Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis

Elena Bellafante; Saraid Mcilvride; Vanya Nikolova; Hei Man  Fan; Luiza Borges Manna; Jenny Chambers; Mavis MacHirori; Anita Banerjee; Kevin Murphy; Marcus G Martineau; Kristina Schoonjans; Hanns-Ulrich Marschall; Peter Jones; Catherine Williamson

Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis

Elena Bellafante, Saraid Mcilvride, Vanya Nikolova, Hei Man Fan, Luiza Borges Manna, Jenny Chambers, Mavis MacHirori, Anita Banerjee, Kevin Murphy, Marcus G Martineau, Kristina Schoonjans, Hanns-Ulrich Marschall, Peter Jones, Catherine Williamson

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Abstract

Women with intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by raised serum bile acids, are at increased risk of developing gestational diabetes mellitus (GDM) and have impaired glucose tolerance whilst cholestatic. FXR and TGR5 are modulators of glucose metabolism, and FXR activity is reduced in normal pregnancy, and further in ICP. We aimed to investigate the role of raised serum bile acids, FXR and TGR5 in gestational glucose metabolism using mouse models. Cholic acid feeding resulted in reduced pancreatic β-cell proliferation and increased apoptosis in pregnancy, without altering insulin sensitivity, suggesting that raised bile acids affect β-cell mass but are insufficient to impair glucose tolerance. Conversely, pregnant Fxr-/- and Tgr5-/- mice are glucose intolerant and have reduced insulin secretion in response to glucose challenge, and Fxr-/- mice are also insulin resistant. Furthermore, fecal bile acids are reduced in pregnant Fxr-/- mice. Lithocholic acid and deoxycholic acid, the principal ligands for TGR5, are decreased in particular. Therefore, we propose that raised serum bile acids and reduced FXR and TGR5 activity contribute to the altered glucose metabolism observed in ICP.

Original language	English
Journal	Scientific Reports
Publication status	Accepted/In press - 28 May 2020

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@article{3e22c11b198e43148fae984cc0df980e,

title = "Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis",

abstract = "Women with intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by raised serum bile acids, are at increased risk of developing gestational diabetes mellitus (GDM) and have impaired glucose tolerance whilst cholestatic. FXR and TGR5 are modulators of glucose metabolism, and FXR activity is reduced in normal pregnancy, and further in ICP. We aimed to investigate the role of raised serum bile acids, FXR and TGR5 in gestational glucose metabolism using mouse models. Cholic acid feeding resulted in reduced pancreatic β-cell proliferation and increased apoptosis in pregnancy, without altering insulin sensitivity, suggesting that raised bile acids affect β-cell mass but are insufficient to impair glucose tolerance. Conversely, pregnant Fxr-/- and Tgr5-/- mice are glucose intolerant and have reduced insulin secretion in response to glucose challenge, and Fxr-/- mice are also insulin resistant. Furthermore, fecal bile acids are reduced in pregnant Fxr-/- mice. Lithocholic acid and deoxycholic acid, the principal ligands for TGR5, are decreased in particular. Therefore, we propose that raised serum bile acids and reduced FXR and TGR5 activity contribute to the altered glucose metabolism observed in ICP. ",

author = "Elena Bellafante and Saraid Mcilvride and Vanya Nikolova and Fan, {Hei Man} and {Borges Manna}, Luiza and Jenny Chambers and Mavis MacHirori and Anita Banerjee and Kevin Murphy and Martineau, {Marcus G} and Kristina Schoonjans and Hanns-Ulrich Marschall and Peter Jones and Catherine Williamson",

year = "2020",

month = may,

day = "28",

language = "English",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis

AU - Bellafante, Elena

AU - Mcilvride, Saraid

AU - Nikolova, Vanya

AU - Fan, Hei Man

AU - Borges Manna, Luiza

AU - Chambers, Jenny

AU - MacHirori, Mavis

AU - Banerjee, Anita

AU - Murphy, Kevin

AU - Martineau, Marcus G

AU - Schoonjans, Kristina

AU - Marschall, Hanns-Ulrich

AU - Jones, Peter

AU - Williamson, Catherine

PY - 2020/5/28

Y1 - 2020/5/28

N2 - Women with intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by raised serum bile acids, are at increased risk of developing gestational diabetes mellitus (GDM) and have impaired glucose tolerance whilst cholestatic. FXR and TGR5 are modulators of glucose metabolism, and FXR activity is reduced in normal pregnancy, and further in ICP. We aimed to investigate the role of raised serum bile acids, FXR and TGR5 in gestational glucose metabolism using mouse models. Cholic acid feeding resulted in reduced pancreatic β-cell proliferation and increased apoptosis in pregnancy, without altering insulin sensitivity, suggesting that raised bile acids affect β-cell mass but are insufficient to impair glucose tolerance. Conversely, pregnant Fxr-/- and Tgr5-/- mice are glucose intolerant and have reduced insulin secretion in response to glucose challenge, and Fxr-/- mice are also insulin resistant. Furthermore, fecal bile acids are reduced in pregnant Fxr-/- mice. Lithocholic acid and deoxycholic acid, the principal ligands for TGR5, are decreased in particular. Therefore, we propose that raised serum bile acids and reduced FXR and TGR5 activity contribute to the altered glucose metabolism observed in ICP.

AB - Women with intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by raised serum bile acids, are at increased risk of developing gestational diabetes mellitus (GDM) and have impaired glucose tolerance whilst cholestatic. FXR and TGR5 are modulators of glucose metabolism, and FXR activity is reduced in normal pregnancy, and further in ICP. We aimed to investigate the role of raised serum bile acids, FXR and TGR5 in gestational glucose metabolism using mouse models. Cholic acid feeding resulted in reduced pancreatic β-cell proliferation and increased apoptosis in pregnancy, without altering insulin sensitivity, suggesting that raised bile acids affect β-cell mass but are insufficient to impair glucose tolerance. Conversely, pregnant Fxr-/- and Tgr5-/- mice are glucose intolerant and have reduced insulin secretion in response to glucose challenge, and Fxr-/- mice are also insulin resistant. Furthermore, fecal bile acids are reduced in pregnant Fxr-/- mice. Lithocholic acid and deoxycholic acid, the principal ligands for TGR5, are decreased in particular. Therefore, we propose that raised serum bile acids and reduced FXR and TGR5 activity contribute to the altered glucose metabolism observed in ICP.

M3 - Article

SN - 2045-2322

JO - Scientific Reports

JF - Scientific Reports

ER -

Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis

Abstract

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