Activation of opioid μ-receptor by loperamide to lower plasma glucose in streptozotocin-induced diabetic rats

Liu, I. Min; Cherng, Tzong; Chen, Yun Chueh; Lu, Feng Hwa; Cheng, Juei Tang

doi:10.1016/s0304-3940(99)00226-8

Cited by 41 publications

(55 citation statements)

References 13 publications

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“…Intravenous injection of synthetic ␤-endorphin lowered plasma glucose in streptozotocin (STZ)-induced diabetic rats, as observed in our previous study (13). Chemical agents such as loperamide or tramadol increased glucose utilization via activation of opioid -receptors to lower plasma glucose in STZ-induced diabetic rats (14,15). In obese Zucker rats, mediation of ␤-endorphin in exercise-induced improvement of insulin resistance has also been observed (16).…”

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confidence: 63%

Novel Mechanism for Plasma Glucose–Lowering Action of Metformin in Streptozotocin-Induced Diabetic Rats

et al. 2006

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To better understand the insulin-independent plasma glucose-lowering action of metformin, we used streptozotocin (STZ)-induced diabetic rats to investigate the possible mechanisms. Oral intake of metformin decreased the plasma glucose of STZ-induced diabetic rats with a parallel increase of plasma ␤-endorphin-like immunoreactivity (BER). Mediation of opioid -receptors in the action of metformin was identified by the blockade of receptors with antagonist in STZ-induced diabetic rats and the failure of action in opioid -receptor knockout diabetic mice. Release of BER from adrenal glands by metformin was characterized, using bilateral adrenalectomy and the release of BER from isolated adrenal medulla of STZ-induced diabetic rats. Repeated treatment with metformin in STZ-induced diabetic rats increased the mRNA and protein levels of GLUT-4 in soleus muscle that was blocked by naloxonazine. Reduction of the mRNA or protein levels of hepatic PEPCK was also impeded in the same group of STZ-induced diabetic rats. In conclusion, our results provide novel mechanisms for the plasma glucose-lowering action of metformin, via an increase of ␤-endorphin secretion from adrenal glands to stimulate opioid -receptor linkage, leading to an increase of GLUT-4 gene expression and an attenuation of hepatic PEPCK gene expression in STZinduced diabetic rats. Diabetes 55:819 -825, 2006

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confidence: 63%

Novel Mechanism for Plasma Glucose–Lowering Action of Metformin in Streptozotocin-Induced Diabetic Rats

et al. 2006

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“…Our previous reports (Liu et al, 1999a;Cheng et al, 2001b, 2002) indicated that opioid -receptors participated in the regulation of glucose metabolism in an insulin deficient state. Endogenous ␤-endorphin has physiological activities that are mediated by opioid -receptors (Goldstein, 1987;Pasternak, 1993).…”

Section: Discussionmentioning

confidence: 96%

“…We have previously demonstrated that endogenous ␤-endorphin via the activation of opioid receptor is a positive regulator in the glucose use and a negative modulator in hepatic gluconeogenesis in the insulin-deficient state (Liu et al, 1999a;Cheng et al, 2001bCheng et al, , 2002. Thus, we used opioid -receptor antagonists to clarify the role of this receptor in isoferulic acid-induced changes in gene expression associated with glucose metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies (Liu et al, 1999a;Cheng et al, 2001bCheng et al, , 2002 have shown that activation of opioid -receptors by either exogenous ␤-endorphin or chemical agents, such as loperamide or tramadol, might improve glucose homeostasis in diabetic rats in the absence of insulin. Also, activation of ␣ 1 -adrenoceptors in adrenal medulla by phenylephrine might enhance the secretion of ␤-endorphin from the rat adrenal gland (Cheng et al, 2001c).…”

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confidence: 99%

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

Liu¹,

Chen²

2003

The Journal of Pharmacology and Experimental Therapeutics

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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.

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“…Chemical agents such as loperamide and tramadol decreased plasma glucose via activation of opioid μ-receptors in a type 1 diabetes rat model [5,6]. Insulin resistance is described as the reduced response of peripheral tissues to insulin [7].…”

Section: Introductionmentioning

confidence: 99%

Activation of opioid μ-receptors by loperamide to improve interleukin-6-induced inhibition of insulin signals in myoblast C2C12 cells

Tzeng

Liu²

2005

Diabetologia

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Aims/hypothesis: This study investigated the role of opioid μ-receptor activation in the improvement of insulin resistance. Methods: Myoblast C 2 C 12 cells were cultured with IL-6 to induce insulin resistance. Radioactive 2-deoxyglucose (2-DG) uptake was used to evaluate the effect of loperamide on insulin-stimulated glucose utilisation. Protein expression and phosphorylation in insulinsignalling pathways were detected by immunoblotting. Results: The insulin-stimulated 2-DG uptake was reduced by IL-6. Loperamide reversed this uptake, and the uptake was inhibited by blockade of opioid μ-receptors. Insulin resistance induced by IL-6 was associated with impaired expression of the insulin receptor (IR), IR tyrosine autophosphorylation, IRS-1 protein content and IRS-1 tyrosine phosphorylation. Also, an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase, Akt serine phosphorylation and the protein of glucose transporter subtype 4 were observed in insulin resistance. Loperamide reversed IL-6-induced decrement of these insulin signals. Conclusions/interpretation: Opioid μ-receptor activation may improve IL-6-induced insulin resistance through modulation of insulin signals to reverse the responsiveness of insulin. This provides a new target in the treatment of insulin resistance.

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Activation of opioid μ-receptor by loperamide to lower plasma glucose in streptozotocin-induced diabetic rats

Cited by 41 publications

References 13 publications

Novel Mechanism for Plasma Glucose–Lowering Action of Metformin in Streptozotocin-Induced Diabetic Rats

Novel Mechanism for Plasma Glucose–Lowering Action of Metformin in Streptozotocin-Induced Diabetic Rats

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

Activation of opioid μ-receptors by loperamide to improve interleukin-6-induced inhibition of insulin signals in myoblast C2C12 cells

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