title: Bile acid sequestration reduces plasma glucose levels in db/db mice by increasing its metabolic clearance rate.
abstract: OBJECTIVE
  Bile acid sequestrants (BAS) reduce plasma glucose levels in type II diabetics and in murine models of diabetes but the mechanism herein is unknown. We hypothesized that sequestrant-induced changes in hepatic glucose metabolism would underlie reduced plasma glucose levels. Therefore, in vivo glucose metabolism was assessed in db/db mice on and off BAS using tracer methodology.
  
  
  METHODS
  Lean and diabetic db/db mice were treated with 2% (wt/wt in diet) Colesevelam HCl (BAS) for 2 weeks. Parameters of in vivo glucose metabolism were assessed by infusing [U-(13)C]-glucose, [2-(13)C]-glycerol, [1-(2)H]-galactose and paracetamol for 6 hours, followed by mass isotopologue distribution analysis, and related to metabolic parameters as well as gene expression patterns.
  
  
  RESULTS
  Compared to lean mice, db/db mice displayed an almost 3-fold lower metabolic clearance rate of glucose (p = 0.0001), a ∼300% increased glucokinase flux (p = 0.001) and a ∼200% increased total hepatic glucose production rate (p = 0.0002). BAS treatment increased glucose metabolic clearance rate by ∼37% but had no effects on glucokinase flux nor total hepatic or endogenous glucose production. Strikingly, BAS-treated db/db mice displayed reduced long-chain acylcarnitine content in skeletal muscle (p = 0.0317) but not in liver (p = 0.189). Unexpectedly, BAS treatment increased hepatic FGF21 mRNA expression 2-fold in lean mice (p = 0.030) and 3-fold in db/db mice (p = 0.002).
  
  
  CONCLUSIONS
  BAS induced plasma glucose lowering in db/db mice by increasing metabolic clearance rate of glucose in peripheral tissues, which coincided with decreased skeletal muscle long-chain acylcarnitine content.
authors.affiliation: Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. meissner.maxi@gmail.com
authors.forename: Maxi
authors.initials: M
authors.lastname: Meissner
authors.forename: Hilde
authors.initials: H
authors.lastname: Herrema
authors.forename: Theo H
authors.initials: TH
authors.lastname: van Dijk
authors.forename: Albert
authors.initials: A
authors.lastname: Gerding
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.forename: Theo
authors.initials: T
authors.lastname: Boer
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: Reijngoud
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism* / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002247:Carbon Isotopes / Q000378:metabolism / Q000493:pharmacokinetics; D002331:Carnitine / Q000031:analogs & derivatives / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005947:Glucose / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D001786:Blood Glucose; D002247:Carbon Isotopes; C116917:acylcarnitine; D005947:Glucose; D002331:Carnitine
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