Soluble receptor for advanced glycation end products (sRAGE) is associated with arterial stiffness only in normalbuminuric type 2 diabetes

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 758-779-Cardiometabolic Risk & Vascular Biology
Clinical
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-766
Ester Chai Kheng Yeoh*1, Jian-Jun Liu2, Lee Ying Yeoh3, Subramaniam Tavintharan1, Chee Fang Sum1, Xiao Wei Ng3, Wan Ching Toy4, Sharon Pek3 and Su Chi Lim3
1Khoo Teck Puat Hospital, Singapore, 2Khoo Teck Puat Hospital/Alexandrahealth Ptd Ltd, Singapore, Singapore, 3Khoo Teck Puat Hospital, Singapore, Singapore, 4Khoo Teck Puat hospital, Singapore, Singapore
Background and Aims: Advanced glycation end products (AGE) and receptor for AGE (RAGE) interaction plays an important role in vasculopathy in diabetes. Soluble RAGE (sRAGE), arising from ectodomain shedding of membrane RAGE and secretion of spliced variants, counteracts the pathogenic effect of AGE-RAGE signaling by acting as a decoy of AGEs. Arterial stiffness is a hallmark of vasculopathy. We aim to study the relationship between sRAGE and arterial stiffness in type 2 diabetes mellitus (T2DM).

Subjects and Methods: T2DM subjects in the present study were selected from the ongoing SMART2D study (Singapore study of MAcro-angiopathy and micro-vascular Reactivity in Type 2 Diabetes). By the cut-off time of this sub-study (August 31, 2012), 486 T2DM with normal albuminuria (urine ACR < 30 μg/mg and eGFR>60 ml/min/1.73m2; age 55.6 ± 11.1 yrs, male 47.9%, T2DM duration 8.9 ± 7.5 yrs), 253 T2DM with microalbuminuria (ACR >=30 μg/mg but < 300 μg/ml and eGFR> 60 ml/min/1.73m2; age 57.3 ± 11.3 yrs, male 46.8%, T2DM duration 12.2 ± 9.8 yrs) and 269 T2DM with overt diabetic nephropathy (DN, ACR>=300 μg/mg and/or eGFR < 60 ml/min/1.73m2 ; age 60.6 ± 9.9 yrs, male 55.8% , T2DM duration 15.0 ± 9.7 yrs) were recruited. Within each group, 200 subjects were randomly selected for this sub-study (n=600 total). Carotid-femoral pulse wave velocity (PWV) was measured by SphygmoCor (AtCor Medical, Australia) and total sRAGE was quantified by ELISA (R&D Systems, Minneapolis, MN).

Results: Plasma sRAGE was increased with the deterioration of renal function (918 ± 411 pg/ml, 975 ± 423 pg/ml and 1437 ± 916 pg/ml in T2DM with normalbuminuria, microalbuminuria and overt DN, respectively. p<0.0001 after adjustment for age and gender). Stepwise linear regression showed that sRAGE was associated with eGFR, logACR, age and BMI, but not PWV, which was also increased with the progression of renal impairment (9.2±2.6 m/s, 9.8±2.7 m/s and 11.0±2.9 m/s in T2DM with normalbuminuria, microalbuminuria and overt DN, respectively. P<0.0001). Cognizant of potential confounding by impaired renal function, we analyzed the association between PWV and sRAGE by stratifying the subjects based on severity of renal impairment. Pearson bivariate correlation analysis showed that PWV and sRAGE was significantly correlated only in T2DM with normalbuminuria (r=-0.177, p=0.012). Further analysis by linear regression revealed that PWV was independently associated with age, SBP, duration of diabetes and sRAGE in T2DM with normalbuminuria after adjustment for multiple covariates (R2=0.436, p<0.0001).

Conclusions: In T2DM, plasma sRAGE was increased with progressive deterioration in renal function.  Soluble RAGE was significantly associated with PWV only in normalbuminuric T2DM. Our finding that sRAGE was inversely associated with arterial stiffness in early stage of T2DM might have clinical implications.

Nothing to Disclose: ECKY, JJL, LYY, ST, CFS, XWN, WCT, SP, SCL

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Singapore National Medical Research Council Grant PPG/AH(KTPH)/2011