Higher mitochondrial DNA copy number is associated with metformin-induced weight loss

Jing Wang, Hua Liang, Rong Huang, Xiong Weng, Li Zheng, You Wang, Xueying Zheng, Zhenglong Gu, Fei Chen, Jian Shao, Zhaoxu Geng, Ewan R. Pearson, Jianping Weng, Wenying Yang, Tao Xu, Kaixin Zhou

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Background: Considerable variability exists in response to metformin with few effective biomarkers to guide the treatment. Here we evaluated whether whole blood derived mitochondrial DNA copy number (mtDNA-CN) is a biomarker of metformin response as measured by glucose reduction or weight loss.

Methods: Using data from the trial of Metformin (n = 304) and AcaRbose (n = 300) in Chinese as the initial Hypoglycaemic treatment (MARCH), we examined the association between mtDNA-CN and two metformin response outcomes of HbA1c reduction and weight loss. The acarbose arm was used as a comparator group. Whole blood mtDNA-CN was estimated by deep whole genome sequencing with adjustments for confounders. Multiple linear regression and repeated measurement analyses were used to evaluate the association between mtDNA-CN and drug response outcomes.

Results: Here we show that glucose reduction is not significantly associated with mtDNA-CN and in either treatment arm. In the metformin arm, each increase of 1 SD in mtDNA-CN is significantly (P = 0.006) associated with a 0.43 kg more weight loss. Repeated measurement analysis shows that after 16 weeks of metformin monotherapy, patients in the top tertile of mtDNA-CN consistently lost 1.21 kg more weight than those in the bottom tertile (P < 0.001). In comparison, mtDNA-CN is not significantly associated with acarbose-induced weight loss.

Conclusions: Patients with higher mtDNA-CN are likely to lose more weight upon metformin treatment, suggesting mtDNA-CN as a potential novel biomarker for more effective weight management in type 2 diabetes.

Original languageEnglish
Article number29
Number of pages6
JournalCommunications Medicine
Publication statusPublished - 18 Feb 2023


  • Mitochondrial genome
  • Predictive markers


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