Loperamide increases glucose ultilization in streptozotocin‐induced diabetic rats

Abstract

1. Loperamide has an ability to lower the plasma glucose concentration in streptozotocin (STZ)-induced diabetic rats. In the present study, we investigated the molecular mechanisms by which loperamide regulates plasma glucose concentrations in the absence of insulin. 2. Loperamide, at a dose sufficient (17.6 microg/kg) to activate mu-opioid receptors, significantly decreased plasma glucose levels in STZ-diabetic rats. The mRNA and protein levels of glucose transporter 4 (GLUT-4) in soleus muscle, detected by northern and western blotting, respectively, were increased after repeated intravenous administration of loperamide (17.6 micro g/kg) to STZ-diabetic rats over 3 days. Moreover, similar treatment with loperamide (17.6 microg/kg) for 3 days reversed the elevated mRNA and protein levels of phosphoenolpyruvate carboxykinase (PEPCK) in the liver of STZ-diabetic rats to near the levels seen in normal rats. 3. These results suggest that activation of mu-opioid receptors by loperamide can increase glucose utilization in peripheral tissues and/or reverse the higher gene expression of PEPCK to inhibit hepatic gluconeogenesis, thereby lower plasma glucose in diabetic rats lacking insulin.

Further studies on the interaction of loperamide with capacitative calcium entry in Leukemic HL‐60 cells

“…In vivo loperamide, through activation of opioid receptors, lowered plasma glucose levels in streptozotocin-induced diabetic rats [Liu et al, 1999;Tzeng et al, 2003] and reversed interleukin-6-induced insulin resistance [Tzeng et al, 2005]. With HIT-T15 cells, loperamide at high micromolar concentrations was found to elevate intracellular calcium through release Fig.…”

Mediation of Endogenous β‐Endorphin in the Plasma Glucose‐Lowering Action of Herbal Products Observed in Type 1‐Like Diabetic Rats

“…We demonstrated that β -endorphin causes an increase in glucose uptake in isolated soleus muscles of STZ-diabetic rats to lower plasma glucose and this effect is antagonized by MOR-specific blockers [58]. The stimulatory effects of loperamide and tramadol on glucose uptake have also been shown in soleus muscles isolated from STZ-diabetic rats and the effects are blocked by an inhibitor specific to MOR [60, 72]. Thus, activation of peripheral MOR results in an increase in glucose uptake into skeletal muscle and is related to the lowering of plasma glucose under an insulin-deficient state.…”

“…In diabetes, elevation of blood glucose is a consequence of increased hepatic glucose output together with reduced peripheral glucose utilization [74]. We have observed that both naloxone and naloxonazine, at concentrations sufficient to block MOR, inhibit the increase in glycogen synthesis in STZ-diabetic rats [58, 60, 72]. Therefore, an increase in glucose utilization through peripheral MOR activation can be considered as one of the mechanism(s) for regulation of plasma glucose in the absence of insulin.…”

“…It has been reported that PKC is involved in the rate-limiting step in GLUT gene expression [79]. The gene expression of GLUT 4 in soleus muscles of STZ-diabetic rats is increased by loperamide after repeated injection for 3 days [72]. Activation of MOR by tramadol to increase glucose uptake into isolated soleus muscles with an elevation of GLUT 4 gene expression in STZ-diabetic rats has also been observed [60].…”

“…Downregulation of the PEPCK gene might be associated with a decrease in hepatic gluconeogenesis to result in the lowering of plasma glucose. We observed that loperamide at the dose which is effective in activating MOR, decreased the plasma glucose of STZ-diabetic rats accompanied by a marked reduction of PEPCK gene expression in the liver [72]. Similarly, an increased expression of the hepatic PEPCK gene in STZ-diabetic rats is reversed by tramadol [60].…”