Mediation of β-Endorphin by Isoferulic Acid to Lower Plasma Glucose in Streptozotocin-Induced Diabetic Rats

Abstract

We investigated the mechanism(s) by which isoferulic acid lowers plasma glucose levels in streptozotocin-induced diabetic rats (STZ-diabetic rats). In STZ-diabetic rats, isoferulic acid dose dependently lowered plasma glucose concentrations and increased plasma ␤-endorphin-like immunoreactivity (BER). Both of these effects of isoferulic acid were abolished by pretreatment of rats with tamsulosin or 2-[2,6-dimethoxyphenoxyethyl]aminomethyl-1,4-benzodioxane hydrochloride (WB 4101) at doses sufficient to block ␣ 1 -adrenoceptors. Also, isoferulic acid enhanced BER release from isolated rat adrenal medulla in a concentration-dependent manner that could be abolished by treatment with ␣ 1 -adrenoceptor antagonists. Moreover, bilateral adrenalectomy in STZ-diabetic rats eliminated the activities of isoferulic acid, including the plasma glucose-lowering effect and the plasma BER-elevating effect. Naloxone and naloxonazine inhibited the plasma glucose-lowering activity of isoferulic acid at doses sufficient to block opioid -receptors. In contrast with the effect in wild-type diabetic mice, isoferulic acid failed to lower plasma glucose levels in opioid -receptor knockout diabetic mice. Treatment of STZ-diabetic rats with isoferulic acid three times in 1 day resulted in an increase in the expression of the glucose transporter subtype 4 form in soleus muscle. This effect was blocked by ␣ 1 -adrenoceptor or opioid -receptor antagonists. The reduction of elevated mRNA or protein level of hepatic phosphoenolpyruvate carboxykinase was also impeded in the same groups of STZ-diabetic rats. In conclusion, our results suggest that isoferulic acid may activate ␣ 1 -adrenoceptors to enhance the secretion of ␤-endorphin, which can stimulate the opioid -receptors to increase glucose use or/and reduce hepatic gluconeogenesis, resulting in a decrease of plasma glucose in STZ-diabetic rats.

A series of cinnamic acid derivatives and their inhibitory activity on intestinal α-glucosidase

“…It has been recently reported that isoferulic acid exhibits antihyperglycemic activity in streptozotocin (STZ)-induced diabetic rats 7 . It activates  1 -adrenoceptors to enhance the secretion of -endorphin, which stimulates the opioid -receptors to increase glucose use and/or reduce hepatic gluconeogenesis, resulting in a reduction of the plasma glucose concentration 23 . Our previous studies demonstrated that ferulic acid, but not isoferulic acid, directly stimulates insulin secretion from the pancreas, leading to decreased plasma glucose concentrations in rats 24 .…”

Study of the Hypoglycemic Activity of Derivatives of Isoflavones from Cicer arietinum L.

“…Considering that isoferulic acid has a strong hypoglycemic activity [18–21], the isoflavones were esterified with acetyl isoferulic acid. This structural modification was expected to improve their efficacy through possible synergy.…”

Role of Opioid Antagonists in the Treatment of Women with Glucoregulation Abnormalities

“…Our data cannot elucidate if it could be direct or indirect, probably mediated by the effect of other still unknown factors, and if such action could be carried out at the receptorial level or in the intracellular enzymatic pathways. In this concern, some investigators tried to identify the role of µ, δ and the recently isolated σ opiates receptors in the liver of rats [53,54], but further studies are needed to throw light in this field.…”