Journal Article

Insulin Regulates Glycogen Synthesis in Human Endometrial Glands Through Increased GYS2

Taylor, Hugh S, Choe, Gina H, Radford, Caitlin C, Kodaman, Pinar H, Flannery, Clare A, Fleming, Andrew G, Cooke, Katherine M, Jurczak, Michael J, Kibbey, Richard G

2018

Overview

Abstract 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. We quantified glycogen in human endometrium and found that synthesis was regulated by insulin, not progesterone, through acute deactivation of GSK and increased glycogen synthase expression.

• Publisher: Endocrine Society,Copyright Oxford University Press,Oxford University Press
• Subject: Adult / Carbohydrate metabolism / Cells, Cultured / Clinical s / Deactivation / Embryo / Embryonic development / Endometrium / Endometrium - drug effects / Endometrium - metabolism / Enzymes / Epithelial cells / Female / Fertility / Fetal development / Fetuses / Gene expression / Gene Expression Regulation, Enzymologic - drug effects / Genes / Glands / Glucose / Glucose - metabolism / Glycogen / Glycogen - biosynthesis / Glycogen Synthase - genetics / Glycogen Synthase - metabolism / Glycogen synthase kinase 3 / Glycogen synthesis / Glycogenolysis - drug effects / Health aspects / Humans / Hyperinsulinemia / Hyperinsulinism - metabolism / Implantation / Insulin / Insulin - pharmacology / Kinases / Liver / Medical examination / Medroxyprogesterone / Medroxyprogesterone - pharmacology / Metabolism / Muscle, Skeletal - drug effects / Muscle, Skeletal - metabolism / Obesity / Polysaccharides / Pregnancy / Progesterone / Sex hormones / Transcription / Type 2 diabetes / Women's health