Cystatin C as a Predictor for Diabetes according to Glycosylated Hemoglobin Levels in Korean Patients
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Cystatin C is entirely filtered by the kidney glomerulus and metabolized by the proximal tubule, and it is mainly used as a biomarker of renal function. It was first proposed by Anders Grubb as a potential alternative to be used as a glomerular filtration rate (GFR) that could overcome the known limitations of serum creatinine [1], and has been investigated for about 30 years. Cystatin C is less influenced by demographic characteristics such age, gender, race, muscle mass, heath status, and drugs than creatinine [2]. Most studies have shown the associations of cystatin C and creatinine with longitudinally adverse outcomes of renal disease such as end-stage renal disease, cardiovascular disease (CVD), heart failure, and death [3]. In addition, three recent researches have reported interesting results regarding cystatin C in kidney function [456]. These had an impact on the 2012 Kidney Disease Improving Global Outcomes (KDIGO) guideline and led to its widespread clinical use.
Cystatin C is considered an important endogenous inhibitor of cysteine protease activity because of its potent in vitro inhibition of cathepsins K, B, H, and S [7]. In human, all cells with a nucleus produce cystatin C. It is found in virtually all tissues and body fluids. The biological roles of cystatin C are known to be varied such as growth-promoting activity, inflammation down-regulating function, and anti-viral and anti-bacterial properties [8]. It is also involved in numerous processes such as renal disease, cancer, diabetes, epilepsy, and Alzheimer's disease [9]. Cystatin C has also been used to detect CVD in patients with diabetes. In Korea, Lee et al. [10] investigated whether insulin resistance has a role in the link between cystatin C and CVD in type 2 diabetes mellitus. The results showed that cystatin C was associated with insulin resistance and biomarkers of inflammation independently of renal function.
At present, there is growing interest in the association of cystatin C and the development of type 2 diabetes mellitus, and several studies have attempted to investigate the link between cystatin C and type 2 diabetes. In a case-control study, Donahue et al. [11] explored whether elevated baseline concentrations of cystatin C predicted progression from normoglycemia by fasting plasma glucose to pre-diabetes over 6 years of follow-up of 1,455 participants from the Western New York Health Study. This study showed an approximately threefold increased risk of progression to pre-diabetes among those in the highest quintile of cystatin C in a population free of diabetes and known CVD. In a population based study, Sahakyan et al. [12] reported the association of serum cystatin C with the incidence of type 2 diabetes mellitus over a 15-year follow-up period. The incidence of diabetes was estimated to be 9.6%. However, the association did not remain significant after adjustment for glycosylated hemoglobin (HbA1c). In the cohort of Data from an Epidemiological Study on the Insulin Resistance syndrome (D.E.S.I.R) study participants, cystatin C was associated with an increased incidence of diabetes when adjusted for sex and age (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.15 to 2.10; P=0.0039) [13]. Cystatin C was an independent predictor of diabetes in people with high waist circumference, fat mass, or insulin resistance, and there was a trend that was significant for body mass index. In a cross-sectional data for 5,083 participants of the nationally representative Third National Health and Nutrition Examination Survey III, with an estimated GFR more than 60 mL/min/1.73 m2 without micro- or macroalbuminuria, overweight and obesity maintained a strong association with elevated cystatin C [14]. After multivariate adjustment, the OR (95% CI) for elevated cystatin C was 1.46 (1.02 to 2.10) for overweight, 2.36 (1.56 to 3.57) for class I obesity, and 2.28 (1.56 to 5.11) for class II to III obesity.
In this regard, the study by Sim et al. [15], provided the association of serum cystatin C with HbA1c in Korean adults. This was the first study investigating the association between cystatin C and diabetes in Asian population. This group previously reported that cystatin C was closely associated with metabolic syndrome and its related components in Korean adults [16]. Although cystatin C is influenced less by demographic characteristics, it is also related to age, gender, and race [17]. In non-obese US adults, the positive association between cystatin C and prediabetes was stronger among non-Hispanic whites [18]. Therefore, they analyzed that data from 1,559 Korean adults. The mean serum cystatin C was 0.92±0.13 mg/L in men and 0.84±0.13 mg/L in women. The cases of prediabetes and diabetes were identified by HbA1c. The subjects aged more than 70 years were excluded. Serum creatinine levels were below 1.5 mg/dL in men and 1.3 mg/dL in women. According to the range group of cystatin C levels, there were no significant differences in HbA1c. In the bivariate correlation analysis, there was a weakly positive correlation between cystatin C and HbA1c in all subjects (r=0.052, P=0.031). Cystatin C was also associated with an increased prevalence of prediabetes and diabetes (OR, 2.35; 95% CI, 1.54 to 3.58; P<0.001). However, there was no significant associations after adjusting for multiple variables such as age, sex, body mass index, total cholesterol, and systolic blood pressure (OR, 1.01; 95% CI, 0.62 to 1.63; P=0.964). This is, in part, thought that most of the metabolic abnormality associate chronic inflammation, insulin resistance, endothelial dysfunction, and so on. Conditions like insulin resistance, obesity, and hypertension are closely related to diabetes. As mentioned by the author, this study was a cross-sectional design and did not identify a causal relationship. There is a possibility that the patients with diabetes who took medicine were classified in the normal glucose or prediabetes groups.
Nevertheless, considering the various roles of cystatin C, it may be possible that higher cystatin C level is a marker for the preclinical and clinical stage of diabetes. Further investigations are needed to demonstrate whether cystatin C is linked to diabetes and whether it is indeed a clinically important predictor related to HbA1c for diabetes.
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CONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.