Journals of

Background and Aims: SNARE proteins are composed of a combination of SNAP-23, Stx-4, and VAMP-2 isoforms that are significantly expressed in skeletal muscle. These proteins control the transport of GLUT4 to the cell membranes. The modifications in the expression of SNARE proteins can cause Type 2 diabetes. The present study aimed to assess the effect of metformin on the expression of these proteins in rats.
Materials and Methods: For the purpose of the study, 40 male Wistar rats were randomly selected. Streptozotocin and Nicotinamide were used for the induction of type 2 diabetes. The animals were assigned to five groups (n=8), including healthy and diabetic groups as control, as well as three experimental groups which were treated with different doses of metformin (100, 150, and 200 mg/kg body weight) for 30 days. The quantitative reverse transcription PCR (RT-qPCR) method was applied to evaluate the expression of SNARE complex proteins.
Results: Based on the results, metformin (100, 150, and 200 mg/kg body weight) decreased serum glucose levels and increased serum insulin levels. This difference in dose of 200 mg/kg body weight was statistically significant (P<0.05). Moreover, all three doses of metformin increased the expression of SNAP- 23, syntaxin-4, and VAMP-2 proteins in skeletal muscle tissue. Metformin at a dose of 200 mg/kg body weight demonstrated the most significant effects (P<0.05).
Conclusion: As evidenced by the results of the current study, another anti-diabetic mechanism of metformin is to increase the expression of SNARE proteins, which effectively improves insulin resistance and lowers blood glucose.
 

1- Chellappan DK, Yap WS, NA BAS, Gupta G, Dua K. Current therapies and targets for type 2 diabetes mellitus. Panminerva Med. 2018; 60(3): 117-31. DOI: 10.23736/s0031-0808.18.03455-9
2- Cho N, Shaw J, Karuranga S, Huang Yd, da Rocha Fernandes J, Ohlrogge A, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018; 138: 271-81. DOI: 10.1016/j.diabres.2018.02.023
3- Zhou T-T, Ma F, Shi X-F, Xu X, Du T, Guo X-D, et al. DMT efficiently inhibits hepatic gluconeogenesis by regulating the Gαq signaling pathway. J Mol Endocrinol. 2017; 59(2): 151-69. DOI: 10.1530/JME-17-0121
4- Lauritzen HP, Schertzer JD. Measuring GLUT4 translocation in mature muscle fibers. Am. J. Physiol. Endocrinol. Metab. AM J PHYSIOL-ENDOC M. 2010;299(2):E169-E79. DOI: 10.1152/ajpendo.00066.2010
5- Stöckli J, Fazakerley DJ, James DE. GLUT4 exocytosis. J Cell Sci. 2011; 124(24): 4147-59. DOI: 10.1242/jcs.097063
6- Mohseni R, ArabSadeghabadi Z, Ziamajidi N, Abbasalipourkabir R, RezaeiFarimani A. Oral administration of resveratrol-loaded solid lipid nanoparticle improves insulin resistance through targeting expression of SNARE proteins in adipose and muscle tissue in rats with type 2 diabetes. Nanoscale Res Lett. 2019; 14(1): 227. DOI: 10.1186/s11671-019-3042-7.
7- Farimani AR, Goodarzi MT, Saidijam M, Yadegarazari R, Zarei S, Asadi S. Effect of resveratrol on SNARE proteins expression and insulin resistance in skeletal muscle of diabetic rats. Iran J Basic Med Sci. 2019; 22(12): 1408-14. DOI: 10.22038/IJBMS.2019.13988
8- Viollet B, Guigas B, Garcia NS, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012; 122(6): 253-70. DOI: 10.1042/CS20110386
9- Yang X, Xu Z, Zhang C, Cai Z, Zhang J. Metformin, beyond an insulin sensitizer, targeting heart and pancreatic β cells. Biochim Biophys Acta Mol Basis Dis. 2017; 1863(8): 1984-90. DOI: 10.1016/j.bbadis.2016.09.019
10- Sheela N, Jose MA, Sathyamurthy D, Kumar BN. Effect of Silymarin on Streptozotocin-Nicotinamide--induced Type 2 Diabetic Nephropathy in Rats. Iran J Kidney Dis. 2013; 7(2):117-23. DOI: 10.1002/jps.20744
11- Choi YH, Kim SG, Lee MG. Dose-independent pharmacokinetics of metformin in rats: Hepatic and gastrointestinal first-pass effects. J. Pharm. Sci. 2006; 95(11):2543-52. DOI: 10.1002/jps.20744
12- Zhai L, Gu J, Yang D, Wang W, Ye S. Metformin ameliorates podocyte damage by restoring renal tissue podocalyxin expression in type 2 diabetic rats. J. Diabetes Res. 2015; 2015. DOI: 10.1155/2015/231825
13- Katsuki A, Sumida Y, Gabazza EC, Murashima S, Furuta M, Araki-Sasaki R, et al. Homeostasis model assessment is a reliable indicator of insulin resistance during follow-up of patients with type 2 diabetes. Diabetes care. 2001; 24(2): 362-5. DOI: 10.2337/diacare.24.2.362
14- Ghasemi A, Khalifi S, Jedi S. Streptozotocin-nicotinamide-induced rat model of type 2 diabetes. Acta Physiologica Hungarica. 2014;101(4):408-20 .DOI: 10.1556/APhysiol.101.2014.4.2
15-  Giannarelli R, Aragona M, Coppelli A, Del Prato S. Reducing insulin resistance with metformin: the evidence today. Diabetes Metab. 2003; 29(4): 6S28-6S35. DOI: 10.1016/S1262-3636(03)72785-2
16- Maier VH, Melvin DR, Lister CA, Chapman H, Gould GW, Murphy GJ. v-and t-SNARE protein expression in models of insulin resistance: normalization of glycemia by rosiglitazone treatment corrects overexpression of cellubrevin, vesicle-associated membrane protein-2, and syntaxin 4 in skeletal muscle of Zucker diabetic fatty rats. Diabetes. 2000; 49(4): 618-25. DOI: 10.2337/diabetes.49.4.618
17- Abbasi Oshaghi E, Goodarzi MT, Higgins V, Adeli K. Role of resveratrol in the management of insulin resistance and related conditions: Mechanism of action. Crit Rev Clin Lab Sci. 2017; 54(4): 267-93. DOI: 10.1080/10408363.2017.1343274
18- Boström P, Andersson L, Vind B, Håversen L, Rutberg M, Wickström Y, et al. The SNARE protein SNAP23 and the SNARE-interacting protein Munc18c in human skeletal muscle are implicated in insulin resistance/type 2 diabetes. Diabetes. 2010; 59(8): 1870-8. DOI: 10.2337/db09-1503
19- Schlaepfer IR, Pulawa LK, Ferreira LDC, James DE, Capell WH, Eckel RH. Increased expression of the SNARE accessory protein Munc18c in lipid-mediated insulin resistance. J Lipid Res. 2003; 44(6): 1174-81. DOI: 10.1194/jlr.M300003-JLR200