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ResearchIn-Press PreviewEndocrinologyMetabolismReproductive biology Open Access | 10.1172/JCI197311

Insulin resistance is associated with mammary mitochondrial dysfunction at the onset of human lactation

Xin Meng,1 Taha Elajnaf,1 Hussam Rostom,1 Michelle Ma,1 Annalee Furst,2 Bryony R. Davies,1 Isabella R. Honess,1 Gaurav Pandey,2 Isadora C. Furigo,3 Craig L. Doig,4 Jayne F. Martin Carli,5 Rajesh V. Thakker,6 Lars Bode,2 Kelsey E. Johnson,7 and Fadil M. Hannan1

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Meng, X. in: PubMed | Google Scholar

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Elajnaf, T. in: PubMed | Google Scholar

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Rostom, H. in: PubMed | Google Scholar

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Ma, M. in: PubMed | Google Scholar

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Furst, A. in: PubMed | Google Scholar

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Davies, B. in: PubMed | Google Scholar

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Honess, I. in: PubMed | Google Scholar

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Pandey, G. in: PubMed | Google Scholar

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Furigo, I. in: PubMed | Google Scholar

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Doig, C. in: PubMed | Google Scholar

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Martin Carli, J. in: PubMed | Google Scholar

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Thakker, R. in: PubMed | Google Scholar |

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Bode, L. in: PubMed | Google Scholar

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Johnson, K. in: PubMed | Google Scholar

1Larsson-Rosenquist Foundation Oxford Centre for the Endocrinology of Human, University of Oxford, Oxford, United Kingdom

2Department of Pediatrics, University of California San Diego, La Jolla, United States of America

3Center for Discoveries in Life Sciences (DLS), Coventry University, Coventry, United Kingdom

4Centre for Systems Health and integrated Metabolic Research (SHiMR), Depart, Nottingham Trent University, Nottingham, United Kingdom

5Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, United States of America

6Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

7Center for Genetic Epidemiology, University of Southern California, Los Angeles, United States of America

Find articles by Hannan, F. in: PubMed | Google Scholar

Published August 13, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI197311.
Copyright © 2026, Meng et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 13, 2026 - Version history
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Abstract

Insulin resistance (IR) has emerged as a risk factor for lactation insufficiency and delays the onset of milk secretion after childbirth, termed secretory activation (SA). This may cause inadequate infant weight gain and early breastfeeding cessation. However, the mechanisms underlying delayed SA in insulin resistant women are unknown. To investigate this, we characterized the mammary transcriptomes and IR-related hormones of 75 breastfeeding women with healthy term infants during postpartum days 1-5. Participants were divided into IR tertiles based on plasma leptin-to-adiponectin ratio measurements. Those in the highest tertile had later SA onset with greater neonatal weight loss during postpartum days 1-5. Transcriptomic analysis on postpartum day 2 (n=4 high IR vs. n=8 low IR participants) showed transient suppression of mammary insulin and prolactin signaling genes, increased pro-inflammatory gene expression and altered expression of >200 mammary mitochondrial genes. These alterations were absent on postpartum days 3-5. Cultured mammary epithelial cells (MECs) treated with insulin showed upregulation of prolactin signaling and oxidative phosphorylation (OXPHOS) genes, with imaging and bioenergetic studies demonstrating that insulin promotes mitochondrial biogenesis and OXPHOS. Thus, our findings delineate roles for insulin in mammary bioenergetics and highlight mitochondrial dysfunction as a mechanism for delayed SA in insulin resistant women.

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Version history
  • Version 1 (August 13, 2026): In-Press Preview
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