A role for placental kisspeptin in β cell adaptation to pregnancy
James E. Bowe, … , Stephanie A. Amiel, Peter M. Jones
James E. Bowe, … , Stephanie A. Amiel, Peter M. Jones
Published October 17, 2019
Citation Information: JCI Insight. 2019;4(20):e124540. https://doi.org/10.1172/jci.insight.124540.
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Research Article Endocrinology Reproductive biology

A role for placental kisspeptin in β cell adaptation to pregnancy

Abstract

During pregnancy the maternal pancreatic islets of Langerhans undergo adaptive changes to compensate for gestational insulin resistance. Kisspeptin has been shown to stimulate insulin release, through its receptor, GPR54. The placenta releases high levels of kisspeptin into the maternal circulation, suggesting a role in modulating the islet adaptation to pregnancy. In the present study we show that pharmacological blockade of endogenous kisspeptin in pregnant mice resulted in impaired glucose homeostasis. This glucose intolerance was due to a reduced insulin response to glucose as opposed to any effect on insulin sensitivity. A β cell–specific GPR54-knockdown mouse line was found to exhibit glucose intolerance during pregnancy, with no phenotype observed outside of pregnancy. Furthermore, in pregnant women circulating kisspeptin levels significantly correlated with insulin responses to oral glucose challenge and were significantly lower in women with gestational diabetes (GDM) compared with those without GDM. Thus, kisspeptin represents a placental signal that plays a physiological role in the islet adaptation to pregnancy, maintaining maternal glucose homeostasis by acting through the β cell GPR54 receptor. Our data suggest reduced placental kisspeptin production, with consequent impaired kisspeptin-dependent β cell compensation, may be a factor in the development of GDM in humans.

Authors

James E. Bowe, Thomas G. Hill, Katharine F. Hunt, Lorna I.F. Smith, Sian J.S. Simpson, Stephanie A. Amiel, Peter M. Jones

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Figure 2

Effects of kisspeptin-234 on glucose homeostasis during pregnancy in mice.

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Effects of kisspeptin-234 on glucose homeostasis during pregnancy in mic...
(A) At day 10 of pregnancy chronic kisspeptin-234 (KP-234) administration had no significant effect on glucose tolerance; however, at day 16 of pregnancy mice treated with KP-234 had significantly impaired glucose tolerance following i.p. glucose administration (2  g/kg) when compared with untreated pregnant controls, as determined by both comparison of individual time points (2-way repeated-measures ANOVA; 60 minutes P = 0.022; 90 minutes P = 0.046) and (B) glucose AUC over the course of the test (1-way ANOVA, P = 0.031). (C) Blocking endogenous kisspeptin signaling with KP-234 did not have any effect on fasting plasma insulin levels at either day 10 or day 16 of pregnancy. At day 16 chronic KP-234 treatment resulted in significantly reduced insulin release in response to i.p. glucose administration (2  g/kg) after 30  minutes when compared with pregnant controls (1-way ANOVA, P = 0.009). A similar trend was observed at day 10; however, this was not significant. (D) KP-234 had no effect on the plasma glucose response to i.p. insulin administration (0.75  IU/kg) when compared to untreated controls at either day 12 or day 18 or pregnancy, through both comparison of individual time points and (E) glucose AUC. Mean ± SEM; n = 6; *P < 0.05 vs. control.