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Systemic bile acids induce insulin resistance in a TGR5-independent manner.
Authors Syring KE, Cyphert TJ, Beck TC, Flynn CR, Mignemi NA, McGuinness OP
Submitted By Submitted Externally on 6/24/2019
Status Published
Journal American journal of physiology. Endocrinology and metabolism
Year 2019
Date Published 5/1/2019
Volume : Pages 316 : E782 - E793
PubMed Reference 30779633
Abstract Bile acids are involved in the emulsification and absorption of dietary fats, as
well as acting as signaling molecules. Recently, bile acid signaling through
farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been
reported to elicit changes in not only bile acid synthesis but also metabolic
processes, including the alteration of gluconeogenic gene expression and energy
expenditure. A role for bile acids in glucose metabolism is also supported by a
correlation between changes in the metabolic state of patients (i.e., obesity or
postbariatric surgery) and altered serum bile acid levels. However, despite
evidence for a role for bile acids during metabolically challenging settings,
the direct effect of elevated bile acids on insulin action in the absence of
metabolic disease has yet to be investigated. The present study examines the
impact of acutely elevated plasma bile acid levels on insulin sensitivity using
hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids
impair hepatic insulin sensitivity by blunting the insulin suppression of
hepatic glucose production. The impaired hepatic insulin sensitivity could not
be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar
inhibition of insulin suppression of hepatic glucose production. Canonical
insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not
perturbed in these animals. Interestingly, bile acid infusion directly into the
portal vein did not result in an impairment in hepatic insulin sensitivity.
Overall, the data indicate that acute increases in circulating bile acids in
lean mice impair hepatic insulin sensitivity via an indirect mechanism.


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