Advanced glycation end products (AGEs) and their receptor (RAGE) system play an important role in the development of diabetic vascular complications (1, 2). Recently, an endogenous secretory RAGE (esRAGE) has been identified as a novel splice variant, which lacks the transmembrane domain and is secreted in human sera. Interestingly, it was reported that esRAGE binds AGE ligands and neutralizes AGE actions (3). It is well known that type 2 diabetes is the most prevalent and serious metabolic disease affecting people all over the world and that vascular complications are clinically often observed in type 2 diabetic patients. However, very little information has been obtained about circulating esRAGE levels in type 2 diabetic subjects. To our knowledge, this is the first report examining circulating esRAGE levels in type 2 diabetic patients.

Subjects were selected from outpatients at the Diabetes Clinic of Osaka University Hospital as follows. All type 2 diabetic patients who visited the hospital from June to July 2005 were asked to participate in the study. The determination of type 2 diabetes was based on American Diabetes Association criteria. Those who were suffering from severe renal dysfunction (serum creatinine >2.0 mg/dl), hepatic disease, infection, connective tissue disease, or malignancy were excluded. After all, a total of 147 Japanese type 2 diabetic patients (50 men and 97 women, aged 63.6 ± 9.9 years [mean ± SD], and duration of diabetes 15.1 ± 9.5 years) met the criteria and attended the study. Eleven patients were treated with diet alone, 100 with oral hypoglycemic agents, and 42 with insulin. The study was approved by the Ethical Committee for Human Studies at Osaka University Graduate School of Medicine, and written informed consent was obtained from each subject.

We measured circulating esRAGE levels in serum using the B-Bridge esRAGE ELISA kit (B-Bridge International, Sunnyvale, CA). The mean ± SD value of esRAGE was 0.394 ± 0.17 ng/ml. BMI (23.9 ± 3.5 kg/m2), systolic and diastolic blood pressure (132 ± 18 and 74 ± 11 mmHg, respectively), smoking (23.1%), HbA1c (A1C) (7.3 ± 1.3%), total cholesterol (4.84 ± 0.91 mmol/l), triglycerides (1.37 ± 0.82 mmol/l), LDL cholesterol (2.87 ± 0.47 mmol/l), and HDL cholesterol (1.48 ± 0.54 mmol/l) were also evaluated.

Pearson’s univariate regression analyses showed that serum esRAGE levels were inversely correlated with A1C (r = −0.250, P = 0.0021) and total cholesterol (r = −0.180, P = 0.0316) but positively correlated with HDL cholesterol (r = 0.237, P = 0.0049). There was no statistically significant association between esRAGE and the other variables. Furthermore, a stepwise multivariate regression analyses demonstrated that high A1C (F = 7.4), high total cholesterol (F = 7.8), and low HDL cholesterol (F = 14.4) were shown to be independent risk factors for a low esRAGE value.

These results suggest that circulating esRAGE levels are related with not only glycemic control but also lipid profiles in type 2 diabetic patients.

1.
Stern DM, Yan SD, Yan SF, Schmidt AM: Receptor for advanced glycation endproducts (RAGE) and the complications of diabetes.
Ageing Res Rev
 
1
:
1
–15,
2002
2.
Wautier JL, Schmidt AM: Protein glycation: a firm link to endothelial cell dysfunction.
Circ Res
 
95
:
233
–238,
2004
3.
Yonekura H, Yamamoto Y, Sakurai S, Petrova RG, Abedin J, Li H, Yasui K, Takeuchi M, Makita M, Takasawa S, Okamoto H, Watanabe T, Yamamoto H: Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endotherial cells and pericytes, and their putative roles in diabetes-induced vascular injury.
Biochem J
 
370
:
1097
–1109,
2003
DIABETES CARE
2006