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A role for placental kisspeptin in ? 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 ? 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 ? cell GPR54 receptor. Our data suggest reduced placental kisspeptin production, with consequent impaired kisspeptin-dependent ? cell compensation, may be a factor in the development of GDM in humans.

SUBMITTER: Bowe JE

PROVIDER: S-EPMC6824306 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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A role for placental kisspeptin in β cell adaptation to pregnancy.

Bowe James E JE Hill Thomas G TG Hunt Katharine F KF Smith Lorna If LI Simpson Sian Js SJ Amiel Stephanie A SA Jones Peter M PM

JCI insight 20191017 20

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 ho ...[more]

PMID: 31619585

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Project description:BackgroundMaintenance of a normal fetal nutrient supply requires major adaptations in maternal metabolic physiology, including of the islet beta-cell. The role of lipid signaling processes in the mechanisms of islet beta-cell adaptation to pregnancy has been minimally investigated.ObjectiveTo determine the effects of pregnancy on islet fatty acid (FA) metabolic partitioning and FA augmentation of glucose-stimulated insulin secretion (GSIS).MethodsAge matched virgin, early pregnant (gestational day-11, G11) and late pregnant (G19) Sprague-Dawley rats were studied. Fasted and fed state biochemistry, oral glucose tolerance tests (OGTT), and fasted and post-OGTT liver glycogen, were determined to assess in vivo metabolic characteristics. In isolated islets, FA (BSA-bound palmitate 0.25 mmol/l) augmentation of GSIS, FA partitioning into esterification and oxidation processes using metabolic tracer techniques, lipolysis by glycerol release, triacylglycerols (TG) content, and the expression of key beta-cell genes were determined.ResultsPlasma glucose in pregnancy was lower, including during the OGTT (glucose area under the curve 0-120 min (AUC0-120); 655±24 versus 849±13 mmol.l-1.min; G19 vs virgin; P<0.0001), with plasma insulin concentrations equivalent to those of virgin rats (insulin AUC0-120; 97±7 versus 83±7 ng.ml-1.min; G19 vs virgin; not significant). Liver glycogen was depleted in fasted G19 rats with full recovery after oral glucose. Serum TG increased during pregnancy (4.4±0.4, 6.7±0.5; 17.1±1.5 mmol/l; virgin, G11, G19, P<0.0001), and islet TG content decreased (147±42, 172±27, 73±13 ng/µg protein; virgin, G11, G19; P<0.01). GSIS in isolated islets was increased in G19 compared to virgin rats, and this effect was augmented in the presence of FA. FA esterification into phospholipids, monoacylglycerols and TG were increased, whereas FA oxidation was reduced, in islets of pregnant compared to virgin rats, with variable effects on lipolysis dependent on gestational age. Expression of Ppargc1a, a key regulator of mitochondrial metabolism, was reduced by 51% in G11 and 64% in G19 pregnant rat islets compared to virgin rat islets (P<0.001).ConclusionA lowered set-point for islet and hepatic glucose homeostasis in the pregnant rat has been confirmed. Islet adaptation to pregnancy includes increased FA esterification, reduced FA oxidation, and enhanced FA augmentation of glucose-stimulated insulin secretion.

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A role for placental kisspeptin in ? cell adaptation to pregnancy.

Publications

A role for placental kisspeptin in β cell adaptation to pregnancy.

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