Activation of mu-opioid receptors improves insulin sensitivity in obese Zucker rats.
In the current study we investigated the effect of mu-opioid receptor activation on insulin sensitivity. In obese Zucker rats, an intravenous injection of loperamide (18 microg/kg, three times daily for 3 days) decreased plasma glucose levels and the glucose-insulin index. Both effects of loperamide were subsequently inhibited by the administration of 10 microg/kg of naloxone or 10 microg/kg of naloxonazine, doses sufficient to block mu-opioid receptors. Other metabolic defects characteristic of obese Zucker rats, such as defects in insulin signaling, the decreased expression of insulin receptor substrate (IRS)-1, the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3 kinase), and the glucose transporter subtype 4 (GLUT 4), and the reduction of phosphorylation in IRS-1 or Akt serine, were also studied. These defects were all reversed by loperamide treatment in a dose which overcame mu-opioid receptor blockade. Moreover, loss of tolbutamide-induced plasma glucose lowering action (10 mg/kg) in wild-type mice given a fructose-rich diet was markedly delayed by repeated treatment with loperamide; however, this delay induced by loperamide did not occur in mu-opioid receptor knockout mice. These results indicate an important role of peripheral mu-opioid receptors in the loperamide-induced improvement of insulin sensitivity. Our results suggest that activation of peripheral mu-opioid receptors can ameliorate insulin resistance in animals, and provide a new target for therapy of insulin resistance.
Tzeng
Thing-Fong
TF
Department of Internal Medicine, Pao Chien Hospital, Ping Tung City, Taiwan, ROC.
Lo
Chia-Ying
CY
Cheng
Juei-Tang
JT
Liu
I-Min
IM
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D007333:Insulin Resistance / Q000502:physiology*; D008139:Loperamide / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009270:Naloxone; D051381:Rats; D011924:Rats, Zucker; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D017450:Receptors, Opioid, mu; D009270:Naloxone; D008139:Loperamide