Insulin Regulates Glycogen Synthesis in Human Endometrial Glands through Increased GYS2.

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Insulin Regulates Glycogen Synthesis in Human Endometrial Glands through Increased GYS2.

J Clin Endocrinol Metab. 2018 May 02;:

Authors: Flannery CA, Choe GH, Fleming AG, Cooke KM, Radford CC, Kodaman PH, Jurczak MJ, Kibbey RG, Taylor HS

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. While glycogen synthesis is attributed to progesterone, we previously found that the metabolic B isoform of 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, Methods: 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 kinase 3α/β (GSK3α/β), relieving inhibition of glycogen synthase (GS). In a novel regulatory mechanism, distinct from liver and muscle, insulin also increased GS by 3.7-fold through increased GYS2 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 constitutively synthesize glycogen, independent of short-term nutrient flux, during implantation and early pregnancy. This suggests 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.

PMID: 29726999 [PubMed - as supplied by publisher]

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