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fenofibrate .and .fish .oil .was .observed, .reflecting .their .property .as .high .or .low .
affinity .agonist .for .peroxisome .proliferator-activated .receptor-, .respectively .
Fenofibrate .specifically .downregulated .genes .involved .in .complement .cascade .
and .inflammatory .response .Fish .oil .specifically .downregulated .genes .involved .
in .cholesterol .and .fatty .acid .biosynthesis .and .upregulated .genes .involved .in .
amino .acid .and .arachidonic .acid .metabolism .Taken .together, .the .data .indicate .
that .despite .being .similarly .potent .toward .modulating .plasma .free .fatty .acids, .
cholesterol, .and .triglyceride .levels, .fish .oil .causes .modest .changes .in .gene .
expression .likely .via .activation .of .multiple .mechanistic .pathways, .whereas .
fenofibrate .causes .pronounced .gene .expression .changes .via .a .single .pathway, .
reflecting .the .key .difference .between .nutritional .and .pharmacological .inter-vention Meissner .M, .Herrema .H, .Van .Dijk .TH, .Gerding .A, .Havinga .R, .Boer .T, .Müller .MR, .
Groen .AK, .and .Kuipers .F .(2011)
Bile acid sequestration reduces plasma glucose levels in db/db mice by
increasing its metabolic clearance rate. PLoS One 6.11, 24564.
doi:10.1371/journal.pone.0024564. .
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-13C]-glucose, .[2-13C]-glycerol, .
[1-2H]-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/interpretations: .BAS .induced .plasma .glucose .
lowering .in .db/db .mice .by .increasing .metabolic .clearance .rate .of .glucose .in .
T H E M E C L U S T E R B I O I N G R E D I E N T S A N D F U N C T I O N A L I T Y | 117

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