Association of Endothelin-I and A symmetric Dimethylarginine Levels with Insulin Resistance in Type-2 Diabetes Mellitus Patients

Main Article Content

Sara Muhammed Khidhir
Almas. MR Mahmud
Ismail M. Maulood

Abstract

Endothelin-I (ET-I) is one of the potent vasoconstrictors secreted from endothelial cells when needed. Many studies revealed the elevation of serum ET-I with human diabetes and microangiopathies. Since insulin resistance is a case of mixed diabetic and pre-diabetic cases, many risk factors beyond obesity and inflammation are proposed. The current study aims to demonstrate the association between serum ET-I and asymmetric dimethylarginine (ADMA) and insulin resistance in type 2 diabetes mellitus (T2DM). Sera of 73 subjects were enrolled currently (control= 35 subjects, and 38 with T2DM for more than 7 years), aged (40-60) years old, with distinct body mass index (BMI) ≤ 25 for control volunteers and (BMI) ≥ 25 for obesity and diabetes patients. Peripheral serum ET-I and ADMA levels were significantly (P≤ 0.0001) higher in T2DM than the control subjects. Receiver operating characteristic curve analysis regarded ET-I and ADMA as good markers for T2DM disease and insulin resistance, correlations between ET-I and anthropometrics revealed a strong increase of urotensin-II (UII), ADMA, homeostatic model assessment for insulin resistance (HOMA-IR) and hemoglobin A1C (HbA1C) with an increase of ET-I. These results are supported by the data of multiple regression analysis, showing that HOMA-IR, HbA1C, UII, BMI, and mean arterial pressure (MAP) are related to ET-I independently. The endothelin-I and ADMA had a positive relationship with increase insulin resistance and may serve as prognostic and diagnostic clinical biomarkers of insulin resistance. Collectively, Therefore, these measurements could evaluate the incidence of DM, and help to better rise up the knowledge about the progression of DM complications.

Downloads

Download data is not yet available.

Article Details

How to Cite
1.
Khidhir SM, Mahmud AM, Maulood IM. Association of Endothelin-I and A symmetric Dimethylarginine Levels with Insulin Resistance in Type-2 Diabetes Mellitus Patients. Baghdad Sci.J [Internet]. [cited 2021Dec.4];19(1):0055. Available from: https://bsj.uobaghdad.edu.iq/index.php/BSJ/article/view/5802
Section
article

References

Chai SB, Li XM, Pang YZ, Qi YF, Tang CS.

Increased plasma levels of endothelin-1 and

urotensin-II in patients with coronary heart disease.

Heart and vessels. 2010;25(2):138-43.

Palmer MK, Barter PJ, Lundman P, Nicholls SJ, Toth

PP, Karlson BW. Comparing a novel equation for

calculating low-density lipoprotein cholesterol with

the Friedewald equation: A VOYAGER analysis.

Clin. Biochem. 2019;64:24-9.

Ruze R, Xiong YC, Li JW, Zhong MW, Xu Q, Yan

ZB, et al. Sleeve gastrectomy ameliorates endothelial

function and prevents lung cancer by normalizing

endothelin-1 axis in obese and diabetic rats. World J

Gastroenterol. 2020;26(20):2599-617.

Fouda AY, Fagan SC, Ergul A. Brain Vasculature

and Cognition. Arterioscler. Thromb. Vasc. Biol.

;39(4):593-602.

Kaur R, Kaur M, Singh J. Endothelial dysfunction

and platelet hyperactivity in type 2 diabetes mellitus:

molecular insights and therapeutic strategies.

Cardiovasc. Diabetol. 2018;17(1):121.

D'Souza A, Hussain M, Howarth FC, Woods NM,

Bidasee K, Singh J. Pathogenesis and

pathophysiology of accelerated atherosclerosis in the

diabetic heart. Mol. Cell. Biochem. 2009;331(1-

:89-116.

Brownlee M. The pathobiology of diabetic

complications: a unifying mechanism. Diabetes.

;54(6):1615-25.

Maamoun H, Abdelsalam SS, Zeidan A, Korashy

HM, Agouni A. Endoplasmic Reticulum Stress: A

Critical Molecular Driver of Endothelial Dysfunction

and Cardiovascular Disturbances Associated with

Diabetes. Int. J. Mol. Sci. 2019;20(7).

Luo Z, Aslam S, Welch WJ, Wilcox CS. Activation

of nuclear factor erythroid 2-related factor 2

coordinates dimethylarginine

dimethylaminohydrolase/PPAR-gamma/endothelial

nitric oxide synthase pathways that enhance nitric

oxide generation in human glomerular endothelial

cells. Hypertension (Dallas, Tex : 1979).

;65(4):896-902.

Muniyappa R, Sowers JR. Role of insulin resistance

in endothelial dysfunction. Rev Endocr Metab

Disord. 2013;14(1):5-12.

Open Access Baghdad Science Journal P-ISSN: 2078-8665

, 19(1): 55-63 E-ISSN: 2411-7986

Patel DM, Bose M, Cooper ME. Glucose and Blood

Pressure-Dependent Pathways-The Progression of

Diabetic Kidney Disease. Int. J. Mol. Sci. 2020;21(6).

Lee W, Lee HJ, Jang HB, Kim HJ, Ban HJ, Kim KY,

et al. Asymmetric dimethylarginine (ADMA) is

identified as a potential biomarker of insulin

resistance in skeletal muscle. Sci. Rep.

;8(1):2133.

Huey-Jen Hsu S, Chen MF, Chen DR, Su TC.

Validation of the Estimation of Low-density

Lipoprotein Cholesterol by the Modified Friedewald

Equation in Ethnic Chinese Adults Living in Taiwan.

Intern Med J (Tokyo, Japan). 2015;54(18):2291-7.

Eldin Ahmed Abdelsalam K, Alobeid MEA.

Influence of Grand Multiparity on the Levels of

Insulin, Glucose and HOMA-IR in Comparison with

Nulliparity and Primiparity. Pak. J. Biol. Sci. : PJBS.

;20(1):42-6.

Duncan GE, Hutson AD, Stacpoole PW. QUICKI

does not accurately reflect changes in insulin

sensitivity with exercise training. The J. Clin.

Endocrinol. Metab. 2001;86(9):4115-9.

Sauzeau V, Le Mellionnec E, Bertoglio J, Scalbert E,

Pacaud P, Loirand G. Human urotensin II–induced

contraction and arterial smooth muscle cell

proliferation are mediated by RhoA and Rho-kinase.

Circ Res. 2001;88(11):1102-4.

Ratajczak-Wrona W, Jablonska E, Antonowicz B,

Dziemianczyk D, Grabowska SZ. Levels of

biological markers of nitric oxide in serum of patients

with squamous cell carcinoma of the oral cavity. Int J

Oral Sci. 2013;5(3):141-5.

Jablonska E, Kiersnowska-Rogowska B, Ratajczak

W, Rogowski F, Sawicka-Powierza J. Reactive

oxygen and nitrogen species in the course of B-CLL.

Advances in medical sciences. 2007;52:154-8.

Kelter R. Analysis of Bayesian posterior significance

and effect size indices for the two-sample t-test to

support reproducible medical research. BMC Med

Res Methodol. 2020;20(1):88.

Rovira-Llopis S, Bañuls C, Diaz-Morales N,

Hernandez-Mijares A, Rocha M, Victor VM.

Mitochondrial dynamics in type 2 diabetes:

Pathophysiological implications. Redox Biol.

;11:637-45.

Berra-Romani R, Guzmán-Silva A, VargazGuadarrama A, Flores-Alonso JC, Alonso-Romero J,

Treviño S, et al. Type 2 Diabetes Alters Intracellular

Ca(2+) Handling in Native Endothelium of Excised

Rat Aorta. Int. J. Mol. Sci. 2019;21(1).

He Y, Ding Y, Liang B, Lin J, Kim TK, Yu H, et al.

A Systematic Study of Dysregulated MicroRNA in

Type 2 Diabetes Mellitus. Int. J. Mol. Sci.

;18(3).

Chalghoum A, Noichri Y, Karkouch I, Dandana A,

Baudin B, Jeridi G, et al. Metabolic interactions

between hyperhomocysteinemia and endothelin-1

among Tunisian patients with acute coronary

diseases. Biol. Res. 2015;48(1):32.

Inoue A, Yanagisawa M, Kimura S, Kasuya Y,

Miyauchi T, Goto K, et al. The human endothelin

family: three structurally and pharmacologically

distinct isopeptides predicted by three separate genes.

PNAS USA. 1989;86(8):2863-7.

Reynolds LJ, Credeur DP, Manrique C, Padilla J,

Fadel PJ, Thyfault JP. Obesity, type 2 diabetes, and

impaired insulin-stimulated blood flow: role of

skeletal muscle NO synthase and endothelin-1.

Physiol. (Bethesda, Md : 1985). 2017;122(1):38-47.

Pfützner A, Standl E, Hohberg C, Konrad T,

Strotmann HJ, Lübben G, et al. IRIS II study: intact

proinsulin is confirmed as a highly specific indicator

for insulin resistance in a large cross-sectional study

design. Diabetes Technol Ther. 2005;7(3):478-86.

Arunagiri A, Haataja L, Pottekat A, Pamenan F, Kim

S, Zeltser LM, et al. Proinsulin misfolding is an early

event in the progression to type 2 diabetes. eLife.

;8.

Schäfer A, Gjerga E, Welford RW, Renz I, Lehembre

F, Groenen PM, et al. Elucidating essential kinases of

endothelin signalling by logic modelling of

phosphoproteomics data. Mol. Syst. Biol.

;15(8):e8828.

Bijelic R, Balaban J, Milicevic S, Sipka SU. The

Association of Obesity and Microvascular

Complications with Glycemic Control in Patients

with Type 2 Diabetes Mellitus. Med Arch (Sarajevo,

Bosnia and Herzegovina). 2020;74(1):14-8.

Reynolds LJ, Credeur DP, Manrique C, Padilla J,

Fadel PJ, Thyfault JP. Obesity, type 2 diabetes, and

impaired insulin-stimulated blood flow: role of

skeletal muscle NO synthase and endothelin-1. J.

Appl. Physiol. 2017;122(1):38-47.

Jayagopal V, Kilpatrick ES, Jennings PE, Hepburn

DA, Atkin SL. Biological variation of homeostasis

model assessment-derived insulin resistance in type 2

diabetes. Diabetes Care. 2002;25(11):2022-5.

El Assar M, Angulo J, Santos-Ruiz M, Ruiz de Adana

JC, Pindado ML, Sánchez-Ferrer A, et al.

Asymmetric dimethylarginine (ADMA) elevation and

arginase up-regulation contribute to endothelial

dysfunction related to insulin resistance in rats and

morbidly obese humans. J Physiol.

;594(11):3045-60.

Caplin B, Leiper J. Endogenous nitric oxide synthase

inhibitors in the biology of disease: markers,

mediators, and regulators? Arterioscler. Thromb.

Vasc. Biol. 2012;32(6):1343-53.

Anderssohn M, Schwedhelm E, Lüneburg N, Vasan

RS, Böger RH. Asymmetric dimethylarginine as a

mediator of vascular dysfunction and a marker of

cardiovascular disease and mortality: an intriguing

interaction with diabetes mellitus. Diabetes Vasc. Dis.

Res. 2010;7(2):105-18.

Beppu M, Obayashi S, Aso T, Goto M, Azuma H.

Endogenous nitric oxide synthase inhibitors in

endothelial cells, endothelin-1 within the vessel wall,

and intimal hyperplasia in perimenopausal human

uterine arteries. J. Cardiovasc. Pharmacol.

;39(2):192-200.

Enevoldsen FC, Sahana J, Wehland M, Grimm D,

Infanger M, Krüger M. Endothelin Receptor

Antagonists: Status Quo and Future Perspectives for

Targeted Therapy. Clin. Med. 2020;9(3).

Open Access Baghdad Science Journal P-ISSN: 2078-8665

, 19(1): 55-63 E-ISSN: 2411-7986

Xiong Y, Hai CX, Fang WJ, Lei YP, Li XM, Zhou

XK. Endogenous asymmetric dimethylarginine

accumulation contributes to the suppression of

myocardial mitochondrial biogenesis in type 2

diabetic rats. NUTR METAB. 2020;17:72.

Sell H, Laurencikiene J, Taube A, Eckardt K, Cramer

A, Horrighs A, et al. Chemerin is a novel adipocytederived factor inducing insulin resistance in primary

human skeletal muscle cells. Diabetes.

;58(12):2731-40.

Burhans MS, Hagman DK, Kuzma JN, Schmidt KA,

Kratz M. Contribution of Adipose Tissue

Inflammation to the Development of Type 2 Diabetes

Mellitus. Compr.Physiol. 2018;9(1):1-58.

Ross R, Neeland IJ, Yamashita S, Shai I, Seidell J,

Magni P, et al. Waist circumference as a vital sign in

clinical practice: a Consensus Statement from the IAS

and ICCR Working Group on Visceral Obesity. Nat.

Rev. Endocrinol. 2020;16(3):177-89.

Li YY, Shi ZM, Yu XY, Feng P, Wang XJ. Urotensin

II-induced insulin resistance is mediated by NADPH

oxidase-derived reactive oxygen species in HepG2

cells. World J Gastroenterol. 2016;22(25):5769-79.

Kaneto H, Nakatani Y, Miyatsuka T, Kawamori D,

Matsuoka TA, Matsuhisa M, et al. Possible novel

therapy for diabetes with cell-permeable JNKinhibitory peptide. Nat. Med. 2004;10(10):1128-32.

Maguire JJ, Kuc RE, Davenport AP. Orphan-receptor

ligand human urotensin II: receptor localization in

human tissues and comparison of vasoconstrictor

responses with endothelin-1. Br. J. Pharmacol.

;131(3):441-6.