Bile acid TUDCA improves insulin clearance by increasing the expression of insulin-degrading enzyme in the liver of obese mice

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.

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

“…This suggested that TUDCA enhances GSIS in pancreatic β-cells likely by activating the TGR5 receptor and initiating the cAMP/PKA pathway [113]. Additionally, TUDCA was demonstrated to be a major helper in counteracting obesity-induced hyperinsulinemia in the liver of high-fat-diet-fed C57Bl/6 mice due to improved insulin clearance [107]. This effect was a result of TUDCA-mediated increase in the expression of insulin-degrading enzyme most probably via bile acid receptor S1PR2 activation and initiation of its downstream signaling cascade involving insulin receptor/PI3K/Akt pathway [107].…”

“…Indeed, increasing evidence postulates that TUDCA evokes beneficial effects in the outcome of diabetes. Recent studies suggest that TUDCA is effective in e.g., increasing insulin sensitivity [99], potentiating insulin clearance [107], and increasing pancreatic beta-cell mass [103] in obese humans and murine models of obesity and diabetes. TUDCA has been demonstrated to prevent palmitate-induced apoptosis in rat pancreatic β-cell line INS-1 and to evoke beneficial effects on acinar cells in the experimental model of acute pancreatitis mostly by reducing ER stress [108,109].…”

“…Additionally, TUDCA was demonstrated to be a major helper in counteracting obesity-induced hyperinsulinemia in the liver of high-fat-diet-fed C57Bl/6 mice due to improved insulin clearance [107]. This effect was a result of TUDCA-mediated increase in the expression of insulin-degrading enzyme most probably via bile acid receptor S1PR2 activation and initiation of its downstream signaling cascade involving insulin receptor/PI3K/Akt pathway [107]. Also, TUDCA was shown to suppress TNF-α-induced lipolysis in 3T3-L1 adipocyte cell line via reduction of ER stress and initiation of the IRE-JNK-perilipin-A signaling pathway [115].…”

Promising new fixed combination for the treatment of diseases of the hepatobiliar system: Substantiation of pharmacotherapeutic properties and pharmaceutical quality profile

“…Since taurine implements its hepatoprotective effect together with UDCA, the choice of dosage forms in this case is limited by its physical and chemical properties. Regarding the quantitative content of taurine in capsules, a number of clinical studies were conducted on dosing regimens (Colombo et al, 1996;Heubi et al, 2002;Vettorazzi et al, 2017). In particular, taurine at a dose (30 mg/kg/day) was administered together with UDCA (15 mg/kg/day) during the year, resulting in an increase in its pharmacological effect in the treatment of liver disease in patients with severe pancreatic dysfunction and in poor condition nutrition (Colombo et al, 1996).…”

“…In particular, taurine at a dose (30 mg/kg/day) was administered together with UDCA (15 mg/kg/day) during the year, resulting in an increase in its pharmacological effect in the treatment of liver disease in patients with severe pancreatic dysfunction and in poor condition nutrition (Colombo et al, 1996). Tauroursodeoxycholic acid (TUDCA) at doses of 10-13 mg/kg/day administered for 3 months induced hepatocyte proliferation in humans (Vettorazzi et al, 2017). The high dose regimens of TUDCA (30 mg/kg/day) during enteral administration were also studied for the pediatric population (Heubi et al, 2002).…”