Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism
✍ Scribed by Gemma Brufau; Frans Stellaard; Kris Prado; Vincent W. Bloks; Elles Jonkers; Renze Boverhof; Folkert Kuipers; Elizabeth J. Murphy
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 402 KB
- Volume
- 52
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Bile acids (BAs) are essential for fat absorption and appear to modulate glucose and energy metabolism. Colesevelam, a BA sequestrant, improves glycemic control in type 2 diabetes mellitus (T2DM). We aimed to characterize the alterations in BA metabolism associated with T2DM and colesevelam treatment and to establish whether metabolic consequences of T2DM and colesevelam are related to changes in BA metabolism. Male subjects with T2DM (n 5 16) and controls (n 5 12) were matched for age and body mass index. BA pool sizes and synthesis/input rates were determined before and after 2 and 8 weeks of colesevelam treatment. T2DM subjects had higher cholic acid (CA) synthesis rate, higher deoxycholic acid (DCA) input rate, and enlarged DCA pool size. Colesevelam resulted in a preferential increase in CA synthesis in both groups. CA pool size was increased whereas chenodeoxycholic acid and DCA pool sizes were decreased upon treatment. Fasting and postprandial fibroblast growth factor 19 (FGF19) levels did not differ between controls and diabetics, but were decreased by treatment in both groups. Colesevelam treatment reduced hemoglobin A1C by 0.7% (P < 0.01) in diabetics. Yet, no relationships between BA kinetic parameters and changes in glucose metabolism were found in T2DM or with colesevelam treatment. Conclusion: Our results reveal significant changes in BA metabolism in T2DM, particularly affecting CA and DCA. Colesevelam treatment reduced FGF19 signaling associated with increased BA synthesis, particularly of CA, and resulted in a more hydrophilic BA pool without altering total BA pool size. However, these changes could not be related to the improved glycemic control in T2DM. (HEPATOLOGY 2010;52:1455-1464) B ile acids (BAs) are amphipathic molecules synthesized from cholesterol in the liver. In addition to the well-established role of BAs in dietary lipid absorption and cholesterol homeostasis, they also act as signaling molecules. BAs activate the nuclear receptor farnesoid X receptor (FXR), act as ligands for the G-protein-coupled bile acid receptor TGR5 and activate mitogen-activated protein kinase pathways. 1 Through activation of these diverse signal-ing pathways, BAs regulate their own enterohepatic circulation at two main sites: in the small intestine via FXR-fibroblast growth factor 19 (FGF19) signaling and in the liver via FXR-short heterodimer partner signaling. Via these pathways, BAs are also thought to contribute to the maintenance of triglyceride, cholesterol, energy, and glucose homeostasis. 1,2 BA sequestrants form nonabsorbable complexes with BAs in the gastrointestinal tract, thereby preventing Abbreviations: BA, bile acid; BMI, body mass index; 13 C-DCA, 24-13 C-deoxycholic acid; CA, cholic acid; CDCA, chenodeoxycholic acid; D 4 -CA, 2,2,4,4-2 H 4cholic acid; D 4 -CDCA, 2,2,4,4-2 H 4 -chenodeoxycholic acid;