Abstract
Disruption of insulin secretion and clearance both contribute to obesity-induced hyperinsulinemia, though reduced insulin clearance seems to be the main factor. The liver is the major site for insulin degradation, a process mainly coordinated by the insulin-degrading enzyme (IDE). The beneficial effects of taurine conjugated bile acid (TUDCA) on insulin secretion as well as insulin sensitivity have been recently described. However, the possible role of TUDCA in insulin clearance had not yet been explored. Here, we demonstrated that 15 days treatment with TUDCA reestablished plasma insulin to physiological concentrations in high fat diet (HFD) mice, a phenomenon associated with increased insulin clearance and liver IDE expression. TUDCA also increased IDE expression in human hepatic cell line HepG2. This effect was not observed in the presence of an inhibitor of the hepatic membrane bile acid receptor, S1PR2, nor when its downstream proteins were inhibited, including IR, PI3K and Akt. These results indicate that treatment with TUDCA may be helpful to counteract obesity-induced hyperinsulinemia through increasing insulin clearance, likely through enhanced liver IDE expression in a mechanism dependent on S1PR2-Insulin pathway activation.
Highlights
Disruption of insulin secretion and clearance both contribute to obesity-induced hyperinsulinemia, though reduced insulin clearance seems to be the main factor
We believe that therapeutic strategies focusing on increased insulin-degrading enzyme (IDE) expression and insulin clearance could be helpful in the prevention and/or treatment of type 2 diabetes (T2D), especially when hyperinsulinemia precedes the development of this pathology
Plasma insulin concentration is controlled by the interaction between insulin secretion and insulin clearance[7,8]
Summary
Disruption of insulin secretion and clearance both contribute to obesity-induced hyperinsulinemia, though reduced insulin clearance seems to be the main factor. We demonstrated that 15 days treatment with TUDCA reestablished plasma insulin to physiological concentrations in high fat diet (HFD) mice, a phenomenon associated with increased insulin clearance and liver IDE expression. We believe that therapeutic strategies focusing on increased IDE expression and insulin clearance could be helpful in the prevention and/or treatment of T2D, especially when hyperinsulinemia precedes the development of this pathology. In this sense, insulin sensitizer agents such as physical exercise, bariatric surgery and pioglitazone treatment have been found to reduce plasma insulin concentrations in obese rodents, through increased insulin clearance and improved glucose homeostasis[19,20,21]. The use of endogenous molecules that increase insulin clearance, without the side effects or adherence concerns, could be a potential treatment for hyperinsulinemia
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
