The Physiological Importance of Bile Acid Structure and Composition on Glucose Homeostasis
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PATHOGENESIS OF TYPE 2 DIABETES AND INSULIN RESISTANCE (ME PATTI, SECTION EDITOR)
The Physiological Importance of Bile Acid Structure and Composition on Glucose Homeostasis Sei Higuchi 1,2
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose of Review Studies have identified several effects of bile acids (BAs) in glucose homeostasis, energy expenditure, and body weight control, through receptor-dependent and independent mechanisms. BAs are produced from cholesterol and characterized by their structures, which result from enzymes in the liver and the gut microbiota. The aim of this review is to characterize the effects of BA structure and composition on diabetes. Recent Findings The hydroxyl groups of BAs interact with binding pockets of receptors and enzymes that affect glucose homeostasis. Human and animal studies show that BA composition is associated with insulin resistance and food intake regulation. Summary The hydroxylation of BAs and BA composition contributes to glucose regulation. Modulation of BA composition has the potential to improve glucose metabolism. Keywords Bile acids . Diabetes . Insulin resistance
Introduction Bile acids (BAs) are molecules that promote the absorption of dietary lipids. Additionally, BAs are suspected to have potential therapeutic effects evidenced by the use of bile from vertebrate animals [1, 2••, 3–7]. Diverse BAs (Table 1) act as a signaling molecule via the BA receptors (TGR5, FXR) and vitamin D receptor (VDR) regulating both glucose and lipid homeostasis. Activation of TGR5 is involved in the regulation of energy expenditure [24], insulin secretion [25, 26], and GLP-1 secretion from enteroendocrine L cells [27–31]. BAs also bind to the nuclear receptor FXR [32–34], which is expressed in the kidneys, liver, and gastrointestinal tract [35–37]. FXR This article is part of the Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance * Sei Higuchi [email protected] 1
Naomi Berrie Diabetes Center and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
2
Russ Berrie Pavilion, Room 315, 1150 St. Nicholas Ave., New York, NY 10032, USA
activation improves hyperglycemia and insulin sensitivity in diabetic rats and mice [10–12, 38]. Considered mechanism are (1) improved IRS-AKT signaling [38], (2) promoted GLP-1 secretion [10], (3) suppressed gluconeogenic genes [11], and (4) decreased adipose differentiation [12]. However, opposing effects using FXR agonists are also reported [2••, 16]; therefore, the effects of FXR on glucose remain under investigation. Studies show that the secondary BA, LCA can activate VDR in the intestine [17, 18]. Direct evidence of LCA-VDR signaling on glucose metabolism has not been demonstrated, but VDR signaling is implicated in glucose metabolism [20, 21]. Based on these effects, BA receptors could be a promising therapeutic target for the treatment of obesity and type 2 diabetes. In addition to the BA receptor– dependent effects, recent studies indicate that B
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