TranslationalCirculating ApoJ is closely associated with insulin resistance in human subjects
Introduction
Type 2 diabetes is a major global health problem that affects millions of people worldwide and is associated with serious comorbidities, including cardiovascular diseases [1]. Insulin resistance, accompanied by failure of the pancreatic β-cells to compensate sufficiently by increased insulin secretion, leads to the development of type 2 diabetes [2]. A major challenge in the field of metabolic diseases has been identifying molecular markers linked to insulin resistance [3], which may contribute to a better understanding of the pathogenesis of type 2 diabetes.
Apolipoprotein J (ApoJ, also called clusterin) is a secreted sulfated glycoprotein that is widely distributed in various tissues, including the liver, brain, ovary, testis, heart and blood vessels [4]. Secreted ApoJ binds a broad network of metabolic mediators, including the anorexigenic hormone leptin, growth hormone, paroxonase, and proinflammatory cytokines, as well as lipid-carrying lipoprotein particles (HDL, LDL) in the circulation [5], [6], [7], [8], [9]. In addition to the ApoJ found in serum, nuclear-localized and cytoplasmic isoforms of ApoJ have been described, each with distinct functions [10]. Emerging data suggests that ApoJ is induced by stress and has a role as a cytoprotective extracellular chaperone [11], [12]. However, the functions of secreted ApoJ on glucose metabolism in human subjects have not been addressed.
ApoJ has been implicated in various human diseases, including atherosclerosis [13], Alzheimer's disease [14], and cancer [15]. It has been reported that circulating ApoJ levels are elevated in humans with type 2 diabetes, obesity and systemic inflammation, all of which are pathogenically featured by insulin resistance [16], [17], [18], as is Alzheimer's [19]. In addition, a human ApoJ gene polymorphism was found to be associated with type 2 diabetes [20], [21]. Interestingly, a recent study reported that ApoJ in HDL is correlated with insulin sensitivity, while ApoJ in LDL/VLDL is associated with insulin resistance [9], suggesting a potential link between ApoJ and insulin action. However, no data are available about the relationship between circulating ApoJ levels and direct measures of insulin resistance in humans.
In this study, we assessed whether serum ApoJ levels are correlated with the magnitude of insulin resistance, and whether therapeutic interventions that improve insulin sensitivity would be associated with changes in serum ApoJ levels in human subjects with type 2 diabetes.
Section snippets
Study 1
For the comparison of circulating ApoJ levels between nondiabetic (ND) and type 2 diabetic (T2D) subjects and for the evaluation of possible associations of serum ApoJ levels with insulin resistance, 27 ND subjects and 26 T2D subjects participated in our study (n = 53). All ND subjects had normal glucose tolerance as defined by 2-h glucose level from a standard 75 g oral glucose tolerance test (OGTT) < 140 mg/dL [22]. The ND subjects were healthy, weight stable, and were not taking any medications
Clinical and Metabolic Characteristics of Study Subjects (Study 1)
The ND and T2D subjects were similar in age (Table 1). BMI was significantly increased in T2D subjects compared with ND subjects. Fasting serum glucose, fasting plasma insulin and HOMA-IR were all markedly elevated in T2D subjects compared with ND subjects. Neither blood pressure nor HOMA-β differed between ND and T2D subjects.
Serum ApoJ Levels and Their Correlations with Metabolic Parameters (Study 1)
ELISA and quantitative western blotting analysis were performed to measure serum ApoJ levels from healthy subjects and those with type 2 diabetes. A strong
Discussion
The current study provides crucial evidence of a close relationship between serum ApoJ levels and measures describing insulin resistance, including after an intervention that improves insulin action. Particularly, we show that the level of ApoJ in the serum correlates with a measure of insulin resistance (HOMA-IR), independently of obesity, especially in ND subjects. In T2D subjects, who had ~ 50% higher levels of serum ApoJ than ND subjects, we found that treatment with the insulin sensitizer
Author Contributions
Y.-B.K., T.P.C., and R.R.H designed the study. J.A.S. M.K., and S.S.K. performed most of immunoblotting analysis for Study 1 and 2. W.M.H. and D.M.L carried out lipoprotein fractions and immunoblotting analysis for Study 3. K.S.P. provided conceptual advice and contributed the data analysis. All of the authors interpreted experimental data, and wrote experimental methods and results. R.R.H., C.C., and T.P.C conducted the clinical study (Study 1 and 2), collected data and contributed to the
Funding
This work was supported by grants from the American Diabetes Association (7-12-BS-094 to YBK) and the National Institutes of Health (R01DK111529 and R01DK106076 to YBK), the Medical Research Service, and the General Clinical Research Branch, Division of Research Resources, a grant from the Korean Diabetes Association (2017S-2 to JAS), and a grant of the Korea Health Technology R&D Project (grant number: HI14C1277) through the Korea Health Industry Development Institute (KHIDI), funded by the
Disclosure Statement
The authors have nothing to disclose.
Acknowledgments
The authors thank the subject volunteers, whose time and effort are critical to the success of this work. The authors are thankful to Hyunjoo Cho who helped statistical analysis.
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Contributed equally.