Bile Acid Sequestration Reduces Plasma Glucose Levels in db/db Mice by Increasing Its Metabolic Clearance Rate
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.
| Main Authors: | , , , , , , , , , |
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| Format: | Article/Letter to editor biblioteca |
| Language: | English |
| Subjects: | carbohydrate-metabolism, colesevelam hydrochloride, double-blind, farnesoid-x-receptor, fatty-acids, glycemic control, nuclear receptor, ob/ob mice, peripheral insulin sensitivity, type-2 diabetes-mellitus, |
| Online Access: | https://research.wur.nl/en/publications/bile-acid-sequestration-reduces-plasma-glucose-levels-in-dbdb-mic |
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