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Circulating LECT2 Levels in Newly Diagnosed Type 2 Diabetes Mellitus

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Circulating LECT2 Levels in Newly Diagnosed Type 2 Diabetes Mellitus ® Observational Study Medicine OPEN Circulating LECT2 levels in newly diagnosed type 2 diabetes mellitus and their association with metabolic parameters An observational study Zhen Zhang, PhDa, Huixian Zeng, MDb, Jianghong Lin, MDc, Yinghui Hu, MDd, Rui Yang, PhDa, ∗ ∗ Jia Sun, PhDa, Rongping Chen, PhDa, , Hong Chen, PhDa, Abstract Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine expressed in hepatocytes and appears to be involved in energy metabolism. The aim of this study was to determine plasma LECT2 levels in newly diagnosed type 2 diabetic patients and to correlate the results with various metabolic parameters. A total of 93 newly diagnosed type 2 diabetic patients and 80 age- and sex-matched nondiabetes mellitus ones were enrolled in the study. Plasma LECT2 levels were measured by enzyme-linked immunosorbent assay. Circulating LECT2 levels were approximately 1.3 times higher in newly diagnosed type 2 diabetic patients than in controls (mean 30.30 vs 23.23ng/mL, P < .001). Correlation analysis showed that LECT2 was negatively associated with high-density lipoprotein- cholesterol (HDL-C) levels in type 2 diabetic patients and obese subjects (P < .05). In multiple stepwise regression analysis, HDL-C, HOMA-IR, BMI, FINS, and TG were significantly independent determinants for LECT2 (P < .05). Our study showed that circulating LECT2 concentrations are significantly higher in newly diagnosed type 2 diabetic patients and further elevated in obese type 2 diabetic patients. LECT2 concentrations are significantly negatively associated with HDL-cholesterol levels in newly diagnosed type 2 diabetic patients and obese subjects. Abbreviations: ALT = alanine transaminase, AMPK = AMP-activated protein kinase, AST = aspartate transaminase, BMI = body mass index, BP = blood pressure, CV = cofficient of variation, FINS = fasting insulin, FPG = fasting plasma glucose, HbA1c = glycosylated hemoglobin, HDL-C = high-density lipoprotein-cholesterol, HOMA-%b = homeostasis model assessment-b cell function, HOMA-IR = homeostasis model assessment-insulin resistance, hs-CRP = high-sensitivity C-reactive protein, IRS-1 = insulin receptor substrates-1, JNK = c-Jun N-terminal kinase, LDL-C = low-density lipoprotein-cholesterol, LECT2 = leukocyte cell- derived chemotaxin 2, mTOR = mammalian target of rapamycin, NDM = nondiabetes mellitus, T2DM = type 2 diabetes mellitus, TC = total Cholesterol, TG = triglycerides, WC = waist circumference, WHO = World Health Organization. Keywords: glycolipid metabolism, insulin resistance, leukocyte cell-derived chemotaxin 2, type 2 diabetes mellitus Editor: Thomas E. Adrian. 1. Introduction ZZ and HZ equally contributed to this work. Type 2 diabetes mellitus (T2DM) is a chronic, progressive This research was supported by grants from National Science Foundation of debilitating disease, characterized by insulin resistance in relation China (81570716/81500623/81770804). to dysregulated insulin secretion and loss of b-cell mass.[1] T2DM The authors have no conflicts of interest to disclose. has become a serious global public health problem, affecting 336 a Department of Endocrinology and Metabolism, Zhujiang Hospital, Southern million individuals worldwide.[2] Complications linked to Medical University, Guangzhou, b Department of Endocrinology, People’s Hospital diabetes, including cardiovascular and cerebrovascular events, c of Yangjiang City, Yangjiang, Department of Endocrinology and Metabolism, The retinopathy and blindness, nephropathy and renal failure, and Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, d The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China. neuropathy, have resulted in tremendous economic costs and ∗ Correspondence: Hong Chen and Rongping Chen, Department of human health risks. The pathogenesis of type 2 diabetes is greatly Endocrinology and Metabolism, Zhujiang Hospital, Southern Medical University, complicated and contains the varying degrees of insulin Guangzhou 510280, China (e-mails: [email protected], deficiency and insulin resistance resulted from pancreatic b-cell [email protected]). dysfunction. During the last 2 decades, numerous metabolic Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. hormones have been shown to be involved in the pathogenesis of This is an open access article distributed under the terms of the Creative type 2 diabetes. Moreover, the molecular mechanisms of insulin Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC- ND), where it is permissible to download and share the work provided it is resistance appear to be affected by the aberrant secretion of properly cited. The work cannot be changed in any way or used commercially organokines (e.g., adipokines from adipose tissue and myokines without permission from the journal. from skeletal muscle) through autocrine/paracrine and endocrine [3] Medicine (2018) 97:15(e0354) pathways. Analogous to adipokines and myokines, liver- Received: 6 August 2017 / Received in final form: 19 February 2018 / Accepted: derived proteins that are defined as hepatokines, significantly 15 March 2018 regulate glucose and lipid metabolism in the pathogenesis of [4] http://dx.doi.org/10.1097/MD.0000000000010354 insulin resistance and T2DM. 1 Zhang et al. Medicine (2018) 97:15 Medicine Leukocyte cell-derived chemotaxin 2 (LECT2) is a 16-kD (cm), waist and hip circumferences (cm), and systolic and pleiotropy protein which was originally identified as a neutrophil diastolic blood pressure (mmHg). Weight was measured in light chemotactic factor.[5] LECT2 (encoded by human Lect2 gene) is clothing without shoes to the nearest 0.1kg using a calibrated expressed predominantly in human adult and fetal hepatocytes balance scale. Height was measured to the nearest centimeter and is secreted into the bloodstream.[6] The early studies have using a rigid measuring rod. Body mass index (BMI) was reported that LECT2 might function in immune and inflamma- calculated as weight in kilograms divided by the square of height tory responses such as hepatitis,[7] arthritis,[8] and antihepato- in meters. Obesity was defined as BMI ≥25kg/m2 according to – carcinogenesis.[9 11] Although accumulating evidence indicates Asia-Pacific BMI criteria created by the World Health Organiza- that LECT2 acts as a regulator of inflammatory reactions, few tion’s (WHO’s) Western Pacific Region.[17] Waist circumferences studies have focused on the possible involvement of LECT2 in (WCs) (cm) were measured with a nonstretchable tape while the metabolic disorders. Recently, Lan et al[12] redefined LECT2 as a subjects were wearing light clothing. WC (to the nearest 0.1cm) novel hepatokine linking obesity to skeletal muscle insulin was measured at the minimum circumference between the rib resistance. In this study, experiments on animal and cellular cage and the iliac crest. Systolic and diastolic blood pressure (BP) indicated that LECT2 induces insulin resistance in the skeletal was measured using an Omron HEM-907XL Digital sphygmo- muscle by activating c-Jun N-terminal kinase (JNK), which can manometer. An average of 2 BP readings, with 10 minutes apart, inhibit the phosphorylation of insulin receptor substrates-1 (IRS- was obtained. 1).[12,13] Meanwhile, Hwang et al[14] revealed that dipeptidyl peptidase 4 inhibitors improve hepatic steatosis as well as insulin 2.3. Biochemical measurements resistance through AMP-activated protein kinase (AMPK)- and JNK-dependent inhibition of LECT2 expression. Furthermore, Blood samples were collected after an overnight fast, for the Okumura et al[15] demonstrated that serum LECT2 levels are determination of fasting plasma glucose (FPG), insulin level, C- increased in obesity and fatty liver. These data suggest that peptide, glycosylated hemoglobin (HbA1c), total cholesterol LECT2 may be involved in metabolic diseases as an energy- (TC), triglycerides (TG), low-density lipoprotein-cholesterol sensing hepatokine. However, the functional role of LECT2 in (LDL-C), high-density lipoprotein-cholesterol (HDL-C), uric type 2 diabetes development and lipid metabolism remains acid, alanine aminotransferase (ALT), aspartate aminotransfer- unclear. To date, there have been few studies examining the ase (AST), high-sensitivity C-reactive protein (hs-CRP), and clinical significance of circulating LECT2 levels in metabolic LECT2 levels. Fasting plasma glucose (FPG) and lipid profiles diseases including type 2 diabetes in humans. Therefore, this were measured by enzymatic methods. Fasting insulin (FINS) and study aimed to determine circulating LECT2 levels in a large C-peptide levels were measured by enzyme-amplied chemilumi- cohort of subjects with type 2 diabetes and in nondiabetic nescence assays. HbA1c was assessed using an affinity-chro- mellitus controls. Moreover, the relationships of anthropometric matographic method. Serum uric acid levels were evaluated by and metabolic parameters with LECT2 were also investigated. the uricase method; ALT and AST were quantitated by kinetic methods (Beckman Coulter Inc., Brea, CA). High sensitivity C- 2. Materials and methods reactive protein (hsCRP) was assayed by particle-enhanced immunoturbidimetric assay. Plasma LECT2 levels were quanti- 2.1. Subjects fied using a commercially available ELISA kit (Ab-Match From January 2016 to December 2016, a total of 173 adult ASSEMBLY Human LECT2 Kit with Ab-Match UNIVERSAL Chinese subjects (90 males and 83 females), aged 18 to 69 years, Kit; Medical & Biological Laboratories, Nagoya, Japan) were recruited consecutively
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