Abstract
Bile acids are important endocrine signalling molecules, modulating glucose homeostasis through activation of cell surface and nuclear receptors. Bile acid metabolism is altered in type 2 diabetes mellitus; however, whether this is of pathogenic consequence is not fully established. In this study urinary bile acid excretion in individuals with type 2 diabetes and matched healthy volunteers was assessed. Urinary bile acid excretion in type 2 diabetes patients was considered in the context of prevailing glycaemia and the patient body mass index. Urine bile acids were measured by liquid chromatography-tandem mass spectrometry, allowing individual quantification of 15 bile acid species. Urinary bile acid excretion in patients with type 2 diabetes who were normal weight (BMI 18.5–24.9 kg/m2) and overweight (BMI 25–29.9 kg/m2) were elevated compared to healthy normal weight volunteers, both p<0.0001. In obese (BMI≥30 kg/m2) type 2 diabetes patients, urinary bile acid excretion was significantly lower than in the normal and overweight type 2 diabetes groups (both p<0.01). Total bile acid excretion positively correlated with HbA1c in normal (rs = 0.85, p = <0.001) and overweight (rs = 0.61, p = 0.02) but not obese type 2 diabetes patients (rs = −0.08, p = 0.73). The glycaemia-associated increases in urine bile acid excretion in normal weight and overweight type 2 diabetes seen in this study may represent compensatory increases in bile acid signalling to maintain glucose homeostasis. As such alterations appear blunted by obesity; further investigation of weight-dependent effects of bile acid signalling on type 2 diabetes pathogenesis is warranted.
Highlights
Bile acids are important endocrine molecules, initiating signalling by the nuclear farnesoid X receptor (FXR) and Gprotein coupled receptor, TGR5 [1]
In this study we demonstrate that urinary bile acid excretion is increased in type 2 diabetes mellitus compared to healthy controls, and that this increase is most evident in normal weight and overweight type 2 diabetic patients
Despite the study groups being relatively small, we clearly show that urinary bile acids are related to glycaemia, reflected by HbA1c, in normal weight and overweight, but not obese type 2 diabetic patients
Summary
Bile acids are important endocrine molecules, initiating signalling by the nuclear farnesoid X receptor (FXR) and Gprotein coupled receptor, TGR5 [1]. Bile acid signalling exerts diverse influence over glucose, lipid and energy homeostasis, functions additional to the classical role of bile acids in lipid solubilisation and absorption in the intestine [2]. In the L-cells of the intestinal epithelium, TGR5 activation by bile acids stimulates the release of gut hormones such as glucagonlike peptide-1 (GLP-1) [3], resulting in improved glucose homeostasis [4]. Bile acid concentrations rise rapidly in response to glucose ingestion, which likely underpins many of the mechanisms by which bile acids play a role in regulation of the body’s response to food intake [5]. Glucose itself stimulates expression of cholesterol 7ahydroxylase, which catalyses the rate-limiting step in bile acid production [8,9]
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