Bile Acid Sequestration Reduces Plasma Glucose Levels in db-db Mice by Increasing Its Metabolic Clearance RateReportar como inadecuado

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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.


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.


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.


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.

Autor: Maxi Meissner , Hilde Herrema, Theo H. van Dijk, Albert Gerding, Rick Havinga, Theo Boer, Michael Müller, Dirk-Jan. Reijngoud, A



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