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

Authors

  • Gemma Brufau,

    Corresponding author
    1. Departments of Pediatrics , Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
    • Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, Hanzeplein 1, 9713 EZ Groningen, The Netherlands
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    • fax: +31-503611746

  • Frans Stellaard,

    1. Departments of Laboratory Medicine, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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  • Kris Prado,

    1. Kinemed, Inc., Emeryville, CA
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  • Vincent W. Bloks,

    1. Departments of Pediatrics , Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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  • Elles Jonkers,

    1. Departments of Laboratory Medicine, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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  • Renze Boverhof,

    1. Departments of Laboratory Medicine, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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  • Folkert Kuipers,

    1. Departments of Pediatrics , Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
    2. Departments of Laboratory Medicine, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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  • Elizabeth J. Murphy

    1. Kinemed, Inc., Emeryville, CA
    2. Department of Medicine, University of California San Francisco, San Francisco, CA
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  • Potential conflict of interest: Kinemed, Inc., represented in this study by Elizabeth Murphy, is the recipient of a research support from Daiichi Sankyo Inc., in the form of an investigator initiated trial grant to fund this trial. University of Groningen, represented by Folkert Kuipers, received a research grant supported by Daiichi Sankyo to study the effects of colesevelam on bile acid metabolism in mice. Both Dr. Murphy and Kuipers have acted as consultants to Daiichi Sankyo within the past year. Dr. Murphy is no longer a consultant.

  • The goal of this mechanistic study is to evaluate the interaction between differences in glucose control and differences in bile acid kinetics. Data reported here are focused on the underlying physiologic effects of the drug on bile acid kinetics and not on clinical outcomes or treatment for a medical condition.

  • §

    Trial is registered at Clinicaltrials.gov. “Effects of colesevelam on bile acid kinetics” www.clinicaltrials.gov/ct2/show/NCT00476710?term=colesevelam+bile+acids&rank=1

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 = 16) and controls (n = 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;)

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