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


CONCLUSIONS
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.
Brufau
Gemma
G
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. g.brufau.dones@med.umcg.nl
Stellaard
Frans
F
Prado
Kris
K
Bloks
Vincent W
VW
Jonkers
Elles
E
Boverhof
Renze
R
Kuipers
Folkert
F
Murphy
Elizabeth J
EJ
D000328:Adult; D000499:Allylamine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001647:Bile Acids and Salts / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism*; D019826:Cholic Acid / Q000378:metabolism; D000069472:Colesevelam Hydrochloride; D003840:Deoxycholic Acid / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction / Q000187:drug effects
D000499:Allylamine; D001647:Bile Acids and Salts; D001786:Blood Glucose; D019826:Cholic Acid; D000069472:Colesevelam Hydrochloride; D003840:Deoxycholic Acid; D005346:Fibroblast Growth Factors; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; C117476:FGF19 protein, human