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.
View: Text | PDF
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

×

Figure 4

Glucose tolerance in female β cell GPR54–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Glucose tolerance in female β cell GPR54–/– mice. (A) There was no signi...
(A) There was no significant difference in glucose tolerance between nonpregnant adult female β cell GPR54–/– mice and any of the female control groups (Cre+/TMX–, Cre–/TMX+, and Cre–/TMX–). Similarly, the β cell GPR54–/– mice did not have (B) significantly altered plasma insulin levels, either fasted or after glucose, or (C) any change in insulin resistance when compared to any control group. (D) At day 16 of pregnancy β cell GPR54–/– mice had significantly impaired glucose tolerance at 15 and 30 minutes after glucose administration (2-way repeated-measures ANOVA; 15 minutes P = 0.028; 30 minutes P = 0.014) and (E) glucose AUC over the course of the test when compared with all control groups (1-way ANOVA; 0–120 minutes AUC P = 0.02; 0–60 minutes AUC P = < 0.001). (F) Pregnant β cell GPR54–/– mice did not have significantly altered basal fasting plasma insulin levels at day 16 of pregnancy; however, GPR54 knockdown did result in significantly reduced insulin release in response to i.p. glucose administration (2  g/kg) after 30  minutes when compared with all controls (1-way ANOVA, P = 0.045). (G) Pregnant β cell GPR54–/– mice did not have significantly different insulin sensitivity either at any individual time point or in (H) glucose AUC. Mean ± SEM; n = 7–9 (A–C); n = 7–12 (D–H); *P < 0.05.