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Relationship Between Serum Secreted Frizzled-Related Protein 4 Levels And EndocrineORIGINAL Journal 2015 Advance Publication doi: 10.1507/endocrj. EJ15-0212 Relationship between serum secreted frizzled-related protein 4 levels and the first-phase of glucose-stimulated insulin secretion in individuals with different glucose tolerance Fang Liu*, Hua Qu*, Yingjie Li, Qian Tang, Zesong Yang, Hang Wang and Huacong Deng Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, P.R.China Abstract. Recent evidence suggests that serum secreted frizzled-related protein (SFRP) 4 may affect β-cell function. In a cross-sectional clinical study, 56 subjects with type 2 diabetes mellitus (T2DM), 52 subjects with impaired glucose tolerance (IGT) and 42 normal glucose tolerance (NGT) subjects were enrolled to investigate the relationship between SFRP4 levels and the first-phase of glucose-stimulated insulin secretion, glucose metabolism and inflammation. Intravenous glucose tolerance tests were conducted, and acute insulin response (AIR), the area under the curve of the first-phase (0-10 min) insulin secretion (AUC), and the glucose disposition index (GDI) were calculated. The serum levels of SFRP4, IL- 1β, plasma glucose, serum lipid, and glycated hemoglobin (HbA1c) were measured. Levels of serum SFRP4 and IL-1β in the T2DM group and IGT group were significantly higher than those in the NGT group (P < 0.01). The AIR, AUC and GDI between the three groups showed a progressive decrease from the NGT to IGT groups with the lowest value in the T2DM groups (P < 0.01). The serum SFRP4 levels were negatively correlated with AIR, AUC, GDI and HOMA-β (P < 0.01) and were positively correlated with fasting plasma glucose, HbA1c, hs-CRP, and IL-1β (P < 0.01). Our study provides evidence that the concentrations of serum SFRP4 in T2DM and IGT subjects were increased and were correlated closely with glycose metabolic disorder, the first-phase of glucose-stimulated insulin secretion and chronic low-grade inflammation. SFRP4 may participate in the development of type 2 diabetes mellitus. Key words: Secreted frizzled-related protein 4, First-phase of insulin secretion, Intravenous glucose tolerance test, IL-1β, Diabetes TYPE 2 DIABETES MELLITUS (T2DM) is a het- is closely linked with glucotoxicity, lipotoxicity, oxida- erogeneous disorder characterized by β-cell dysfunc- tive stress, and endoplasmic reticulum (ER) stress in the tion and insulin resistance. A defect in β-cell func- pathogenesis of type 2 diabetes [2-5]. Several studies tion can be found in patients with impaired glucose have found abnormally high circulating levels of pro- tolerance (IGT) and with newly diagnosed T2DM [1]. inflammatory cytokines, such as IL-1β, IL-6, and CRP, Progressive β-cell dysfunction occurs in the natural which may induce the activation of the innate immune course of T2DM, but the detailed molecular mecha- system in type 2 diabetic patients and potentiate the nisms involved are not entirely understood. inflammatory mechanisms in pancreatic islets as well Increasing evidence suggests that chronic low-grade as in peripheral tissues [6]. On the one hand, hypergly- inflammation, which is activated by metabolic stress, cemia and/or elevated free fatty acid levels induce the plays a crucial role in the development of T2DM and production and secretion of various proinflammatory mediators, such as IL-1β, TNF-a, IL-6, and IL-1 depen- Submitted Apr. 14, 2015; Accepted May 18, 2015 as EJ15-0212 Released online in J-STAGE as advance publication Jun. 4, 2015 dent cytokines in pancreatic islets [4, 7]. IL-1β is a Correspondence to: Huacong Deng, M.D., Ph.D., Department of pivotal cytokine that stimulates β-cells to produce and Endocrinology, The First Affiliated Hospital of Chongqing Medical secrete more IL-1β and increases nitric oxide produc- University, Chongqing Medical University, No.1Youyi Road, tion, leading to β-cell dysfunction and reduced insulin Yuan jiagang, Yuzhong District, Chongqing 400016, P. R. China. E-mail: [email protected] secretion [8]. On the other hand, dysfunctional adi- * These authors contributed equally to this work and should be pocytes in obesity also contribute to elevated circulat- considered as co-first authors. ing inflammatory cytokines, potentially affecting β-cell ©The Japan Endocrine Society Endocrine Journal Advance Publication 2 Liu et al. function [9]. Adipocytokines are uniquely produced All subjects also underwent intravenous glucose toler- by adipocytes, such as leptin, adiponectin, omentin, ance testing (IVGTT) to assess the first-phase of glu- and visfatin, and may contribute to β-cell dysfunction cose-stimulated insulin secretion. The IGT and T2DM during insulin resistance and connect adipose tissue patients were newly diagnosed and did not receive any inflammation to β-cell failure [10, 11]. treatment, including diet, exercise and medication. T2DM may be referred to as a chronic auto-inflam- The diagnoses of T2DM and IGT were based on the matory disease, and inflammatory cytokines play an diagnostic criteria of the World Health Organization important role in the process of β-cell dysfunction (WHO) in 1999 [16]. [12]. Therefore, anti-inflammatory drugs may offer attractive advantages to preserving β-cell mass and Exclusion criteria function rather than just palliating the hyperglycemia. (1) Acute and chronic complications of diabetes. Consequently, there is a need for a better understanding (2) Hepatic or renal disease, sustained hypertension, or of mechanisms that may help identify new therapeutic coronary heart disease. targets for the treatment of β-cell dysfunction. (3) History of tumor diseases. A new inflammation mediator, called secreted friz- (4) Systemic corticosteroid treatment. zled-related protein (SFRP) 4, was recently found, (5) Women who were currently pregnant, breastfeeding which affects insulin secretion in human and mouse or taking contraceptive pills. β-cells as an extracellular regulator of the Wingless The study was approved by the Ethical Committee (Wnt) pathway. SFRP4 expression and release from of Chongqing Medical University. Signed informed islets is stimulated by IL-1β [13] and is connected to consent was obtained from all participants in this study. chronic low-grade inflammation and β-cell dysfunc- tion. Adipose tissue contributes by elevating circulating Clinical and biochemical evaluations SFRP4 in obesity [14]. SFRP4 may be a new adipocy- Body weight, height, waist and hip circumferences, tokine, which also relates adipose tissue inflammation and blood pressure (BP) were measured in all subjects to β-cell dysfunction. Thereby, SFRP4 may be a bio- with standard protocols. Height, waist, and hip cir- marker of β-cell dysfunction and a potential therapeu- cumferences were measured to a minimum recorded tic target for preserving β-cell function. However, until unit of 0.1 cm, and blood pressure was measured twice now, available data on SFRP4 have been limited, espe- with a standard mercury manometer with the subjects cially the relationship between serum SFRP4 and β-cell seated. The body mass index (BMI) and the waist to function in human subjects. One of the most reliable hip ratio (WHR) were also calculated. methods of measuring β-cell function is the intrave- Blood samples were collected after overnight fast- nous glucose tolerance test (IVGTT). The first-phase ing. Serum samples were obtained by centrifuga- of insulin secretion (0-10 min) is particularly impor- tion at 4°C and were stored at -80°C. Plasma glu- tant in terms of β-cell function, and the acute insulin cose was determined by the glucose oxidase method. response may be a better indicator of early β-cell dys- Fasting insulin (FINS) was measured by the chemilu- function than HOMA-β [1, 15]. Therefore, we initi- minescence method. HbA1c was measured by isoelec- ated a study to investigate the relationships of serum tric focusing. The triglyceride (TG), total cholesterol SFRP4 levels with inflammation and the first-phase of (TC), high-density lipoprotein cholesterol (HDL-C), glucose-stimulated insulin secretion from pancreatic low-density lipoprotein cholesterol (LDL-C), and β-cells in individuals with different glucose tolerance. high-sensitivity C-reaction protein (hs-CRP) concen- trations were assayed by enzymatic methods. Materials and Methods Assessment of serum SFRP4 and IL-1β concentrations Subjects Serum SFRP4 and IL-1β levels were determined by A total of 150 Chinese volunteers were enrolled in enzyme-linked immunosorbent assays (ELISA) accord- the study and were divided into three groups according ing to the manufacturer’s instructions (Human ELISA to their glucose tolerance status: normal glucose toler- kit, Wuhan USCN Science Co., Ltd., China). The ance (NGT) (n =42), impaired glucose tolerance (IGT) intra-assay coefficient of variation was 10%, and the (n =52), or Type 2 diabetes mellitus (T2DM) (n =56). inter-assay coefficient of variation was 12%. No sig- Endocrine Journal Advance Publication SFRP4 and β-cell function 3 nificant cross-reactivity or interference was observed. for statistical analysis. One-way analysis of vari- ance (ANOVA) was used for group comparisons. Intravenous glucose tolerance test (IVGTT) Interrelationships between variables were analyzed IVGTT was performed to estimate the first-phase of by Pearson correlation analysis and partial correlation insulin secretion after an overnight fast. Subjects had analysis. All calculations were performed by SPSS a diet containing at least 150 g of carbohydrate/day
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