults, metformin has metabolic and non-metabolic effects that may be linked to aging.


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