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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

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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 1

In vivo effects of chronic kisspeptin administration on glucose homeostasis in nonpregnant mice.

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In vivo effects of chronic kisspeptin administration on glucose homeosta...
(A) In nonpregnant female ICR mice, chronic subcutaneous administration of kisspeptin resulted in improved glucose tolerance after intraperitoneal (i.p.) glucose administration (2 g/kg) when compared with untreated controls (2-way repeated-measures ANOVA, 15 minutes P < 0.001). (B) There was no significant difference in overall 120 minutes area under the curve (AUC), but kisspeptin treatment did result in a significant reduction in glucose AUC over 0–60 minutes (2-tailed Student’s t test, P = 0.0321). (C) Although chronic kisspeptin treatment had no significant effect on fasting plasma insulin levels, kisspeptin-treated animals had significantly increased insulin release in response to i.p. glucose administration (2  g/kg) after 30  minutes when compared with controls (1-way ANOVA, P = 0.033). (D) Kisspeptin had no effect on the plasma glucose response to i.p. insulin administration (0.75  IU/kg) when compared to controls, through comparison of both individual time points and (E) glucose AUC. Mean ± SEM, n = 11–12, and *P < 0.05 vs. control.

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