To our knowledge, this is the first systematic review and meta-analysis to assess the relationship between YKL-40 and DM. Our study indicate that DM patients have a significantly higher level of YKL-40 compared with healthy controls. In addition, YKL-40 concentrations are higher in DM patients with different degree of albuminuria than those in healthy controls and increase with increasing severity of albuminuria.
Diabetes mellitus is a complex group of metabolic diseases characterized by hyperglycemia and is a major public health problem throughout the world. Both of T1DM and T2DM are genetic predisposition and influenced by environment. The genes responsible for T1DM are carried on chromosome 6p21 and take control of the immune system . Many genes are relative to T2DM, but most of them have not been identified. Recently, inflammation is involved in the pathogenesis of DM. Previous study have found that long-term T1DM patients have a significantly higher level of CRP than healthy controls . Besides, CRP is also higher in T2DM patients than in healthy controls . But the role of inflammatory processes seems to be more important in the development of T2DM than T1DM. Some studies have indicated that inflammatory markers such as CRP and IL-6 are increased in healthy population who later developed T2DM [46, 47], suggesting that inflammation may occur ahead of the diagnosis of T2DM. Insulin resistance is common in T2DM and most patients with T2DM are obese, which itself can cause some degree of insulin resistance. Obesity, especially activation of adipose tissue, might enhance the release of inflammatory factors .
YKL-40, a new inflammatory marker, is related to both acute and chronic inflammation. Some studies have showed that levels of YKL-40 are increased in patients with purulent menigitis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus and inflammatory bowel disease [49, 50]. Obesity is related to increased macrophage infiltration of adipose tissue and plays an important role in the development of insulin resistance . YKL-40 is possibly with relation to the insulin resistance based on the macrophage infiltration and adipose tissue . All the evidences above indicate that YKL-40 might have a relationship with DM. And our study, with more strong power, confirm that patients with DM have significantly higher levels of YKL-40 compared with healthy controls. What’s more, some studies have showed that inflammation is associated with hyperglycemia. And inflammatory markers, including IL-6, IL-1βand TNF-α, are often found increased in DM patients, whose glucose in poorly controlled [7, 8]. The great majority of studies (22 studies) included in our meta-analysis provided data of HhA1c values. In some studies, HbA1c values were higher than upper limits of normal range, but 5 studies [23-25, 27, 30] showed that YKL-40 levels are positively correlated with HbA1c, while 3 studies [19, 21, 22] did not show any correlation. Therefore, although YKL-40 is also an inflammatory cytokine, the relationship between hyperglycemia and YKL-40 needs to be confirmed.
The prevalence of GDM is increasing all over the world, of which the exact pathogenesis is not quietly understood. But many findings have showed that GDM patients have a trend of developing to T2MD. There are also some studies indicating that insulin resistance is an important pathophysiological contributor of GDM [52, 53]. Our present study find that the serum YKL-40 levels are higher in GDM patients than in healthy pregnancies. However, when the study by XunShengli et al.  is deleted during sensitivity analysis, YKL-40 is not associated with GDM. In the study by XunShengli et al., Enzyme Linked Immunosorbent Assay (ELISA) without details about the machine and reagents was used to measure the serum YKL-40 levels and the unit was pg/ml (ng/ml was used in other included studies). Compared with other included studies, the values of YKL-40 in this study were extremely small, which may have a strong contribution to obtain statistical significance. Anyway, the association between YKL-40 and GDM remains to be further confirmed by larger number of studies.
There are three types of complications of DM, including macrovascular, microvascular and neurologic. Kidney is the most obviously involved organ in microvascular complications and urinary albumin is a sign of DN. Some studies have found a high prevalence of microalbuminuria in DM patients [54, 55]. The pathogenesis of DN is multiple, and inflammation seems to be a major mechanism. Interaction of metabolism and hemodynamics, which activates many inflammatory molecules and pathway, results in DN [56, 57]. In addition, vascular endothelial dysfunction is a major factor in the pathogenesis of diabetic micro-angiopathy . And YKL-40 is expressed in the development of endothelial dysfunction, during the differentiation and maturation of CD14+ monocytes to CD14-, CD16+ macrophages .YKL-40, as a marker of inflammation and endothelial dysfunction, is found associated with albuminuria in T2DM patients [59, 60]. Consistent with previous studies, we find that the levels of YKL-40 are higher in DM patients with different degree of albuminuria compared with healthy controls and the levels of YKL-40 are positively related with the severe degree of albuminuria.
Some limitations of this study should be mentioned. First, the heterogeneity is high and the major causes are not found by the Galbraith plot and subgroup analyses. Second, the criteria of normoalbuminuria, microalbuminuria and macroalbuminuria were different among the studies included in this meta-analysis. In some studies, urinary albumin excretion rate was used as classification criterion, but in others, albumin/creatinine was used. As thus, the results of our study are not stable enough.