Connors-BRI Symposium

Incorporating Sex as Biologic Variable to Advance Health

May 24, 2021 | 3-5PM

Virtual Event

Nida Haider, PhD

Joslin Diabetes Center, Harvard Medical School
Integrative Physiology and Metabolism


Insulin resistance in muscle precedes and predicts type 2 diabetes in offspring of diabetic parents and is also observed in ~25% of the general population. However, whether these changes represent cell autonomous defects or are secondary to changes in circulating factors is unclear. The aim of this study was to uncover the cell autonomous determinants of insulin resistance on cellular signaling using human induced pluripotent stem cell-derived myoblasts (iMyos). We have utilized iMyos from 10 insulin sensitive and 10 insulin resistant non-diabetic individuals as assessed using the steady-state plasma glucose approach. Here, we show that iMyos from insulin resistant non-diabetic individuals show defective insulin-stimulated glucose uptake as compared to insulin sensitive individuals. Global phosphoproteomics uncovered a large network of altered protein phosphorylations in insulin resistance, most outside the canonical insulin-signaling cascade. In addition to these insulin resistance-related changes, perhaps the most striking finding of this study are the unexpected differences in protein phosphorylation in cells from male versus female donors. Indeed, we identified a comprehensive network of 3,420 phosphosites in 1,143 unique proteins, with almost 2,000 phosphosites showing higher phosphorylation in males as compared to females and another over 1,450 sites, which showed the opposite pattern. Analysis of the proteins involved in these differences reveals that male cells show enhanced phosphorylation of proteins associated with transcription, Rho GTPases, SUMOylation, mRNA splicing, and membrane trafficking, while the female dominance includes proteins involved in cell cycle, chromatin organization, gene expression, Rho GTPase cycle, and protein ubiquitination. The sexually dimorphic protein phosphorylation pattern observed may be linked to several potential upstream regulators under investigation, such as the sex hormone dependent epigenetic modifications. Further studies will be needed to explore how this sexually dimorphic nature of the phosphoproteome impacts normal physiology and the risk of different metabolic diseases between males and females.


3PM – Welcome Remarks
3:05PM – Keynote Address
3:45PM – Featured Short Talks
4:20PM – Lightning Talks
4:50PM – Closing Remarks

Keynote Speaker

Janine Austin Clayton, MD

Janine Austin Clayton, M.D., Associate Director for Research on Women’s Health and Director of the Office of Research on Women’s Health (ORWH) at the National Institutes of Health (NIH), is the architect of the NIH policy requiring scientists to consider sex as a biological variable across the research spectrum. This policy is part of NIH’s initiative to enhance reproducibility through rigor and transparency. As co-chair of the NIH Working Group on Women in Biomedical Careers with NIH Director Dr. Francis Collins, Dr. Clayton also leads NIH’s efforts to advance women in science careers.

Prior to joining the ORWH, Dr. Clayton was the Deputy Clinical Director of the National Eye Institute (NEI) for seven years. A board-certified ophthalmologist, Dr. Clayton’s research interests include autoimmune ocular diseases and the role of sex and gender in health and disease. She is the author of more than 120 scientific publications, journal articles, and book chapters.
Dr. Clayton, a native Washingtonian, received her undergraduate degree with honors from Johns Hopkins University and her medical degree from Howard University College of Medicine. She completed a residency in ophthalmology at the Medical College of Virginia. Dr. Clayton completed fellowship training in cornea and external disease at the Wilmer Eye Institute at Johns Hopkins Hospital and in uveitis and ocular immunology at NEI.

Dr. Clayton has received numerous awards, including the Senior Achievement Award from the Board of Trustees of the American Academy of Ophthalmology in 2008 and the European Uveitis Patient Interest Association Clinical Uveitis Research Award in 2010. She was selected as a 2010 Silver Fellow by the Association for Research in Vision and Ophthalmology. In 2015, she was awarded the American Medical Women’s Association Lila A. Wallis Women’s Health Award and the Wenger Award for Excellence in Public Service. Dr. Clayton was granted the Bernadine Healy Award for Visionary Leadership in Women’s Health in 2016. She was also selected as an honoree for the Woman’s Day Red Dress Awards and the American Medical Association’s Dr. Nathan Davis Awards for Outstanding Government Service in 2017.