DOI: https://doi.org/10.22141/2224-0721.13.5.2017.110024

The role of the immune system in mechanism of metformin therapeutic effect in patients with type 2 diabetes

K.P. Zak, V.L. Orlenko, V.V. Popova, S.V. Melnichenko, Ya.A. Saenko, К.M. Tronko, A.V. Kulikovskaya, К.Yu. Ivaskiva

Abstract


Background. Metformin is one of the most prescribed hypoglycemic drugs of the first line of treatment for patients with type 2 diabetes (T2D). However, the mechanism of its therapeutic effect has not been sufficiently studied. At the same time, T2D is considered a disease of an inflammatory nature, wherein different immune responses are disturbed. However, only single articles are devoted to the role of the immune system in the mechanism of the therapeutic action of metformin. Purpose of the study. Elucidation of the question to what extent different types of leukocytes, immunophenotype of lymphocytes and some cytokines are involved in the mechanism of the therapeutic action of metformin. Materials and methods. A group of patients of both sexes with a newly diagnosed T2D with BMI of 33.1 ± 1.3 kg/m2 who had not yet taken hypoglycemic agents and a group of normoglycemic healthy individuals of the same age and sex were examined. The number of leukocytes in blood was determined using the hematological analyzers, and the leukocyte composition — in Pappenheim stained smears. Immunophenotype of lymphocytes (CD3+ T, CD4+ T, CD8+ T, CD56+) — by flow cytometry using the FACStar plus cytofluorimeter. The content of different cytokines (I-1b, TNF-a and IL-10) — with immunosorbent ELISA assay. Results. The metformin therapy of newly diagnosed T2D patients with obesity leads to normalization of the increased number of leukocytes, neutrophils and monocytes, as well as a decrease in CD4+ T cells in the blood, especially in patients with high BMI. A characteristic feature of the therapy is a sharp decrease in anti-inflammatory cytokines (IL-1b and TNF-a) that were elevated before treatment. The obtained data indicate significant disorders of natural and adaptive immunity in T2D and confirm the hypothesis about the inflammatory nature of this disease. Conclusions. The favorable therapeutic effect of metformin in T2D, especially complicated by obesity, is largely due to the normalization of inflammation and immunity indices.


Keywords


immunity; type 2 diabetes; treatment with metformin

Full Text:

PDF

References


Abbasi F, Chu JW, McLaughlin T, Lamendola C, Leary ET, Reaven GM. Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus. Metabolism. 2004 Feb;53(2):159-64. PMID: 14767866.

Baig S, Rizi EP, Shabeer M, et al. Acute meal challenge and modulation of postprandial immune-metabolic response in peripheral blood mononuclear cells, in lean, insulin-sensitive and obese, insulin-resistant Chinese. Diabetes. 2015;64(1):467.

Bouter KP, Meyling FH, Hoekstra JB, Masurel N, Erkelens DW, Diepersloot RJ. Influence of blood glucose levels on peripheral lymphocytes in patients with diabetes mellitus. Diabetes Res. 1992 Feb;19(2):77-80. PMID: 1286542.

Brooks-Worrell BM, Palmer JP. Attenuation of islet-specific T cell responses is associated with C-peptide improvement in autoimmune type 2 diabetes patients. Clin Exp Immunol. 2013 Feb; 171(2): 164–70. doi: 10.1111/cei.12012

Buse JB, DeFronzo RA, Rosenstock J, et al. The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care. 2016 Feb;39(2):198-205. doi: 10.2337/dc15-0488.

Cameron AR, Morrison V, McNeilly AD, et al. The anti-inflammatory role of metformin. Diabetes. 2015 Jun;64(6):1822.

Сhe TT, Ren Y, Liu SF. Expression of circulating CD4+CD25+ FOXP3+ regulatory T cells in obese patients. Diabetologia. 2013;56(1):563.

Coppola A, Caputo MP, Pastore D, et al. Metformin inhibits leptin release induced by HMGB1 and exerts an anti-inflammatory action reducing TLR4/2 expression in T2D subjects. Diabetes. 2015;64(1):1830.

De la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, et al. Metformin Is Associated With Higher Relative Abundance of Mucin-Degrading Akkermansia muciniphila and Several Short-Chain Fatty Acid-Producing Microbiota in the Gut. Diabetes Care. 2017 Jan;40(1):54-62. doi: 10.2337/dc16-1324.

Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011 Apr 7;117(14):3720-32. doi: 10.1182/blood-2010-07-273417.

Donath MY. Multiple benefits of targeting inflammation in the treatment of type 2 diabetes. Diabetologia. 2016 Apr;59(4):679-82. doi: 10.1007/s00125-016-3873-z.

Fabbrini E, Cella M, McCartney SA, et al. Association between specific adipose tissue CD4+ T-cell populations and insulin resistance in obese individuals. Gastroenterology. 2013 Aug;145(2):366-74.e1-3. doi: 10.1053/j.gastro.2013.04.010.

Ford ES. Leukocyte count, erythrocyte sedimentation rate, and diabetes incidence in a national samples of US adults. Am J Epidemiol. 2002 Jan 1;155(1):57-64. PMID: 11772785.

Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011 Feb;50(2):81-98. doi: 10.2165/11534750-000000000-00000.

Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415-45. doi: 10.1146/annurev-immunol-031210-101322.

Hattori Y, Hattori K, Hayashi T. Pleiotropic benefits of metformin: macrophage targeting its anti-inflammatory mechanisms. Diabetes. 2015 Jun;64(6):1907-9. doi: 10.2337/db15-0090.

Herder C1, Peltonen M, Koenig W, et al. Anti-inflammatory effect of lifestyle changes in the Finnish Diabetes Prevention Study. Diabetologia. 2009 Mar;52(3):433-42. doi: 10.1007/s00125-008-1243-1.

Hong SJ, Kim ST, Kim TJ, et al. Cellular and molecular changes associated with inhibitory effect of pioglitazone on neointimal growth in patients with type 2 diabetes after zotarolimus-eluting stent implantation. Arterioscler Thromb Vasc Biol. 2010 Dec;30(12):2655-65. doi: 10.1161/ATVBAHA.110.212670.

Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012 Jun;35(6):1364-79. doi: 10.2337/dc12-0413.

Kim JA, Park HS. White blood cell count and abdominal fat distribution in female obese adolescents. Metabolism. 2008 Oct;57(10):1375-9. doi: 10.1016/j.metabol.2008.05.005.

Konopka AR, Esponda RR, Robinson MM, et al. Hyperglucagonemia mitigates the effect of metformin on glucose production in prediabetes. Cell Rep. 2016 May 17;15(7):1394-1400. doi: 10.1016/j.celrep.2016.04.024.

Kűhtreiber WM, Burger D, Reinhold III PE. et al. Heterogeneity in type 1 diabetics is defined by contrasting C-peptide declines, autoreactive T cell burdens, and metabolic differences. Diabetes. 2015;64(4):1105-7.

Kullo IJ, Hensrud DD, Allison TG. Comparison of numbers of circulating blood monocytes in men grouped by body mass index (<25, 25 to <30, > or =30). Am J Cardiol. 2002 Jun 15;89(12):1441-3. PMID: 12062747.

Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2011 Mar;13(3):221-8. doi: 10.1111/j.1463-1326.2010.01349.x.

Luo T, Nocon A, Fry J. et al. AMPK activation by metformin suppresses abnormal extracellular matrix remodelling in adipose tissue and ameliorates insulin resistance in obesity. Diabetes. 2016 Aug;65(8):2295-310. doi: 10.2337/db15-1122. Epub 2016 May 13.

Mulherin AJ1, Oh AH, Kim H, Grieco A, Lauffer LM, Brubaker PL. Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell. Endocrinology. 2011 Dec;152(12):4610-9. doi: 10.1210/en.2011-1485.

O’Rourke RW, White AE, Metcalf MD, et al. Hypoxia-induced inflammatory cytokine secretion in human adipose tissue stromovascular cells. Diabetologia. 2011 Jun;54(6):1480-90. doi: 10.1007/s00125-011-2103-y.

Orlenko VL, Zak KP. Treatment with Glucagon-Like Peptide-1 Analogues — a Breakthrough in Diabetes Mellitus Type 2 Therapy. Mezhdunarodnyi Endokrinologicheskii Zhurnal. 2014;4(60):112-7. doi:10.22141/2224-0721.4.60.2014.76690. (in Russian).

Pernicova I, Korbonits M. Metformin – mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014 Mar;10(3):143-56. doi: 10.1038/nrendo.2013.256.

Pham MN, Hawa MI, Pfleger C, et al. Pro- and anti-inflammatory cytokines in latent autoimmune diabetes in adults, type 1 and type 2 diabetes patients: Action LADA 4. Diabetologia. 2011 Jul;54(7):1630-8. doi: 10.1007/s00125-011-2088-6.

Sang R. Mechanism of metformin: a tale of two sites. Diabetes Care. 2016 Feb;39(2):187-9. doi: 10.2337/dci15-0013.

Saienko YaA, Zak KP, Popova VV, Semionova TA. Leukocyte Composition and Immunophenotype of the Blood Lymphocytes in Women with Type 2 Diabetes Mellitus and Obesity. Mezhdunarodnyi Endokrinologicheskii Zhurnal. 2016;5(77):13-9. doi:10.22141/2224-0721.5.77.2016.78748. (in Russian).

Schipper HS, Nuboer R, Prop S, et al. Systemic inflammation in childhood obesity: circulating inflammatory mediators and activated CD14++ monocytes. Diabetologia. 2012 Oct;55(10):2800-2810. doi: 10.1007/s00125-012-2641-y.

Seyhan A, Nunes-Lopez Yu, Garufi G. Differences in serum cytokine concentration in lean and obese individuals with prediabetes and type 2 diabetes. Diabetes. 2015;64(1):472.

Simmons RK, Alberti KG, Gale EAM, et al. The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation. Diabetologia. 2010 Apr;53(4):600-5. doi: 10.1007/s00125-009-1620-4.

Tsai S, Clemente-Casares X, Revelo XS, Winer S, Winer DA. Are obesity-related insulin resistance and type 2 diabetes autoimmune diseases? Diabetes. 2015 Jun;64(6):1886-97. doi: 10.2337/db14-1488.

Tseng E, Yeh HC, Maruthur NM. Metformin Use in Prediabetes Among U.S. Adults, 2005-2012. Diabetes Care. 2017 Jul;40(7):887-893. doi: 10.2337/dc16-1509.

Wang Q, Zhang M, Torres G. et al. Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission. Diabetes. 2017 Jan;66(1):193-205. doi: 10.2337/db16-0915.

Womack J, Tien PC, Feldman J, et al. Obesity and immune cell counts in women. Metabolism. 2007 Jul;56(7):998-1004. doi: 10.1016/j.metabol.2007.03.008.

Zak KP, Popova VV. The Prediction of Type 1 Diabetes Development and Diagnosis of Its Asymptomatic Phase Using Autoantibodies to Human Islets of Langerhans Long Before the Onset of the Disease. Mezhdunarodnyi Endokrinologicheskii Zhurnal. 2016;7(79):11-21. doi:10.22141/2224-0721.7.79.2016.86414. (in Russian).

Zak KP. The Role of Neutrophilic Leukocytes in the Pathogenesis of Human Type 1 Diabetes (Analytical Review with the Inclusion of Our Own Data). Mezhdunarodnyi Endokrinologicheskii Zhurnal. 2016;2(74):130-9. doi: 10.22141/2224-0721.2.74.2016.70956 . (in Russian).




Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

 

© "Publishing House "Zaslavsky", 1997-2018

 

   Seo анализ сайта