Plasma Advanced Glycation End Products Research Articles

Hibiscus sabdariffa Polyphenolic Extract Inhibits Hyperglycemia, Hyperlipidemia, and Glycation-Oxidative Stress while Improving Insulin Resistance

H. sabdariffa polyphenolic extract (HPE) was demonstrated to inhibit high glucose-stimulated cellular changes. In this study, we analyzed the composition of HPE and used a type 2 diabetic rat model to test its protective effect. At least 18 phenolic compounds were found in HPE. Treatment with HPE reduced hyperglycemia and hyperinsulinemia, especially at the dose of 200 mg/kg. HPE decreased serum triacylglycerol, cholesterol, and the ratio of low density lipoprotein/high density lipoprotein (LDL/HDL). Diabetes promoted plasma advanced glycation end product (AGE) formation and lipid peroxidation, while HPE significantly reduced these elevations. Immunohistological observation revealed that HPE inhibited the expression of connective tissue growth factor (CTGF) and receptor of AGE (RAGE), which was increased in type 2 diabetic aortic regions. Furthermore, HPE recovered the weight loss found in type 2 diabetic rats. In conclusion, we demonstrated the anti-insulin resistance properties of HPE and its effect on hypoglycemia, hypolipidemia, and antioxidation. HPE has the potential to be an adjuvant for diabetic therapy.

Prognostic Potential and Tumor Growth-Inhibiting Effect of Plasma Advanced Glycation End Products in Non-Small Cell Lung Carcinoma

The plasma fluorescence related to the standard fluorescence of advanced glycation end products (AGEs) is a simple measurable blood parameter for distinct diseases but its importance in human cancer, including non-small cell lung carcinoma (NSCLC), is unknown. Plasma samples of 70 NSCLC patients who underwent resection surgery of the tumor were analyzed for the distinct AGE-related fluorescence at 370 nm excitation/440 nm emission. In a retrospective study, we tested the prognostic relevance of this AGE-related plasma fluorescence. The effect of circulating AGEs on the NSCLC growth was studied experimentally in vitro and in vivo. NSCLC patients with high (> median) AGE-related plasma fluorescence were characterized by a later reoccurrence of the tumor after curative surgery and a higher survival rate compared with patients with low plasma fluorescence (25% versus 47% 5-y survival, P = 0.011). Treating NSCLC cell spheroids with patients' plasma showed an inverse correlation between the growth of spheroids in vitro and the individual AGE-related fluorescence of each plasma sample. To confirm the impact of circulating AGEs on the NSCLC progression, we studied the NSCLC growth in mice whose circulating AGE level was elevated by AGE-rich diet. In vivo tumorigenicity assays demonstrated that mice with higher levels of circulating AGEs developed smaller tumors than mice with normal AGE levels. The AGE-related plasma fluorescence has prognostic relevance for NSCLC patients in whom the tumor growth-inhibiting effect of circulating AGEs might play a critical role.

Plasma advanced glycation endproduct, methylglyoxal-derived hydroimidazolone is elevated in young, complication-free patients with Type 1 diabetes

Objectives Elevated advanced glycation endproducts (AGEs) are implicated in diabetic complications. Methylglyoxal-derived hydroimidazolone (MG-H) is one of the most abundant AGEs in vivo. Our objective was to develop a time-saving, specific method to measure free MG-H in plasma and determine its levels in complication-free young individuals with Type 1 diabetes (T1DM). The relationship of plasma free MG-H to hemoglobin A1C (A1C) and plasma methylglyoxal levels was also determined. Design and methods A solid phase extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed, and free plasma MG-H levels were measured in 40 T1DM patients (DM group), aged 6–21 years, and 11 non-diabetics (ND group), 6–22 years. Methylglyoxal was measured using LC-MS/MS and A1C by a Tosoh G7 high-performance liquid chromatograph. Results Our method showed high recovery, sensitivity and short run-time. Plasma free MG-H (nmol/L) was higher ( p < 0.001) in the DM group (1318 ± 569; mean ± standard deviation) as compared to the ND group (583 ± 419). Within the DM group, plasma free MG-H did not correlate with plasma methylglyoxal or A1C. Conclusions Our LC-MS/MS method to measure free MG-H in plasma may be useful for future clinical application. The increased levels of free MG-H observed in individuals with TIDM are not merely the result of short term changes in glucose or methylglyoxal, but may reflect long-term alterations to tissue proteins.

Plasma advanced glycation end products are decreased in obese children compared with lean controls

In obesity, the combined effects of enhanced food consumption, enhanced oxidative stress and microinflammation could augment the advanced glycation end products (AGEs) accumulation in plasma. We compared the plasma concentrations of AGEs and the soluble receptor for AGEs (sRAGE) in relation to markers of oxidative stress, microinflammation and renal function in obese and lean children/adolescents. In 18 apparently healthy obese children/adolescents (7 females/11 males; age: 5-18 years; body mass index, BMI: 27.3+/-3.3 kg/m2) and 18 healthy lean controls (10 females/8 males; age: 4-17 years, BMI: 22.4+/-2.1 kg/m2) the plasma concentration of N(epsilon)-carboxymethyllysine (CML), fructoselysine (FL), AGE-associated fluorescence, sRAGE, high sensitive-C-reactive protein (hsCRP), interleukin-6 (IL-6) and urinary 8-hydroxy-2-deoxyguanosine (U-8-OHdG) excretion, plasma advanced oxidation protein products (AOPPs), renal function, and the HOMA index of insulin resistance were determined. Obese children/adolescents had significantly lower concentrations of plasma FL (6.8+/-0.3 mmol/mol lysine vs. 7.7+/-0.3, p<0.02), CML (0.14+/-0.03 mmol/mol lysine vs. 0.22+/-0.04, p<0.001), and fluorescent AGEs (223+/-37 arbitrary units (AU) vs. 318+/-64, p<0.01) than their lean counterparts. Plasma sRAGE concentration did not differ (2.3+/-0.6 ng/ml vs. 2.6+/-0.6). Obese children/adolescents were more insulin-resistant (HOMA index: p<0.01), exhibited higher levels of markers of inflammation (hs-CRP: p<0.03; IL-6: p<0.02), of oxidative stress (AOPPs: p<0.05; 8-OHdG: p<0.04) and had a higher creatinine clearance (p<0.01) and proteinuria (p<0.01). We present the first evidence that childhood/adolescent obesity is characterized by lower plasma AGE levels, despite lower insulin sensitivity, enhanced oxidative stress and microinflammation. An enhanced removal of AGE peptides via hyperfiltration may partially contribute to the lower plasma AGE levels.

Effect of metformin administration on plasma advanced glycation end product levels in women with polycystic ovary syndrome

Metformin therapy in polycystic ovary syndrome (PCOS) improves metabolic and hormonal profiles. Its therapeutic effect on cardiovascular risk factors is under investigation. Advanced glycation end products (AGEs), well-known atherogenic molecules, were recently found to be elevated in plasma of women with PCOS. The purpose of the study was to investigate the effect of metformin treatment in plasma AGE levels of women with PCOS. This was a descriptive clinical trial. The study involved 22 patients with PCOS (age, 25.09 ± 1.05 years; body mass index [BMI], 28.44 ± 1.51 kg/m 2) and 22 healthy women (age, 26.50 ± 0.85 years; BMI, 25.62 ± 1.30 kg/m 2). Measurements of plasma AGE levels (U/mL) were performed, and the metabolic and hormonal profiles were determined in all subjects. All women with PCOS received a dose of 1700 mg metformin daily for 6 months. AGEs levels were reduced after metformin administration in 22 women with PCOS (9.98 ± 0.13 [before metformin] vs 9.86 ± 0.11 [after metformin], P = .05). In a subgroup analysis, of 16 women with PCOS and normal glucose tolerance, the drop of AGE levels was potentiated (9.98 ± 0.19 [before] vs 9.81 ± 0.15 [after], P = .02). Body mass index as well as the other parameters studied remained unchanged after metformin therapy apart from a drop of testosterone levels ( P = .01) and free androgen index ( P = .009). In conclusion, after metformin therapy, the atherogenic AGE molecules were reduced in the serum of women with PCOS .The clinical relevance of this finding in PCOS, a high-risk group for type 2 diabetes mellitus and cardiovascular disease, remains to be seen. Future studies are required to confirm the need of therapeutic intervention for short-term abnormalities and for prevention of long-term sequelae characterizing this syndrome.

Advanced Glycation End Product Free Adducts Are Cleared by Dialysis

Plasma advanced glycation end product (AGE) free adducts are increased up to 50-fold among patients on dialysis. We examined the ability of hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) to clear these compounds. The AGE free adducts Nepsilon-carboxymethyl-lysine (CML) and Nepsilon-(1-carboxyethyl)lysine (CEL) and the hydroimidazolones derived from glyoxal (G-H1), methylglyoxal (MG-H1), and 3-deoxyglucosone (3DG-H) were determined by LC-MS/MS and pentosidine by HPLC with fluorimetric detection in ultrafiltrates of plasma, urine, or PD effluent as appropriate from patients on HD (n = 8) or PD (n = 8), and from healthy controls (n = 8). Among patients on HD, all free AGEs predialysis were significantly higher than in controls and were decreased with dialysis. The removal of MG-H1 and 3DG-H was comparable to that of urea, whereas that of CML and pentosidine was some 20% higher; in contrast, the removal of CEL and G-H1 was 25% lower. Among patients on CAPD, free AGEs in PD effluent increased with increasing dwell time. The combined renal and peritoneal 24-h excretion rates of CML (4.7 micromol), CEL (6.5 micromol), 3DG-H (16.6 micromol), and pentosidine (0.08 micromol) were twofold higher than the amount excreted in healthy controls, whereas MG-H1 was ninefold higher (59 micromol); the combined clearances of all free AGEs except pentosidine were lower than in healthy controls. Impaired renal clearance contributes to increased plasma free AGEs in uremia, but the increased excretion rate among patients on PD demonstrates that there was also an increased synthesis of free AGEs. Both HD and PD are able to remove free AGEs.

Markedly elevated levels of plasma advanced glycation end products in patients with liver cirrhosis – amelioration by liver transplantation

Background/Aims : Modification by advanced glycation renders macromolecules susceptible to elimination in the liver via scavenger receptors. Thus, in advanced liver disease an accumulation of advanced glycation end products (AGEs) in circulation might occur, due to the reduction of effective liver mass. Methods : Plasma AGE levels (fluorescent AGEs-AGE-Fl and N ε -carboxymethyllysine – CML) were determined in 51 patients with liver cirrhosis (Ci) and 19 healthy controls. Five patients were followed 36 months after liver transplantation. Results : In cirrhotic patients, markedly elevated concentrations of AGEs were revealed (AGE-Fl: control, 0.3±0.01×10 5 AU, Ci: 1.06±0.06×10 5 AU, P <0.01; CML, control: 431.7±16.3 ng/ml, Ci: 647.6±258.5, P <0.01). CML levels correlated with the severity of liver disease, as determined by clinical score ( r =0.663, P <0.001), albumin level ( r =0.704, P <0.001) and monoethylglycinexylide test ( r =0.852, P <0.01). Reduced renal function contributed to the rise of CML in proportion to the degree of renal impairment. Liver transplantation resulted in about 50% decline of CML levels within 3 months, while impairment of renal function still persisted, underlying the central role of the liver for AGE removal. Conclusions : In liver Ci, hepatic removal of AGEs is impaired. With regard to the toxicity of AGEs, their accumulation could be of pathophysiological relevance.

Effect of metformin on advanced glycation endproduct formation and peripheral nerve function in streptozotocin-induced diabetic rats

The effects of metformin treatment on advanced glycation endproduct formation and peripheral nerve function in streptozotocin-induced diabetic rats were examined. Streptozotocin-induced diabetic rats were treated with low dose metformin (50–65 mg kg −1 daily) or high dose metformin (500–650 mg kg −1 daily) for 10 weeks. While the metformin-untreated diabetic group showed a significant increase of advanced glycation endproducts (6.1-fold in the lens, 1.6-fold in the sciatic nerve, 2.3-fold in the renal cortex, and 1.9-fold in plasma; all P<0.01) compared with the healthy control group, both metformin-treated groups had significantly less advanced glycation endproduct deposition. The % decrease in the diabetes-induced increase in advanced glycation endproduct formation by low and high dose metformin treatment was 25% and 72% in the lens (both P<0.01), 31% and 42% in the sciatic nerve (both P<0.05), and 16% and 33% in the renal cortex ( P<0.05 and P<0.01), respectively. However, the plasma advanced glycation endproduct level showed no significant difference from that in the untreated diabetic group, in spite of slight decrease in plasma glucose and glycated hemoglobin levels in the metformin-treated groups. The diabetes-induced sciatic nerve conduction velocity deficits were improved by 46% and 42% by low and high dose metformin treatment, respectively (both P<0.01). These data suggest that metformin may have a direct antiglycative action, which in turn contributes to amelioration of peripheral nerve function. Thus, metformin treatment may be effective in the prevention of diabetic complications through not only lowering plasma glucose, but also directly inhibiting advanced glycation endproduct formation.