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

TY - JOUR

T1 - Higher mitochondrial DNA copy number is associated with metformin-induced weight loss

AU - Wang, Jing

AU - Liang, Hua

AU - Huang, Rong

AU - Weng, Xiong

AU - Zheng, Li

AU - Wang, You

AU - Zheng, Xueying

AU - Gu, Zhenglong

AU - Chen, Fei

AU - Shao, Jian

AU - Geng, Zhaoxu

AU - Pearson, Ewan R.

AU - Weng, Jianping

AU - Yang, Wenying

AU - Xu, Tao

AU - Zhou, Kaixin

N1 - Funding Information: This work was supported by the National Key R&D Program of China under Grant No. 2018YFC2001003, Strategic Initiative of the Chinese Academy of Sciences, project XDB38020100, China Postdoctoral Science Foundation-2021M703413 and BX2021342. Copyright: © 2023. The Author(s).

PY - 2023/2/18

Y1 - 2023/2/18

N2 - 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.

AB - 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.

KW - Mitochondrial genome

KW - Predictive markers

U2 - 10.1038/s43856-023-00258-0

DO - 10.1038/s43856-023-00258-0

M3 - Article

C2 - 36806755

SN - 2730-664X

VL - 3

JO - Communications Medicine

JF - Communications Medicine

M1 - 29

ER -