Diabetes & Metabolic Syndrome: Clinical Research & Reviews 13 (2019) 1005e1010 Contents lists available at ScienceDirect Diabetes & Metabolic Syndrome: Clinical Research & Reviews journal homepage: www.elsevier.com/locate/dsx Original Article Serum AGEs and sRAGE levels are not related to vascular complications in patients with prediabetes * Antoaneta T. Gateva a, , Yavor S. Assyov a, Adelina D. Tsakova b, Zdravko A. Kamenov a a Clinic of Endocrinology, University Hospital “Alexandrovska”, Medical UniversityeSofia, 1 Georgi Sofiiski str, 1431, Sofia, Bulgaria b Central Clinical Laboratory, University Hospital “Alexandrovska”, Medical UniversityeSofia, 1 Georgi Sofiiski str, 1431, Sofia, Bulgaria article info abstract Article history: Background: While hyperglycemia has a key role in the pathogenesis of microvascular complications of Received 15 December 2018 diabetes, it is just one of the many factors contributing to macrovascular damage. The aim of the present Accepted 17 January 2019 study is to investigate the link between serum pentosidine and sRAGE levels and vascular complications in patients with prediabetes compared to normal glucose tolerance controls with obesity. Keywords: Methods: In this study were included 76 patients with mean age 50.7 ± 10.7 years, divided into two age Prediabetes and BMI-matched groups e group 1 with obesity without glycemic disturbances (n ¼ 38) and group 2 Vascular complications with obesity and prediabetes (n ¼ 38). sRAGE fi Pentosidine Results: There was no signi cant difference in pentosidine and sRAGE levels between patients with obesity and prediabetes. Patients with hypertension had lower levels of sRAGE compared to non- hypertensive subjects. sRAGE showed a weak negative correlation to blood glucose on 60th min of OGTT and HOMA index. There was no correlation between sRAGE and pentosidine levels and the markers of micro- and macrovascular complications. There was no difference in sRAGE and pentosidine levels be- tween patients with and without endothelial dysfunction. Conclusions: sRAGE and pentosidine levels are similar in patients with obesity with and without pre- diabetes and do not correlate to the markers of micro- and macrovascular complications. © 2019 Diabetes India. Published by Elsevier Ltd. All rights reserved. 1. Introduction homeostasis, because vascular damage in many cases is usually present at diagnosis of type 2 diabetes [1e4] and probably even at Diabetes mellitus (DM2) comprises a heterogeneous group of prediabetic stage. Prediabetes represents a metabolic condition, metabolic disorders characterized by hyperglycaemia, which is which stands inbetween normal glucose homeostasis and diabetes caused by abnormalities in insulin secretion, or action, or both. and includes impaired fasting glucose (IFG) and impaired glucose Diabetes is a chronic disease that requires continuous medical care tolerance (IGT). These two terms are not synonymous and reflect and education of the patient in order to prevent acute and reduce different disturbances of glucose regulation, although they may the risk of chronic complications. Chronic complications of diabetes occur simultaneously. Patients who have these conditions of mellitus include retinopathy with potential loss of vision; ne- impaired glucose homeostasis have an increased risk of developing phropathy causing chronic renal failure; peripheral neuropathy and diabetes [5e7]. While microvascular complications occurring dur- risk of diabetic ulcers on the feet, amputations and Charcot joints; ing prediabetes are often mild, they are clinically significant and in and autonomic neuropathy causing gastrointestinal, genitourinary, some cases can give us information on the mechanisms and path- sudomotor and cardiovascular symptoms and sexual dysfunction. ogenesis of diabetic angiopathy. Until now it was believed that Diabetic patients also have an increased incidence of atheroscle- microvascular complications seen in prediabetes are entirely due to rotic cardiovascular, peripheral artery and cerebrovascular disease. hyperglycemia. New studies, however, showed the large contribu- Now it is evident however that chronic diabetic complications tion of other metabolic factors such as obesity, dyslipidemia and begin their development in the earlier stages of impaired glucose hypertension. Additional evidence in this field came from a study that demonstrated that metabolic syndrome has an additive effect on the risk of microvascular complications of type 2 diabetes [8]. * Corresponding author. While hyperglycemia undoubtedly has a key role in the E-mail address: [email protected] (A.T. Gateva). https://doi.org/10.1016/j.dsx.2019.01.014 1871-4021/© 2019 Diabetes India. Published by Elsevier Ltd. All rights reserved. 1006 A.T. Gateva et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 13 (2019) 1005e1010 pathogenesis of microvascular complications of diabetes, it is just for clinical studies and all patients included in the study signed an one of the many factors contributing to the development of mac- informed consent for participation in the project. rovascular damage. The following study methods were used: Hyperglycemia induces oxidative stress via poliol pathway, advanced glycation end-products (AGEs), proteinkinase C dis- 1. Anthropometric measurements regulation and hexosamine pathway. AGEs are elevated in case of - Height prolonged hyperglycemia as a result non-enzymatic reaction be- - Weight tween glucose residuals and amino groups of proteins, lipids and - BMI calculation (weight in kilograms divided by height in nucleic acids [9e11], causing irreversible structural changes. Some meters squared) of the best studied AGEs in patients with diabetes include - waist circumference (WC) - measurement is made midway carboxymethyl-lisine, carboxyethyl-lisine and pentosidine, which between the 8th rib and the iliac crest can serve as markers of AGEs formation and accumulation [12]. At - Hip circumference - measurement is made at the level of the molecular level AGEs, including pentosidine, can induce oxidative greater trochanter stress and endothelial dysfunction [13,14]and some growth factor - Calculation of waist-to-hip ratio (WHR) expression [15]. As a result of this they are linked to many patho- - Calculation of the waist-to-height ratio (WSR) logical conditions such as ageing, hypertension, kidney failure, - Calculation of VAI (visceral adiposity index): VAI ¼ (WC/ diabetes and diabetic retinopathy and nephropathy [16,17]. (36.58 þ (1.89 xBMI))) x (TG/0,81) x (1,52/HDL) AGEs affect microvascular homeostasis via interaction with 2. Investigation of carbohydrate metabolism AGEs receptor (RAGE) [18]. There are many data that this interac- - An oral glucose tolerance test (OGTT) with measurement of tion has a role in the development of microvascular diabetes glucose and immunoreactive insulin (IRI) (electro- complications [19,20]. The soluble form of RAGE (sRAGE) is missing chemiluminescence immunoassay (ECLIA e Roche Di- its transmebrane domain and is recently identified as an inhibitor agnostics™) on 0 min, 60 min and 120 min. HOMA index of AGE-RAGE mediated pathological changes [21]. sRAGEis linked (fasting glucose X fasting immunoreactive insulin)/22.5) was to some of the metabolic syndrome components (body mass index calculated. and insulin resistance) [22] and a negative relationship between sRAGE and HbA1c levels was found [23]. Biological role of sRAGE is Insulin resistance was assumed at IRI 0 min >17 mU/l, IRI not well understood, but it probably acts as a competitive inhibitor 60 min > 130 mU/l, IRI 120 min > 80 mU/l, HOMA index> 2,6 of AGE-RAGE interaction. sRAGE can also act as a scavenger re- [27e29]. ceptor for circulating AGEs and other RAGE-ligands [24]. As a result sRAGE is considered a protective factor regarding microvascular 3. Laboratory tests damage in type 2 diabetic patients [25]. Until now there is very few - Blood count data about the role of sRAGE in atherosclerotic changes in humans. - ESR In middle-age coronary disease patients without diabetes sRAGE - ASAT, ALAT, GGT levels are lower compared to subjects without coronary artery - Tchol, TG, HDL, LDL, VLDL disease [26]. - Creatinine The aim of the present study is to investigate the link between - Uric acid serumpentosidineand sRAGE levels and vascular complications in 4. Measurement of serum sRAGE and pentosidine levels was patients with prediabetes compared to normal glucose tolerance performed by enzyme-linked immunosorbent assay (ELISA) controls with obesity. (BYOVENDOR). The blood was taken after overnight fasting, was immediately centrifuged for 15 min on 4000 rpm and the serum о 2. Patients and methods was stored at (À80 С) until the test was performed 5. Evaluation of the presence of peripheral neuropathy e eval- In the present study we included patients that met the following uation of tactile (10 g monophylament), termal (termal including and excluding criteria: discriminator) and vibration sensation (128 Hz tuning fork and biothesiometer) and tendon reflexes (neurological hammer) 2.1. Inclusion criteria 6. Detection of distal small fiber neuropathy by the measure- ment of sudomotor function, usingSudoscan. This is a quick, Age 35e74 years non-invasive and quantitative method. It is based on an elec- Impaired glucose tolerance (glucose on 120 min of OGTT be- trochemical reaction between sweat chlorides and stainless- tween 7.8 and 11.0 mmol/l) and/or impaired fasting glucose steel electrodes in contact with the palms of the hands and (fasting