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 3

Effects of β cell GPR54 deletion on islet function in vitro.

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Effects of β cell GPR54 deletion on islet function in vitro. (A) There w...
(A) There were no significant differences in islet insulin content between β cell GPR54–/– mice and any control groups (Cre+/TMX–, Cre–/TMX+, and Cre–/TMX–). Mean ± SEM, n = 9. (B) In static incubation experiments there was no significant difference in the insulin secretory response to physiological glucose concentrations between β cell GPR54–/– and Cre+/TMX– islets. (C) In perifusion experiments there was no significant difference in basal insulin secretion at 2 mM glucose or first- or second-phase insulin secretion in response to 20 mM glucose in β cell GPR54–/– compared to Cre+/TMX– islets. Exposure of Cre+/TMX– islets to kisspeptin (1 μM, 30–50 minutes) resulted in a sustained enhancement of second-phase insulin secretion for the duration of kisspeptin administration. However, in β cell GPR54–/– islets this response was transient and not maintained beyond 10 minutes as determined by comparison of individual time points and (D) AUC over 10-minute phases of the perifusion (2-tailed Student’s t test; KP — prolonged response; P = 0.007). Mean ± SEM; n = 8 (A); n = 7–8 (B); n = 4 (C and D); data representative of experiments conducted 2–3 times; *P < 0.05.