Insulin Regulates Glycogen Synthesis in Human Endometrial Glands Through Increased GYS2

Abstract

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.

Glycogen metabolism in mink uterine epithelial cells and its regulation by estradiol, progesterone and insulin

“…Detection of INSR in mink uterine GE and LE in vivo (Fig. 3) agrees with findings for horse (53), rat (45,46) and human (42,43,44). Although INSR was not detected in mink uterine stroma, the protein was expressed by the stroma of other species (54,55).…”

“…Because the hormone concentrations used by us were supraphysiological, it is worth noting that many investigators propose that high E 2 and/or P 4 concentrations contribute to insulin resistance and gestational diabetes mellitus (80,81,82). Flannery et al, (42) showed that while insulin increased glycogen content of primary human uterine epithelial cells, the hormone had no effect on the same cell type obtained from women taking oral contraceptives containing E 2 + P 4 . Nevertheless, treatment of GMMe cells with E 2 →P 4 (without insulin) caused a 2-fold increase in Insr expression when compared to cells treated with E 2 , P 4 or as controls (Fig.…”

“…Moreover, glycogen content in response to insulin + E 2 was greater than for insulin alone. Because the uteri of many mammalian species express the insulin receptor (42,43,44,45,46), we hypothesized that E 2 and P 4 interact with insulin to regulate uterine glycogen metabolism in mink, perhaps in a reproductive cycle-dependent pattern. Our objectives were to determine: 1) if mink uterine GE and LE express the insulin receptor protein (INSR) in vivo and if the amount differs between estrus, diapause and pregnancy; 2) if E 2 , P 4 or insulin regulate insulin receptor gene (Insr) expression by GMMe cells; and 3) if E 2 and P 4 act independently of each other and/or interact with insulin to regulate glycogen metabolism by GMMe cells.…”

A Glycolysis-Related Five-Gene Signature Predicts Biochemical Recurrence-Free Survival in Patients With Prostate Adenocarcinoma

“…Some of the 5 genes have been implicated to be involved in cancers, including PCa. GYS2 encodes a protein that catalyzes the rate-limiting step in the synthesis of glycogen (39). It has been reported that GYS2 acted as a tumor suppressor in hepatocellular carcinoma (HCC) (40).…”

The Enigmatic Role of Serum & Glucocorticoid Inducible Kinase 1 in the Endometrium

“…In diabetes mellitus, excessive plasma glucose concentrations can upregulate intestinal SGK1 expression and thus SGK1dependent stimulation of SGLT1, contributing to the maintenance of obesity (Dieter et al, 2004). A number of studies have proposed that abnormal glucose metabolism in the endometrium contributes to the increased risk of adverse pregnancy outcomes (Salker et al, 2017;Flannery et al, 2018;Raglan et al, 2020). It has now been reported, that SGLT1 is indeed expressed in the endometrium and controls glycogen accumulation essential for histiotrophic nutrition in pregnancy (Salker et al, 2017).…”