Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism

Abstract

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

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

“…This may suggest that individual bile acids respond differently to BAS but also that the percentage contribution of newly synthesised cholesterol to CA vs CDCA may not depend on the total bile acid production rate. As shown previously [12], colesevelam treatment significantly reduced FGF-19 concentrations in both the fasting and the postprandial states. We also found that fasting and postprandial FGF-19 concentrations were negatively correlated with CDCA and CA synthesis in type 2 diabetes before treatment.…”

“…We also found that fasting and postprandial FGF-19 concentrations were negatively correlated with CDCA and CA synthesis in type 2 diabetes before treatment. Studies in healthy participants have suggested that BA synthesis is regulated in part by FGF-19 [12,48], but a similar relationship in type 2 diabetes was not seen in a previous study [12]. FGF-19 has been shown to inhibit fatty acid synthesis in cultured hepatocytes [49] and bile acid sequestration in diabetic db/db mice resulted in an increase in DNL [3].…”

“…Colesevelam increased the fractional synthesis of CDCA and CA from newly synthesised cholesterol, although the main source for CA and CDCA remained pre-formed cholesterol. While it has been shown by others [12,47] that increases in total BA synthesis for CA are greater than for CDCA, new cholesterol contributed more to the fractional synthesis of CDCA than to CA after colesevelam treatment. This may suggest that individual bile acids respond differently to BAS but also that the percentage contribution of newly synthesised cholesterol to CA vs CDCA may not depend on the total bile acid production rate.…”

“…It is not clear how BAS increase incretin secretion. It is possible that changes in the composition of the bile-acid pool or a change to a more hydrophilic bile acid pool with colesevelam [12] are involved in its incretinincreasing effect.…”

“…Alternatively, BAS might promote secretion of glucagonlike peptide 1 (GLP-1) [9] and increase energy expenditure [10] via TGR5 activation. There are no data supporting these hypotheses in humans and despite a consistent glucose lowering effect, existing data suggest no change in insulin sensitivity [11] with BAS, no association between glycaemic control and bile acid metabolism [12] and no association between bile acids and energy expenditure in humans [13]. Accordingly, the primary objective of this study was to elucidate the mechanisms of glucose lowering by colesevelam through in-depth examination of glucose metabolic pathways in people with type 2 diabetes.…”