Prolactin-Induced Adaptation in Glucose Homeostasis in Mouse Pregnancy Is Mediated by the Pancreas and Not in the Forebrain.

Sharon R. Ladyman,David R. Grattan,Ilona C. Kokay,Zin Khant Aung

doi:10.3389/fendo.2021.765976

Sharon R. Ladyman, David R. Grattan + Show 2 more

Open Access

https://doi.org/10.3389/fendo.2021.765976

Copy DOI

Abstract

Adaptive changes in glucose homeostasis during pregnancy require proliferation of insulin-secreting beta-cells in the pancreas, together with increased sensitivity for glucose-stimulated insulin secretion. Increased concentrations of maternal prolactin/placental lactogen contribute to these changes, but the site of action remains uncertain. Use of Cre-lox technology has generated pancreas-specific prolactin receptor (Prlr) knockouts that demonstrate the development of a gestational diabetic like state. However, many Cre-lines for the pancreas also express Cre in the hypothalamus and prolactin could act centrally to modulate glucose homeostasis. The aim of the current study was to examine the relative contribution of prolactin action in the pancreas and brain to these pregnancy-induced adaptations in glucose regulation. Deletion of prolactin receptor (Prlr) from the pancreas using Pdx-cre or Rip-cre led to impaired glucose tolerance and increased non-fasting blood glucose levels during pregnancy. Prlrl ox/lox /Pdx-Cre mice also had impaired glucose-stimulated insulin secretion and attenuated pregnancy-induced increase in beta-cell fraction. Varying degrees of Prlr recombination in the hypothalamus with these Cre lines left open the possibility that central actions of prolactin could contribute to the pregnancy-induced changes in glucose homeostasis. Targeted deletion of Prlr specifically from the forebrain, including areas of expression induced by Pdx-Cre and Rip-cre, had no effect on pregnancy-induced adaptations in glucose homeostasis. These data emphasize the pancreas as the direct target of prolactin/placental lactogen action in driving adaptive changes in glucose homeostasis during pregnancy.

Highlights

During pregnancy, glucose regulation undergoes major adaptations to ensure a consistent supply of glucose to the fetus [1]
Pregnant Prlrlox/lox/Rip-Cre mice had impaired glucose tolerance compared to pregnant Prlrlox/lox mice, there was no difference in glucose tolerance between pregnant Prlrlox/lox/Rip-Cre and Rip-Cre mice, suggesting that the Cre, by itself, was having an adverse effect on glucose tolerance in pregnancy (Figures 1D, E)
Day 14 pregnant Prlrlox/lox/Rip-Cre mice (BW taken before fasting for Glucose tolerance tests (GTT)) had significantly lower body weight than Crenegative Prlrlox/lox mice at the same stage of pregnancy (Figure 1F) they had similar weight gain during pregnancy as that seen in controls (Figure 1G)

Summary

Introduction

Glucose regulation undergoes major adaptations to ensure a consistent supply of glucose to the fetus [1]. To establish higher maternal glucose levels and thereby maintain the gradient, many maternal tissues develop a state of relative insulin resistance. To protect the fetus from excessively high glucose levels, such as following a meal, the maternal pancreatic beta-cells develop an increased capacity to respond to acute increases in maternal blood glucose. This adaptive response involves proliferation of the insulin-secreting beta-cells in the pancreas, together with increased sensitivity of glucose-stimulated insulin secretion [2]. Dysfunction of glucose regulation during pregnancy, when beta-cells fail to compensate for the insulin resistance of late pregnancy, leads to gestational diabetes mellitus, which can have long term adverse consequences on the mother and offspring

Objectives

Methods

Results

Conclusion