Nε-carboxymethyl-lysine and inflammatory cytokines, markers and mediators of coronary artery disease progression in diabetes

Abstract

This editorial refers to the article "Comparative analysis of Nε-carboxymethyl-lysine and inflammatory markers in diabetic and non-diabetic coronary artery disease patients", published in the recent issue of the World Journal of Diabetes 2023 is based on glucose metabolism, advanced glycation end products (AGEs), inflammation and adiposity on diabetes and coronary artery disease (CAD). This study has included CAD patients who were stratified according to glycosylated hemoglobin higher than 6.5 and sex-matched. A higher prevalence of hypertension, dyslipidemia, and non-vegetarian diet were found in the diabetic group. These risk factors might influence body weight and adiposity and explain the increment of the left atrium. Although this data was not supported by the study. The diet can also explain the non-enzymatic reactions on lipids, proteins, or nucleic acids and consequently an increment of AGEs. These molecules can emit fluorescence. However, one of the non-fluorescent and most abundant AGEs is Nε-carboxymethyl-lysine (CML). Its association with coronary artery stenosis and severity in the diabetic group might suggest its role as a player in CAD progression. Thus, CML, after binding with its receptor (RAGE), can induce calcification cascade through reactive oxygen species and mitogen-activated protein kinase. Moreover, this interaction AGE-RAGE can cause activation of the transcription nuclear factor-kb and induce inflammatory cytokines. It might explain the relationship between CML and pro-inflammatory cytokines in diabetic and CAD patients. Although this is a population from one center, the determination of CML and inflammatory cytokines might improve the diagnosis of severe and progressive CAD. Future and comparative studies among glycosylated hemoglobin, CML, and other AGE levels according to diagnosis and prognosis value might modify the clinical practice. Although these molecules are irreversible, they can act through a specific receptor inducing a signal transduction that might be modu-lated by inhibitors, antibodies, or siRNA. Further mechanistic studies might improve the development of future preventive therapies for diabetic patients.

Keywords: Adiposity; Coronary artery disease; Diabetes; Inflammatory cytokines; Nε-carboxymethyl-lysine.

Figure 1

A summary of Nε-carboxymethyl-lysine signals transduction effects on cells. The Nε-carboxymethyl-lysine (CML) levels can be induced by an increment of adiposity, insulin resistance, and consequently, circulating glucose levels that modify molecules in a non-enzymatic way. It provokes the advanced glycation end products and CML is one of the most prevalent. But the increment of its levels might be also induced by diet. High levels of CML are markers for coronary artery disease risk. CML can also induce signal transduction and be involved in a pathological mechanism through activation of protein kinase C, mitogen-activated protein kinase, or nuclear factor kappa b, causing muscle cell proliferation or inflammatory cytokines transcription, respectively. CML can be a marker and therapeutic target. CML: Nε-carboxymethyl-lysine; PKC: Protein kinase C; MAPK: Mitogen-activated protein kinase; NFkb: Nuclear factor kappa b.