Activation of Imidazoline I-2B Receptor by Metformin to Increase Glucose Uptake in Skeletal Muscle

C.-T Chen; W. Chen; H.-H Chung; K.-C Cheng; C.-H Yeh; J.-T Cheng

doi:10.1055/s-0031-1286259

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2011; 43(10): 708-713
DOI: 10.1055/s-0031-1286259

Original Basic

Georg Thieme Verlag KG Stuttgart · New York

Activation of Imidazoline I-2B Receptor by Metformin to Increase Glucose Uptake in Skeletal Muscle

C.-T Chen

¹Department of Pediatrics and Department of Medical Research, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan

,

W. Chen

²Department of Internal Medicine, E-Da Hospital and I-Shou University, Kaohsiung County, Taiwan

,

H.-H Chung

³Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan

,

K.-C Cheng

⁴Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City, Japan

,

C.-H Yeh

⁵Institute of Medical Science, College of Health Science, Chang Jung Christian University, Guei-Ren, Tainan City, Taiwan

,

J.-T Cheng

¹Department of Pediatrics and Department of Medical Research, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan

³Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan

⁵Institute of Medical Science, College of Health Science, Chang Jung Christian University, Guei-Ren, Tainan City, Taiwan

› Author Affiliations

Abstract

Metformin (dimethylbiguanide) belongs to guanidinium-derivative and is widely used for treatment of diabetic disorders in clinic. Metformin lowers blood glucose in diabetic animals through increase of glucose uptake into skeletal muscle. Recent evidence indicates that activation of imidazoline I_2B receptor (I_2BR) by guanidinium-derivatives also increased glucose uptake; however, the effect of metformin on I_2BR is still unknown. The blood glucose levels were determined by a glucose kit. The ability of glucose uptake into isolated skeletal muscle or cultured C₂C₁₂ cells was determined using 2-[¹⁴C]-deoxyglucose as tracer. The expressions of 5′ AMP-activated protein kinase (AMPK) and glucose transporter 4 (GLUT-4) were identified by Western blotting analysis. The metformin-induced blood glucose-lowering action was dose-dependently blocked by BU224, a specific I₂R antagonist, in Wistar rats. Also, similar reversion by BU224 was observed in isolated skeletal muscle regarding the metformin-induced glucose uptake. Moreover, AMPK phosphorylation by metformin was concentration-dependently reduced by BU224 in isolated skeletal muscle. In addition, signals for metformin increased glucose uptake were identified via I2R/PI3K/PKC/AMPK dependent pathway in C2C12 cells. Thus, we suggest that metformin can activate I_2BR to increase glucose uptake and I_2BR will be a new target for diabetic therapy.

Key words

5′ AMP-activated protein kinase - BU224 - diabetes - glucose transporter 4 - metformin

Full Text

References

References
1 Kim YD, Park KG, Lee YS, Park YY, Kim DK, Nedumaran B, Jang WG, Cho WJ, Ha J, Lee IK, Lee CH, Choi HS. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes 2008; 57: 306-314
2 Sakamoto K, McCarthy A, Smith D, Green KA, Grahame Hardie D, Ashworth A, Alessi DR. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J 2005; 24: 1810-1820
3 Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108: 1167-1174
4 Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348: 607-614
5 El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 2000; 275: 223-228
6 Hawley SA, Gadalla AE, Olsen GS, Hardie DG. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes 2002; 51: 2420-2425
7 Fryer LG, Parbu-Patel A, Carling D. The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 2002; 277: 25226-25232
8 Xie Z, Dong Y, Scholz R, Neumann D, Zou MH. Phosphorylation of LKB1 at serine 428 by protein kinase C-zeta is required for metformin-enhanced activation of the AMP-activated protein kinase in endothelial cells. Circulation 2008; 117: 952-962
9 Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005; 310: 1642-1646
10 Dardonville C, Rozas I. Imidazoline binding sites and their ligands: an overview of the different chemical structures. Med Res Rev 2004; 24: 639-661
11 Michel MC, Insel PA. Are there multiple imidazoline binding sites?. Trends Pharmacol Sci 1989; 10: 342-344
12 Bousquet P, Feldman J, Schwartz J. Central cardiovascular effects of alpha adrenergic drugs: differences between catecholamines and imidazolines. J Pharmacol Exp Ther 1984; 230: 232-236
13 Morgan NG, Chan SL, Mourtada M, Monks LK, Ramsden CA. Imidazolines and pancreatic hormone secretion. Ann N Y Acad Sci 1999; 881: 217-228
14 Meana JJ, Barturen F, Martin I, Garcia-Sevilla JA. Evidence of increased non-adrenoceptor [3H]idazoxan binding sites in the frontal cortex of depressed suicide victims. Biol Psychiatry 1993; 34: 498-501
15 Boronat MA, Olmos G, Garcia-Sevilla JA. Attenuation of tolerance to opioid-induced antinociception by idazoxan and other I2-ligands. Ann N Y Acad Sci 1999; 881: 359-363
16 Yang TT, Liu IM, Wu HT, Cheng JT. Mediation of protein kinase C zeta in mu-opioid receptor activation for increase of glucose uptake into cultured myoblast C2C12 cells. Neurosci Lett 2009; 465: 177-180
17 Chang CH, Tsao CW, Huang SY, Cheng JT. Activation of imidazoline I(2B) receptors by guanidine to increase glucose uptake in skeletal muscle of rats. Neurosci Lett 2009; 467: 147-149
18 Cheng TC, Lu CC, Chung HH, Hsu CC, Kakizawa N, Yamada S, Cheng JT. Activation of muscarinic M-1 cholinoceptors by curcumin to increase contractility in urinary bladder isolated from Wistar rats. Neurosci Lett 2010; 473: 107-109
19 Sato K, Iemitsu M, Aizawa K, Ajisaka R. DHEA improves impaired activation of Akt and PKC zeta/lambda-GLUT4 pathway in skeletal muscle and improves hyperglycaemia in streptozotocin-induced diabetes rats. Acta Physiol 2009; 197: 217-225
20 Hardie DG. AMPK: a key regulator of energy balance in the single cell and the whole organism. Int J Obes 2008; 32: S7-S12
21 Sajan MP, Bandyopadhyay G, Miura A, Standard ML, Nimal S, Longnus SL, Van Obberghen E, Hainault I, Foufelle F, Kahn R, Braun U, Leitges M, Farese RV. AICAR and metformin, but not exercise, increase muscle glucose transport through AMPK-, ERK-, and PDK1-dependent activation of atypical PKC. Am J Physiol Endocrinol Metab 2010; 298: E179-E192
22 Sarabia V, Lam L, Burdett E, Leiter LA, Klip A. Glucose transport in human skeletal muscle cells in culture. Stimulation by insulin and metformin. J Clin Invest 1992; 90: 1386-1395
23 MacInnes N, Handley SL. Potential serotonergic and noradrenergic involvement in the discriminative stimulus effects of the selective imidazoline I2-site ligand 2-BFI. Pharmacol Biochem Behav 2003; 75: 427-433
24 Diamant S, Eldar-Geva T, Atlas D. Imidazoline binding sites in human placenta: evidence for heterogeneity and a search for physiological function. Br J Pharmacol 1992; 106: 101-108
25 Lui TN, Tsao CW, Huang SY, Chang CH, Cheng JT. Activation of imidazoline I2B receptors is linked with AMP kinase pathway to increase glucose uptake in cultured C2C12 cells. Neurosci Lett 2010; 474: 144-147
26 Chang CH, Wu HT, Cheng KC, Lin HJ, Cheng JT. Increase of beta-endorphin secretion by agmatine is induced by activation of imidazoline I(2A) receptors in adrenal gland of rats. Neurosci Lett 2010; 468: 297-299
27 Ou HY, Cheng JT, Yu EH, Wu TJ. Metformin increases insulin sensitivity and plasma beta-endorphin in human subjects. Horm Metab Res 2006; 38: 106-111
28 Cheng JT, Huang CC, Liu IM, Tzeng TF, Chang CJ. Novel mechanism for plasma glucose-lowering action of metformin in streptozotocin-induced diabetic rats. Diabetes 2006; 55: 819-825
29 Zolk O. Current understanding of the pharmacogenomics of metformin. Clin Pharmacol Ther 2009; 86: 595-598
30 Mu J, Brozinick Jr JT, Valladares O, Bucan M, Birnbaum MJ. A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol Cell 2001; 7: 1085-1094
31 Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci USA 2002; 99: 15983-15987
32 Zheng D, MacLean PS, Pohnert SC, Knight JB, Olson AL, Winder WW, Dohm GL. Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase. J Appl Physiol 2001; 91: 1073-1083
33 Watson RT, Kanzaki M, Pessin JE. Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes. Endocr Rev 2004; 25: 177-204
34 Liu XJ, He AB, Chang YS, Fang FD. Atypical protein kinase C in glucose metabolism. Cell Signal 2006; 18: 2071-2076
35 Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F. Metformin in cancer therapy: a new perspective for an old antidiabetic drug?. Mol Cancer Ther 2010; 9: 1092-1099
36 Limon I, Coupry I, Lanier SM, Parini A. Purification and characterization of mitochondrial imidazoline-guanidinium receptive site from rabbit kidney. J Biol Chem 1992; 267: 21645-21649
37 Raddatz R, Parini A, Lanier SM. Localization of the imidazoline binding domain on monoamine oxidase B. Mol Pharmacol 1997; 52: 549-553
38 Carpene C, Collon P, Remaury A, Cordi A, Hudson A, Nutt D, Lafontan M. Inhibition of amine oxidase activity by derivatives that recognize imidazoline I2 sites. J Pharmacol Exp Ther 1995; 272: 681-688
39 Wang P, Wang ZW, Lin FH, Han Z, Hou ST, Zheng RY. 2-BFI attenuates experimental autoimmune encephalomyelitis-induced spinal cord injury with enhanced B-CK, CaATPase, but reduced calpain activity. Biochem Biophys Res Commun 2011; 406: 152-157