Elevated CD14 ++ CD16 + Monocytes in Hyperhomocysteinemia-Associated Insulin Resistance in Polycystic Ovary Syndrome

Abstract

Background:

Hyperhomocysteinemia, chronic low-grade inflammation, and insulin resistance are predominant features in women with polycystic ovary syndrome (PCOS). CD14⁺⁺CD16⁺ inflammatory monocytes are elevated in cardiovascular diseases and diabetes, in which inflammation is one of the pathogenesis. We aimed to determine whether homocysteine levels are associated with monocyte subtypes or insulin resistance in women with PCOS.

Methods:

A cross-sectional study was conducted between December 2014 and June 2015 at Peking University Third Hospital. Among 196 Chinese patients with PCOS enrolled, 102 had homocysteine levels ≥10 µmol/L and 94 exhibited normal homocysteine levels. Monocyte surface markers and related cytokines were detected in peripheral blood samples using a flow cytometry, and data on insulin resistance and homocysteine levels were collected.

Results:

Our results showed that fasting insulin and homeostasis model assessment indices that reflect the severity of insulin resistance were increased in the hyperhomocysteinemia PCOS group. Simple linear regression analysis revealed that homocysteine level is one of the influence factors of insulin resistance in PCOS. Compared with the normal homocysteine group, patients with hyperhomocysteinemia had increased numbers of CD14⁺⁺CD16⁺ inflammatory monocyte in their peripheral blood and elevated plasma levels of interleukin-1β and interleukin-6, 2 typical cytokines secreted by the inflammatory monocytes. Unlike CD14⁺CD16⁺⁺ nonclassical monocytes, CD14⁺⁺CD16⁺ inflammatory monocytes are characterized by high expression of Human leukocyte antigen-antigen D related (HLA-DR).

Conclusions:

Our findings indicate that CD14⁺⁺CD16⁺ inflammatory monocytes are associated with hyperhomocysteinemia and insulin resistance in patients with PCOS. Notably, CD14⁺⁺CD16⁺ monocytes may contribute to the pathogenesis of insulin resistance in women with PCOS.

Keywords

polycystic ovary syndrome insulin resistance hyperhomocysteinemia

Get full access to this article

View all access options for this article.

References

Norman

Dewailly

Legro

Hickey

. Polycystic ovary syndrome. Lancet. 2007;370(9588):685–697.

Dumesic

Oberfield

Stener-Victorin

Marshall

Laven

Legro

. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev. 2015;36(5):487–525.

DeUgarte

Bartolucci

Azziz

. Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertil Steril. 2005;83(5):1454–1460.

Zhang

Yang

. Prevalence of polycystic ovary syndrome in women in China: a large community-based study. Hum Reprod. 2013;28(9):2562–2569.

Legro

Arslanian

Ehrmann

; Endocrine Society. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(12):4565–4592.

Glass

Olefsky

. Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab. 2012;15(5):635–645.

Wynn

Chawla

Pollard

. Macrophage biology in development, homeostasis and disease. Nature. 2013;496(7446):445–455.

Olefsky

Glass

. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–246.

Italiani

Boraschi

. From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation. Front Immunol. 2014;5:514.

10.

Wong

Yeap

Tai

Ong

Dang

Wong

. The three human monocyte subsets: implications for health and disease. Immunol Res. 2012;53(1-3):41–57.

11.

Fadini

Cappellari

Mazzucato

Agostini

Vigili de Kreutzenberg

Avogaro

. Monocyte-macrophage polarization balance in pre-diabetic individuals. Acta Diabetol. 2013;50(6):977–982.

12.

Clarke

Daly

Robinson

. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991;324(17):1149–1155.

13.

Refsum

Ueland

Nygard

Vollset

. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31–62.

14.

Yang

Fan

Zhi

. Prevalence of hyperhomocysteinemia in China: a systematic review and meta-analysis. Nutrients. 2014;7(1):74–90.

15.

Jiang

. Homocysteine upregulates resistin production from adipocytes in vivo and in vitro. Diabetes. 2008;57(4):817–827.

16.

Zhang

Jiang

. Hyperhomocysteinemia promotes insulin resistance by inducing endoplasmic reticulum stress in adipose tissue. J Biol Chem. 2013;288(14):9583–9592.

17.

Jiang

Zhang

. Homocysteine promotes vascular smooth muscle cell migration by induction of the adipokine resistin. Am J Physiol Cell Physiol. 2009;297(6):C1466–C1476.

18.

Zeng

Dai

Remick

Wang

. Homocysteine mediated expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human monocytes. Circ Res. 2003;93(4):311–320.

19.

Zhang

Jiang

Fang

. Hyperhomocysteinemia promotes inflammatory monocyte generation and accelerates atherosclerosis in transgenic cystathionine beta-synthase-deficient mice. Circulation. 2009;120(19):1893–1902.

20.

Nafiye

Sevtap

Muammer

Emre

Senol

Leyla

. The effect of serum and intrafollicular insulin resistance parameters and homocysteine levels of nonobese, nonhyperandrogenemic polycystic ovary syndrome patients on in vitro fertilization outcome. Fertil Steril. 2010;93(6):1864–1869.

21.

Salehpour

Manzor-Al-Ajdad

Samani

Abadi

. Evaluation of homocysteine levels in patients with polycystic ovarian syndrome. Int J Fertil Steril. 2011;4(4):168–171.

22.

Berker

Kaya

Aytac

Satiroglu

. Homocysteine concentrations in follicular fluid are associated with poor oocyte and embryo qualities in polycystic ovary syndrome patients undergoing assisted reproduction. Hum Reprod. 2009;24(9):2293–2302.

23.

Grodnitskaya

Kurtser

. Homocysteine metabolism in polycystic ovary syndrome. Gynecol Endocrinol. 2012;28(3):186–189.

24.

Maleedhu

S B

Kodumuri

Devi

. Status of homocysteine in polycystic ovary syndrome (PCOS). J Clin Diagn Res. 2014;8(2):31–33.

25.

Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41–47.

26.

Qin

Huo

. H-type hypertension, stroke and diabetes in China: opportunities for primary prevention. J Diabetes. 2016;8(1):38–40.

27.

Chen

Wang

Zheng

Zeng

Liu

. H-type hypertension is an important risk factor of carotid atherosclerotic plaques. Clin Exp Hypertens. 2016;38(5):424–428.

28.

Yang

. Prevalence and predictors of metabolic abnormalities in Chinese women with PCOS: a cross-sectional study. BMC Endocr Disord. 2014;14:76.

29.

Xiong

Liang

Yang

Wei

. Low-grade chronic inflammation in the peripheral blood and ovaries of women with polycystic ovarian syndrome. Eur J Obstet Gynecol Reprod Biol. 2011;159(1):148–150.

30.

Diamanti-Kandarakis

Paterakis

Alexandraki

. Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin. Hum Reprod. 2006;21(6):1426–1431.

31.

Tang

Zhang

Kwak-Kim

Liao

. CD14++ CD16+ HLA-DR+ monocytes in peripheral blood are quantitatively correlated with the severity of pre-eclampsia. Am J Reprod Immunol. 2015;74(2):116–122.

32.

Wildgruber

Aschenbrenner

Wendorff

. The “intermediate” CD14++CD16+ monocyte subset increases in severe peripheral artery disease in humans. Sci Rep. 2016;6:39483.

33.

Kzhyshkowska

Gudima

Moganti

Gratchev

Orekhov

. Perspectives for monocyte/macrophage-based diagnostics of chronic inflammation. Transfus Med Hemother. 2016;43(2):66–77.

34.

Rogacev

Cremers

Zawada

. CD14++CD16+ monocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective coronary angiography. J Am Coll Cardiol. 2012;60(16):1512–1520.

35.

Ozaki

Imanishi

Taruya

. Circulating CD14+CD16+ monocyte subsets as biomarkers of the severity of coronary artery disease in patients with stable angina pectoris. Circ J. 2012;76(10):2412–2418.

36.

Belge

Dayyani

Horelt

. The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J Immunol. 2002;168(7):3536–3542.

37.

Libby

Nahrendorf

Swirski

. Monocyte heterogeneity in cardiovascular disease. Semin Immunopathol. 2013;35(5):553–562.

38.

Chimen

Yates

McGettrick

. Monocyte subsets coregulate inflammatory responses by integrated signaling through TNF and IL-6 at the endothelial cell interface. J Immunol. 2017;198(7):2834–2843.

39.

Antonelli

Leoratti

Costa

. The CD14+CD16+ inflammatory monocyte subset displays increased mitochondrial activity and effector function during acute Plasmodium vivax malaria. PLoS Pathog. 2014;10(9):e1004393.

40.

Rossol

Kraus

Pierer

Baerwald

Wagner

. The CD14(bright) CD16+ monocyte subset is expanded in rheumatoid arthritis and promotes expansion of the Th17 cell population. Arthritis Rheum. 2012;64(3):671–677.

41.

Smeekens

van de Veerdonk

Joosten

. The classical CD14⁺⁺ CD16⁻ monocytes, but not the patrolling CD14⁺ CD16⁺ monocytes, promote Th17 responses to Candida albicans . Eur J Immunol. 2011;41(10):2915–2924.