title: Opioid μ-receptors as new target for insulin resistance.
abstract: Type-2 diabetes is one of the fastest growing public health problems worldwide resulting from both environmental and genetic factors. Activation of μ-opioid receptor (MOR) could result in reversal of the impairment of insulin-stimulated glucose disposal in genetically obese Zucker rats via exercise training. This improvement of insulin resistance was associated with an elevation of circulating β-endorphin to ameliorate the post-receptor insulin signaling cascade, including downstream effectors of the phosphatidylinositol 3-kinase (PI3-kinase) signaling pathway. In insulin resistant rats, Loperamide treatment effected on the insulin receptor substrate (IRS)-1/PI3-kinase/Akt signaling cascade and subsequent insulin-stimulated glucose transport trafficking on skeletal muscle, which were all suppressed by MOR antagonism. In addition, induction of insulin resistance by the intake of high fructose is more rapid in MOR knockout mice than in wild-type mice. Improvements in insulin sensitivity through the peripheral MOR activation overcoming defects related to the post-receptor in IRS-1-associated PI3-kinase step have been defined. Opioid receptor activation, especially of the μ-subtype, may provide merits in the amelioration of defective insulin action. Atypical zeta (ζ) isoform of protein kinase C serves as a factor that integrates with peripheral MOR pathway and insulin signals for glucose utilization. The developments call new insights into the chemical compounds and/or herbal products that might enhance opioid peptide secretion and/or stimulate MOR in peripheral insulin-sensitive tissues to serve as potential agents or adjuvants for helping the glucose metabolism. In the present review, we update these topics and discuss the concept of targeting peripheral MOR pathway for the treatment of insulin resistance.
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan.
authors.forename: Kai-Chun
authors.initials: KC
authors.lastname: Cheng
authors.forename: Akihiro
authors.initials: A
authors.lastname: Asakawa
authors.forename: Ying-Xiao
authors.initials: YX
authors.lastname: Li
authors.forename: I-Min
authors.initials: IM
authors.lastname: Liu
authors.forename: Haruka
authors.initials: H
authors.lastname: Amitani
authors.forename: Juei-Tang
authors.initials: JT
authors.lastname: Cheng
authors.forename: Akio
authors.initials: A
authors.lastname: Inui
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008139:Loperamide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018847:Opioid Peptides / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007328:Insulin; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu; D008139:Loperamide; D005947:Glucose
keywords: CNS; Central nervous system; DAG; DOR; Diacylglycerol; GDR; GLUT4; Glucose disposal; Hepatic phosphoenolpyruvate carboxykinase; IL; IRS; Including interleukin; Insulin receptor substrate; Insulin resistance; JNK; Jun N-terminal kinase; KOR; Loperamide; MOR; Muscle glucose transporters subtype 4 form; Opioid μ-receptor; Opioids; PDK; PEPCK; PI3; PIP2; PIP3; PKC; PLC; Phosphatidylinositol 3; Phosphatidylinositol 3,4,5 triphosphate; Phosphatidylinositol 4,5 bisphosphate; Phosphoinositide-dependent kinase; Phospholipase C; Protein kinase C; Signals; TNF; Tumor necrosis factor; β-Endorphin; δ opioid receptors; κ opioid receptors; μ opioid receptor