Insulin Regulates Glycogen Synthesis in Human Endometrial Glands Through Increased GYS2
Open accessAbstract
Context: Glycogen synthesis is a critical metabolic function of the endometrium to prepare for successful implantation and sustain embryo development. Yet, regulation of endometrial carbohydrate metabolism is poorly characterized. Whereas glycogen synthesis is attributed to progesterone, we previously found that the metabolic B isoform of the insulin receptor is maximally expressed in secretory-phase endometrium, indicating a potential role of insulin in glucose metabolism. Objective: We sought to determine whether insulin or progesterone regulates glycogen synthesis in human endometrium. Design, Participants, Outcome Measurements: Endometrial epithelial cells were isolated from 28 healthy women and treated with insulin, medroxyprogesterone (MPA), or vehicle. Intracellular glycogen and the activation of key enzymes were quantified. Results: In epithelia, insulin induced a 4.4-fold increase in glycogen, whereas MPA did not alter glycogen content. Insulin inactivated glycogen synthase (GS) kinase 3α/β (GSK3α/β), relieving inhibition of GS. In a regulatory mechanism, distinct from liver and muscle, insulin also increased GS by 3.7-fold through increased GS 2 (GYS2) gene expression. Conclusions: We demonstrate that insulin, not progesterone, directly regulates glycogen synthesis through canonical acute inactivation of GSK3α/β and noncanonical stimulation of GYS2 transcription. Persistently elevated GS enables endometrium to synthesize glycogen constitutively, independent of short-term nutrient flux, during implantation and early pregnancy. This suggests that insulin plays a key, physiological role in endometrial glucose metabolism and underlines the need to delineate the effect of maternal obesity and hyperinsulinemia on fertility and fetal development.
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Robust evidence demonstrates that estrogen and progesterone have important roles in regulating substrate metabolism.
“Robust evidence exists that demonstrates the important roles estrogen and progesterone have in regulating substrate metabolism [20,24,66,70,80,82,84,154–159].”
From International society of sports nutrition position stand: nutritional concerns of the female athlete (2023) · cites this paper as [82]
In “Insulin, not progestin, regulates glycogen synthesis in primary endometrial cells” (page not provided), the authors suggest that sustained combined estrogen–progestin exposure may reduce insulin-induced glycogen accumulation. That limited, tentative finding does not establish robust, separate roles for estrogen and progesterone in substrate metabolism. The reported results instead show that insulin, not progestin, directly increased glycogen in the endometrial cells studied. (LLM, conf=0.84)
Experimental — accuracy not yet measuredProgesterone affects glucose metabolism through upregulation of GLUT1 expression to increase endometrial glycolytic metabolism, attenuating skeletal and hepatic glycolytic pathways.
“affects glucose metabolism through the upregulation of GLUT1 expression to increase endometrial glycolytic metabolism, attenuating skeletal and hepatic glycolytic pathways [82–85]”
From International society of sports nutrition position stand: nutritional concerns of the female athlete (2023) · cites this paper as [82]
The Abstract and Results address glycogen synthesis, not GLUT1 expression or glycolysis. Searches for GLUT1, glycolysis, and skeletal and hepatic glycolytic pathways found no passage supporting the attributed mechanism. The finding that insulin, rather than progesterone, directly regulates endometrial glycogen synthesis does not resolve the separate claim about glycolysis. (LLM, conf=0.77)
Experimental — accuracy not yet measuredEstrogen, specifically 17β-estradiol, promotes lipolysis and increases fatty acid availability while decreasing the rate of gluconeogenesis with muscle and liver glycogen sparing.
“Estrogen, specifically 17β-estradiol, promotes lipolysis and increases fatty acid availability while decreasing the rate of gluconeogenesis with muscle and liver glycogen sparing.”
From International society of sports nutrition position stand: nutritional concerns of the female athlete (2023) · cites this paper as [82]
The Discussion (page unavailable) describes insulin-regulated glycogen synthesis and glycogenolysis in liver and muscle, but does not link either to estrogen. The passage on combined oral estradiol and progestin concerns glycogen accumulation in endometrial cells. Searches for 17β-estradiol, lipolysis, fatty acid availability, gluconeogenesis, and glycogen sparing found no passage addressing the claimed effects. (LLM, conf=0.75)
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International society of sports nutrition position stand: nutritional concerns of the female athlete
Sims, S. T., Kerksick, C. M., Smith-Ryan, A. E., Janse de Jonge, X. A. K., Hirsch, K. R., Arent, S. M., Hewlings, S. J., Kleiner, S. M., Bustillo, E., Tartar, J. L., et al. (2023) · Journal of the International Society of Sports Nutrition · doi:10.1080/15502783.2023.2204066 · Cited by 91 · see citing works
- Authors
- Flannery, C. A., Choe, G. H., Cooke, K. M., Fleming, A. G., Radford, C. C., Kodaman, P. H., Jurczak, M. J., Kibbey, R. G., & Taylor, H. S.
- Affiliations
- Yale University (US)
- Corresponding author
- Flannery, Clare A
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2018-05-02
- Volume
- 103
- Issue
- 8
- Pages
- 2843-2850
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC6276707
- OpenAlex
- W2800719010
- Cited by
- 29
- References
- 31
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 2 · 2021: 5 · 2020: 1 · 2019: 3
- FWCI
- 0.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Yale University
- National Institutes of Health
- Raymond and Beverly Sackler Institute for Biological, Physical and Engineering Sciences, Yale University
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01DK110181, P30DK045735)
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K08HD071010, L30 HD067000, HD-052668, U54HD052668)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- insulin, glycogen synthesis, endometrium, glycogen synthase, medroxyprogesterone, progesterone, endometrial epithelial cells, glucose metabolism, implantation, pregnancy, maternal obesity, hyperinsulinemia, fertility
- MeSH terms
- Adult, Cells, Cultured, Endometrium, Female, Glucose, Glycogen, Glycogen Synthase, Humans, Hyperinsulinism, Insulin, Medroxyprogesterone, Gene Expression Regulation, Enzymologic, Muscle, Skeletal, Glycogenolysis
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