Effect of combined treatment with insulin and metformin on 5′AMP-activated protein kinase activity in lymphocytes of diabetic patients

1Sokolova, LK
1Pushkarev, VM
1Belchina, Yu.B
1Pushkarev, VV
1Tronko, MD
1V.P. Komisarenko Institute of Endocrinology and Metabolism of the NAMS of Ukraine, Kyiv
Dopov. Nac. akad. nauk Ukr. 2018, 5:100-104
Section: Medicine
Language: English

The activity of 5′adenosine monophosphate-activated protein kinase (AMPK), controlling the energy balance of a cell, in blood cells at the combined treatment of patients with type 2 diabetes with metformin and insulin was determined by enzyme immunoassay. It has been shown that metformin increases three-fold the AMPK activity in lymphocytes of patients with type 2 diabetes, compared with patients before treatment. Insulin and its analog reduced the activity of the protein kinase stimulated by metformin in the blood cells, acting as metformin antagonists. The mechanisms of drug interaction and the consequences of their antagonism are discussed.

Keywords: AMPK, insulin, metformin, type 2 diabetes
  1. Standards of medical care in diabetes — 2018. (2018). Diabetes Care., 41, Suppl. 1, pp. S1-S2. doi: https://doi.org/10.2337/dc18-Sint01
  2. Hung, A. M., Roumie, C. L., Greevy, R. A., Grijalva, C. G., Liu, X., Murff, H. J., Ikizler, T. A. & Griffin, M. R. (2016). Comparative effectiveness of second-line agents for the treatment of diabetes type 2 in preventing kidney function decline. Clin. J. Am. Soc. Nephrol., 11, No. 12, pp. 2177-2185. doi: https://doi.org/10.2215/CJN.02630316
  3. Roumie, C. L., Greevy, R. A., Grijalva, C. G., Hung, A. M., Liu, X., Murff, H. J., Elasy, T. A. & Griffin, M. R. (2014). Association between intensification of metformin treatment with insulin vs sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes. JAMA, 311, No. 22, pp. 2288-2296. doi: https://doi.org/10.1001/jama.2014.4312
  4. Roumie, C. L., Min, J. Y., D'Agostino McGowan, L., Presley, C., Grijalva, C. G., Hackstadt, A. J., Hung, A. M., Greevy, R. A., Elasy, T. & Griffin, M. R. (2017). Comparative safety of sulfonylurea and metformin monotherapy on the risk of heart failure: a cohort study. J. Am. Heart Assoc., 6, No. 4, e005379. doi: https://doi.org/10.1161/JAHA.116.005379
  5. Molinuevo, M. S., Schurman, L., McCarthy, A. D., Cortizo, A. M., Tolosa, M. J., Gangoiti, M. V., Arnol, V. & Sedlinsky, C. (2010). Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies. J. Bone Miner. Res., 25, No. 2, pp. 211-221. doi: https://doi.org/10.1359/jbmr.090732
  6. Meng, S., Cao, J., He, Q., Xiong, L., Chang, E., Radovick, S., Wondisford, F. E. & He, L. (2015). Metformin activates AMP-activated protein kinase by promoting formation of the αβγ heterotrimeric complex. J. Biol. Chem., 290, pp. 3793-3802. doi: https://doi.org/10.1074/jbc.M114.604421
  7. Yang, X., Xu, Z., Zhang, C., Cai, Z. & Zhang, J. (2017). Metformin, beyond an insulin sensitizer, targeting heart and pancreatic β cells. Biochim. Biophys. Acta., 1863, No. 8, pp. 1984-1990. doi: https://doi.org/10.1016/j.bbadis.2016.09.019
  8. Valentine, R. J., Coughlan, K. A., Ruderman, N. B. & Saha, A. K. (2014). Insulin inhibits AMPK activity and phosphorylates AMPK Ser485/491 through Akt in hepatocytes, myotubes and incubated rat skeletal muscle. Arch. Biochem. Biophys., 562, pp. 62-69. doi: https://doi.org/10.1016/j.abb.2014.08.013
  9. Omar, B., Zmuda-Trzebiatowska, E., Manganiello, V., Göransson, O. & Degerman, E. (2009). Regulation of AMP-activated protein kinase by cAMP in adipocytes: roles for Phosphodiesterases, Protein kinase B, Protein kinase A, Epac and lipolysis. Cell Signal., 21, No. 5, pp. 760-766. doi: https://doi.org/10.1016/j.cellsig.2009.01.015
  10. Kido, K., Yokokawa, T., Ato, S., Sato, K. & Fujita, S. (2017). Effect of resistance exercise under conditions of reduced blood insulin on AMPKα Ser485/491 inhibitory phosphorylation and AMPK pathway activation. Am. J. Physiol. Regul. Integr. Comp. Physiol., 313, No. 2, pp. R110-R119. doi: https://doi.org/10.1152/ajpregu.00063.2017
  11. Hemmingsen, B., Schroll, J. B., Wetterslev, J., Gluud, C., Vaag, A., Sonne, D. P., Lundstrøm, L. H. & Almdal, T. (2014). Sulfonylurea versus metformin monotherapy in patients with type 2 diabetes: A Cochrane systematic review and meta-analysis of randomized clinical trials and trial sequential analysis. CMAJ Open., No. 2, pp. E162-E175. doi: https://doi.org/10.9778/cmajo.20130073