Elsevier

Metabolism

Volume 78, January 2018, Pages 155-166
Metabolism

Translational
Circulating ApoJ is closely associated with insulin resistance in human subjects

https://doi.org/10.1016/j.metabol.2017.09.014Get rights and content

Abstract

Objective

Insulin resistance is a major risk factor for type 2 diabetes. ApolipoproteinJ (ApoJ) has been implicated in altered pathophysiologic states including cardiovascular and Alzheimer's disease. However, the function of ApoJ in regulation of glucose homeostasis remains unclear. This study sought to determine whether serum ApoJ levels are associated with insulin resistance in human subjects and if they change after interventions that improve insulin sensitivity.

Methods

Serum ApoJ levels and insulin resistance status were assessed in nondiabetic (ND) and type 2 diabetic (T2D) subjects. The impacts of rosiglitazone or metformin therapy on serum ApoJ levels and glucose disposal rate (GDR) during a hyperinsulinemic/euglycemic clamp were evaluated in a separate cohort of T2D subjects. Total ApoJ protein or that associated with the HDL and LDL fractions was measured by immunoblotting or ELISA.

Results

Fasting serum ApoJ levels were greatly elevated in T2D subjects (ND vs T2D; 100 ± 8.3 vs. 150.6 ± 8.5 AU, P < 0.0001). Circulating ApoJ levels strongly correlated with fasting glucose, fasting insulin, HOMA-IR, and BMI. ApoJ levels were significantly and independently associated with HOMA-IR, even after adjustment for age, sex, and BMI. Rosiglitazone treatment in T2D subjects resulted in a reduction in serum ApoJ levels (before vs. after treatment; 100 ± 13.9 vs. 77 ± 15.2 AU, P = 0.015), whereas metformin had no effect on ApoJ levels. The change in ApoJ levels during treatment was inversely associated with the change in GDR. Interestingly, ApoJ content in the LDL fraction was inversely associated with HOMA-IR.

Conclusion

Serum ApoJ levels are closely correlated with the magnitude of insulin resistance regardless of obesity, and decrease along with improvement of insulin resistance in response only to rosiglitazone in type 2 diabetes.

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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