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PLoS One. 2011;6(11):e24564. doi: 10.1371/journal.pone.0024564. Epub 2011 Nov 7.

Bile acid sequestration reduces plasma glucose levels in db/db mice by increasing its metabolic clearance rate.

Author information

1
Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. meissner.maxi@gmail.com

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-(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/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.

PMID:
22087215
PMCID:
PMC3210115
DOI:
10.1371/journal.pone.0024564
[Indexed for MEDLINE]
Free PMC Article

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