Systemic bile acids induce insulin resistance in a TGR5-independent manner

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.

Fasting serum total bile acid levels are associated with insulin sensitivity, islet <i>β</i>-cell function and glucagon levels in response to glucose challenge in patients with type 2 diabetes

“…Based on the fasting glucose and C-peptide levels, IS HOMA-cp predominantly represents hepatic insulin sensitivity [16,32], so increased fasting S-TBA levels were closely associated with blunted hepatic insulin sensitivity. Syring et al [33] documented that direct elevation of S-TBAs by BA infusion could reduce hepatic insulin sensitivity and disturb insulin levels to suppress hepatic glucose production, which supported our results. In addition, our study also showed that systemic insulin sensitivity assessed by ISI M-cp was inversely associated with fasting S-TBAs.…”

“…Those defects in BA metabolism were associated with high levels of markers of total BA synthesis and defective hepatic BA transport [5], which may lead to increased S-TBA levels in peripheral circulation. Increased systemic BAs, regardless of the status of BAs (conjugation or unconjugated species), can directly induce hepatic insulin resistance and impair insulin action to inhibit hepatic glucose production [33]. However, in the portal vein, increased BAs cannot impair hepatic insulin sensitivity.…”

“…Second, different BA species, such as primary/secondary BAs, amino acidconjugated BAs and 12α-hydroxylated BAs, may play different roles in T2D and other metabolic diseases. Although diverse serum BA species contribute to insulin resistance [31,33], we did not analyse the associations of BA species with major metabolic features in T2D. Third, serum BAs play vital roles in regulating intestinal hormones, such as GLP-1 and 2, which in turn regulate βcell and α-cell secretions.…”

Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis

“…In light of this, and the role of TGR5 in glucose metabolism, we hypothesised that impaired activity of this receptor contributes to glucose homeostasis in ICP, and so pregnant Tgr5 −/− mice were also studied. To our knowledge, glucose homeostasis in pregnant Tgr5 −/− mice has not previously been investigated, however it has been observed in male Tgr5 −/− mice that there was no impact on insulin action and hyperinsulinemic-euglycemic clamp studies revealed that glucose infusion rates were no different to wild type mice 43 . Our data showed that pregnant Tgr5 −/− mice were significantly glucose intolerant and had reduced insulin secretion in response to an oral glucose challenge.…”

Enhanced Bilosomal Properties Resulted in Optimum Pharmacological Effects by Increased Acidification Pathways

“…FXR has also been shown to reverse insulin resistance in animal models, suggesting it may be beneficial in the treatment of T2D [ 69 ]. Interestingly, increased levels of BAs in the plasma of mice was also found to decrease insulin sensitivity through an undetermined mechanism; however, exogenous administration of insulin was found to have no effect on insulin sensitivity [ 70 ]. It may be that CDCA is improving both insulin production and diffusion within the capsules.…”