Bile Acid Sequestration Reduces Plasma Glucose Levels in db/db Mice by Increasing Its Metabolic Clearance Rate

M. Meissner, H.J. Herrema, Th. van Dijk, A. Gerding, R. Havinga, T. Boer, M.R. Müller, D.J. Reijngoud, A.K. Groen, F. Kuipers

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Scopus)

Abstract

Aims/Hypothesis: 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-C-13]- glucose, [2-C-13]- glycerol, [1-H-2]- 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 similar to 300% increased glucokinase flux (p = 0.001) and a similar to 200% increased total hepatic glucose production rate (p = 0.0002). BAS treatment increased glucose metabolic clearance rate by similar to 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/Interpretation: 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.
Original languageEnglish
Article numbere24564
JournalPLoS ONE
Volume6
Issue number11
DOIs
Publication statusPublished - 2011

Keywords

  • farnesoid-x-receptor
  • type-2 diabetes-mellitus
  • peripheral insulin sensitivity
  • colesevelam hydrochloride
  • nuclear receptor
  • glycemic control
  • carbohydrate-metabolism
  • double-blind
  • fatty-acids
  • ob/ob mice

Fingerprint Dive into the research topics of 'Bile Acid Sequestration Reduces Plasma Glucose Levels in db/db Mice by Increasing Its Metabolic Clearance Rate'. Together they form a unique fingerprint.

Cite this