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 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.

Sulfated Progesterone Metabolites That Enhance Insulin Secretion via TRPM3 Are Reduced in Serum From Women With Gestational Diabetes Mellitus

“…PMΔ5S-induced calcium signals (32), further supporting our results. It is intriguing that a previous study of pregnant Tgr5 -/and Fxr -/mice demonstrated impaired insulin release in vivo, whereas the ex vivo islet studies reported in this manuscript did not show impaired insulin secretion (12). It is possible that there are whole-body differences and compensatory mechanisms in the Tgr5 -/and Fxr -/mice that are not replicated using direct islet stimulations.…”

“…Some progesterone sulfates bind receptors that influence lipid, glucose, and bile acid metabolism. The progesterone sulfate 5β-pregnan-3α-20α-diol-sulfate (pregnanediol sulfate [PM3S]) activates the G-protein–coupled bile acid receptor 1 (GPBAR1, or TGR5) ( 11 ), and 5α-pregnan-3β-ol-20-one-sulfate (epiallopregnanolone sulfate [PM5S]) is a partial agonist for the bile acid receptor farnesoid X receptor (FXR) ( 10 ); this may be of relevance to the etiology of GDM, as Fxr −/− and Tgr5 −/− mice have impaired glucose tolerance in pregnancy ( 12 ). Another cholesterol-based sulfated endogenous neurosteroid, 5-pregnen-3β-ol-20-one-sulfate (pregnenolone sulfate [PMΔ5S]), is a well-established modulator of receptors and channels such as transient receptor potential cation channel subfamily M member 3 (TRPM3).…”

ENDOCRINOLOGY IN PREGNANCY: Metabolic impact of bile acids in gestation

“…Since both receptors play a role in regulation of glucose homeostasis, changes to normal receptor function are also likely to affect glucose metabolism. Consistent with this, mice deficient of FXR or TGR5 develop gestational impaired glucose tolerance, and FXR -/mice have insulin resistance in pregnancy (135). It is plausible both FXR and TGR5 could contribute to the pathophysiology of GDM and could be the link between the increased risk of developing GDM in ICP women.…”

Proteomic Biomarkers of Intrahepatic Cholestasis of Pregnancy

“…The bile acid receptors FXR and TGR5 are involved in glucose homeostasis. Decreased activity of these receptors and elevated levels of circulating bile acid may contribute to altered glucose metabolism in pregnant women with ICP [ 21 ]. Studies showed that bile acids recognized with G protein-coupled bile acid receptor 1 could induce NF-κB pathway activation, consequently upregulated inflammatory genes in trophoblasts, leading to inflammation and aberrant leukocyte infiltration in placenta [ 22 ].…”