Infusion of β-Endorphin Improves Insulin Resistance in Fructose-fed Rats

Abstract

In an attempt to probe the effect of β-endorphin on insulin resistance, we used Wistar rats that were fed fructose-rich chow to induce insulin resistance. Insulin action on glucose disposal rate (GDR) was measured using the hyperinsulinemic euglycemic clamp technique, in which glucose (variable), insulin (40 mU/kg/min), and β-endorphin (6 ng/kg/min) or vehicle were initiated simultaneously and continued for 120 min. A marked reduction in insulin-stimulated GDR was observed in fructose-fed rats compared to normal control rats. Infusion of β-endorphin reversed the value of GDR, which was inhibited by naloxone and naloxonazine each at doses sufficient to block opioid µ-receptors. Opioidµ-receptors may therefore be activated by β-endorphin to improve insulin resistance. Next, soleus muscle was isolated to investigate the effect of β-endorphin on insulin signals. Insulin resistance in rats induced by excess fructose was associated with the impaired insulin receptor (IR), tyrosine autophosphorylation, and insulin receptor substrate (IRS)-1 protein content in addition to the significant decrease in IRS-1 tyrosine phosphorylation in soleus muscle. This impaired glucose transportation was also due to signaling defects that included an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and Akt serine phosphorylation. However, IR protein levels were not markedly changed in rats with insulin resistance. β-endorphin infusion reversed the fructose-induced decrement in the insulin-signaling cascade with increased GDR. Apart from IR protein levels, infusion of β-endorphin reversed the decrease in protein expression for the IRS-1, p85 regulatory subunit of PI3-kinase, and Akt serine phosphorylation in soleus muscle in fructose-fed rats. The decrease in insulin-stimulated protein expression of glucose transporter subtype 4 (GLUT 4) in fructose-fed rats returned to near-normal levels after β-endorphin infusion. Infusion of β-endorphin may improve insulin resistance by modulating the insulin-signaling pathway to reverse insulin responsiveness.

Key words

Akt · β-Endorphin · Glucose transporter subtype 4 · Insulin receptor · Insulin receptor substrate-1 · Phosphatidylinositol 3-kinase

References

• 1 Chevlen E. Opioids: a review.  Curr Pain Headache Rep. 2003;  7 15-23
• 2 Yaksh T L. Pharmacology and mechanisms of opioid analgesic activity.  Acta anaesthesiol Scand. 1997;  41 94-111
• 3 Smith E M. Opioid peptides in immune cells.  Adv Exp Med Biol. 2003;  521 51-68
• 4 Curry D L, Li C H. Stimulation of insulin secretion by beta-endorphin (1-27 and 1-31).  Life Sci. 1987;  40 2053-2058
• 5 Locatelli A, Spotti D, Caviezel F. The regulation of insulin and glucagon secretion by opiates: a study with naloxone in healthy humans.  Acta Diabetol. 1985;  22 25-31
• 6 Khawaja X Z, Green I C, Thorpe J R, Titheradge M A. The occurrence and receptor specificity of endogenous opioid peptides with pancreas and liver of the rat. Comparison with brain.  Biochem J. 1990;  267 233-240
• 7 Cheng J T, Liu I M, Tzeng T F, Tsai C C, Lai T Y. Plasma glucose lowering effect of β-endorphin in streptozotocin-induced diabetic rats.  Horm Meta Res. 2002;  34 570-576
• 8 Cheng J T, Liu I M, Hsu C F. Rapid induction of insulin resistance in opioid mu-receptor knock-out mice.  Neurosci lett. 2003;  339 139-142
• 9 Kruszynska Y T, Olefsky J M. Cellular and molecular mechanisms of non-insulin dependent diabetes mellitus.  J Invest Med. 1996;  44 413-428
• 10 DeFronzo R A. Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview.  Diabetologia. 1992;  35 389-397
• 11 Shulman G I. Cellular mechanisms of insulin resistance.  J Clin Invest. 2000;  106 171-176
• 12 Higashiura K, Ura N, Takada T, Li Y, Torii T, Togashi N, Takada M, Takizawa H, Shimamoto K. The effects of an angiotensin-converting enzyme inhibitor and an angiotensin II receptor antagonist on insulin resistance in fructose-fed rats.  Am J Hypertens. 2000;  13 290-297
• 13 Lambert K, Py G, Robert E, Mercier J. Does high-sucrose diet alter skeletal muscle and liver mitochondrial respiration?.  Horm Metab Res. 2003;  35 546-550
• 14 Steele R. Influence of glucose loading and injected insulin on hepatic glucose output.  Ann N Y Acad Sci. 1959;  82 420-430
• 15 Bessesen D H. The role of carbohydrates in insulin resistance.  J Nutr. 2001;  131 S2782-S 2786
• 16 James D E, Jenkins A B, Kraegen E W. Heterogeneity of insulin action in individual muscles in vivo: euglycemic clamp studies in rats.  Am J Physiol. 1985;  248 E567-E574
• 17 Kurokawa K, Oka Y. Insulin resistance and glucose transporter.  Nippon Rinsho. 2000;  58 310-314
• 18 King P A, Horton E D, Hirshman M F, Horton E S. Insulin resistance in obese Zucker rat (fa/fa) skeletal muscle is associated with a failure of glucose transporter translocation.  J Clin Invest. 1992;  90 1568-1575
• 19 Anai M, Funaki M, Ogihara T, Kanda A, Onishi Y, Sakoda H, Inukai K, Nawano M, Fukushima Y, Yazaki Y, Kikuchi M, Oka Y, Asano T. Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats.  Diabetes. 1999;  48 158-169
• 20 Jiang Z Y, Lin Y W, Clemont A, Feener E P, Hein K D, Igarashi M, Yamauchi T, White M F, King G L. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats.  J Clin Invest. 1999;  104 447-457
• 21 White M F. The insulin signalling system and the IRS proteins.  Diabetologia. 1997;  40 S2-S17
• 22 Kitamura T, Ogawa W, Sakaue H, Hino Y, Kuroda S, Takata M, Matsumoto M, Maeda T, Konishi H, Kikkawa U, Kasuga M. Requirement for activation of the serine-threonine kinase Akt (protein kinase B) in insulin stimulation of protein synthesis but not of glucose transport.  Mol Cell Biol. 1998;  18 3708-3717
• 23 Klippel A, Kavanaugh W M, Pot D, Williams L T. A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain.  Mol Cell Biol. 1997;  17 338-344
• 24 Lima M H, Ueno M, Thirone A C, Rocha E M, Carvalho C R, Saad M J. Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance.  Endocrine. 2002;  18 1-12
• 25 Carvalho E, Rondinone C, Smith U. Insulin resistance in fat cells from obese Zucker rats - evidence for an impaired activation and translocation of protein kinase B and glucose transporter 4.  Mol Cell Biol. 2000;  206 7-16
• 26 Cusi K, Maezono K, Osman A, Pendergrass M, Patti M E, Pratipanawatr T, DeFronzo R A, Kahn C R, Mandarino L J. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle.  J Clin Invest. 2000;  105 311-320
• 27 Goldstein A. Binding selectivity profiles for ligands of multiple receptor types: focus on opioid receptors.  Trends Pharmacol Sci. 1987;  8 456-459
• 28 Ishizuka T, Cooper D R, Hernandez H, Buckley D, Standaert M, Farese R V. Effects of insulin on diacylglycerol-protein kinase C signaling in rat diaphragm and soleus muscles and relationship to glucose transport.  Diabetes. 1990;  39 181-190
• 29 Van Epps-Fung M, Gupta K, Hardy R W, Wells A. A role for phospholipase C activity in GLUT4-Mediated glucose transport.  Endocrinology. 1997;  138 5170-5175
• 30 Narita M, Ohnishi O, Nemoto M, Aoki T, Suzuki T. The involvement of phosphoinositide 3-kinase (PI3-Kinase) and phospholipase C gamma (PLC gamma) pathway in the morphine-induced supraspinal antinociception in the mouse.  Nihon Shinkei Seishin Yakurigaku Zasshi. 2001;  21 7-14
• 31 Freye E, Latasch L. Development of opioid tolerance - molecular mechanisms and clinical consequences.  Anasthesiol Intensivmed Notfallmed Schmerzther. 2003;  38 14-26
• 32 Liu I M, Liou S S, Chen W C, Chen P F, Cheng J T. Signals in the activation of opioid µ-receptors by loperamide to enhance glucose uptake into cultured C₂C₁₂ cells.  Horm Metab Res. 2004;  36 210-214
• 33 Bandyopadhyay G, Standaert ML, Kikkawa U, Ono Y, Moscat J, Farese RV. Effects of transiently expressed atypical (zeta, lambda), conventional (alpha, beta) and novel (delta, epsilon) protein kinase C isoforms on insulin-stimulated translocation of epitope-tagged GLUT4 glucose transporters in rat adipocytes: specific interchangeable effects of protein kinases C-zeta and C-lambda.  Biochem J. 1999;  337 461-470
• 34 Vollenweider P, Menard B, Nicod P. Insulin resistance, defective insulin receptor substrate 2-associated phosphatidylinositol-3′ kinase activation, and impaired atypical protein kinase C (zeta/lambda) activation in myotubes from obese patients with impaired glucose tolerance.  Diabetes. 2002;  51 1052-1059
• 35 Ravichandran L V, Esposito D L, Chen J, Quon M J. Protein kinase C-zeta phosphorylates insulin receptor substrate-1 and impairs its ability to activate phosphatidylinositol 3-kinase in response to insulin.  J Biol Chem. 2001;  276 3543-3549
• 36 Liu I M, Niu C S, Chi T C, Kuo D H, Cheng J T. Investigations of the mechanism of the reduction in plasma glucose by cold-stress in streptozotocin-induced diabetic rats.  Neurosci. 1999;  92 1137-1142