imidazolone and Diabetic-Nephropathies

Topics: Adult; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Glycation End Products, Advanced; Humans; Imidazoles; Indians, North American; Kidney; Kidney Glomerulus; Losartan; Lysine; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Pyruvaldehyde

Six skin collagen advanced glycation end products (AGEs) originally measured near to the time of the Diabetes Control and Complications Trial (DCCT) closeout in 1993 may contribute to the "metabolic memory" phenomenon reported in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. We have now investigated whether the addition of four originally unavailable AGEs (i.e., glucosepane [GSPNE], hydroimidazolones of methylglyoxal [MG-H1] and glyoxal, and carboxyethyl-lysine) improves associations with incident retinopathy, nephropathy, and neuropathy events during 13-17 years after DCCT. The complete 10-AGE panel is associated with three-step Early Treatment of Diabetic Retinopathy Study scale worsening of retinopathy (P ≤ 0.002), independent of either mean DCCT or EDIC study A1C level. GSPNE and fructose-lysine (furosine [FUR]) correlate with retinopathy progression, independently of A1C level. The complete panel also correlates with microalbuminuria (P = 0.008) and FUR with nephropathy independently of A1C level (P ≤ 0.02). Neuropathy correlates with the complete panel despite adjustment for A1C level (P ≤ 0.005). MG-H1 and FUR are dominant, independent of A1C level (P < 0.0001), whereas A1C loses significance after adjustment for the AGEs. Overall, the added set of four AGEs enhances the association of the original panel with progression risk of retinopathy and neuropathy (P < 0.04) but not nephropathy, while GSPNE and MG-H1 emerge as the principal new risk factors. Skin AGEs are robust long-term markers of microvascular disease progression, emphasizing the importance of early and sustained implementation of intensive therapy.

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Disease Progression; Female; Glycation End Products, Advanced; Humans; Imidazoles; Logistic Models; Male; Microvessels; Multivariate Analysis; Pyruvaldehyde; Skin; Young Adult

Increased advanced glycation end products (AGEs) and oxidation products (OPs) are proposed to lead to progression of diabetic nephropathy (DN). We investigated the relationship between AGEs, OPs, and progression of DN in 103 subjects with type 1 diabetes participating in the Natural History of Diabetic Nephropathy Study.. Mean age of subjects was 17.6±7.4 years, and mean duration of diabetes was 8.3±4.9 years. All patients were normoalbuminuric. Change in glomerular basement membrane (GBM) width from baseline to 5 years, measured using electron micrographs of renal biopsies, was our primary end point, and mesangial fractional volume was a secondary end point. Fast progressors (FPs) were defined as those in the upper quartile of GBM change, and the remaining patients were classified as slow progressors (SPs). AGEs (3-deoxyglucosone and methylglyoxal hydroimidazolones [MGHI]), carboxymethyl lysine (CML), carboxyethyl lysine (CEL), and OPs (methionine sulfoxide and 2-aminoadipic acid) were measured at year 5 by liquid chromatography/triple-quadruple mass spectroscopy on 10-K plasma filtrates.. We found that MGHI, CEL, and CML levels were significantly higher in FPs relative to SPs. No product predicted mesangial expansion. A model containing only HbA1c accounted for 4.7% of GBM width variation, with the total variability explained by the model increasing to 11.6% when MGHI, CEL, and CML were added to the regression model (7.9% increase). MGHI was a significant independent predictor of FP. Using a logistic regression model to relate each biomarker to the probability of a subject's classification as an FP, CML, CEL, and MGHI, but not HbA1c, showed a significant relationship to the probability of FP.. The results suggest that these three major AGEs may be early indicators of progression of important DN lesions.

Topics: Adolescent; Adult; Child; Diabetic Nephropathies; Female; Glycation End Products, Advanced; Humans; Imidazoles; Male; Pyruvaldehyde; Young Adult

To study large- and small-nerve fiber function in type 1 diabetes of long duration and associations with HbA1c and the advanced glycation end products (AGEs) N-ε-(carboxymethyl)lysine (CML) and methylglyoxal-derived hydroimidazolone.. In a long-term follow-up study, 27 persons with type 1 diabetes of 40 ± 3 years duration underwent large-nerve fiber examinations, with nerve conduction studies at baseline and years 8, 17, and 27. Small-fiber functions were assessed by quantitative sensory thresholds (QST) and intraepidermal nerve fiber density (IENFD) at year 27. HbA1c was measured prospectively through 27 years. Serum CML was measured at year 17 by immunoassay. Serum hydroimidazolone was measured at year 27 with liquid chromatography-mass spectrometry.. Sixteen patients (59%) had large-fiber neuropathy. Twenty-two (81%) had small-fiber dysfunction by QST. Heat pain thresholds in the foot were associated with hydroimidazolone and HbA1c. IENFD was abnormal in 19 (70%) and significantly lower in diabetic patients than in age-matched control subjects (4.3 ± 2.3 vs. 11.2 ± 3.5 mm, P < 0.001). IENFD correlated negatively with HbA1c over 27 years (r = -0.4, P = 0.04) and CML (r = -0.5, P = 0.01). After adjustment for age, height, and BMI in a multiple linear regression model, CML was still independently associated with IENFD.. Small-fiber sensory neuropathy is a major manifestation in type 1 diabetes of 40 years duration and more prevalent than large-fiber neuropathy. HbA1c and the AGEs CML and hydroimidazolone are important risk factors in the development of large- and small-fiber dysfunction in long-term type 1 diabetes.

Topics: Adolescent; Adult; Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Imidazoles; Lysine; Male; Middle Aged; Nerve Fibers; Pyruvaldehyde; Sensory Thresholds; Young Adult

3-Deoxyglucosone (3-DG) accumulating in uremic serum plays an important role in the formation of advanced glycation end products (AGEs). To determine if 3-DG is involved in the formation of intracellular AGEs, we measured the erythrocyte levels of 3-DG and AGEs such as imidazolone and N epsilon-carboxymethyllysine (CML) in hemodialysis (HD) patients with diabetes. Further, to determine if the polyol pathway is involved in the formation of erythrocyte 3-DG and AGEs, an aldose reductase inhibitor (ARI) was administered to these patients.. The erythrocyte levels of sorbitol, 3-DG, imidazolone, and CML were measured in ten diabetic HD patients before and after treatment with ARI (epalrestat) for eight weeks, and were compared with those in eleven healthy subjects. 3-DG was incubated in vitro with hemoglobin for two weeks to determine if imidazolone and CML are formed by reacting 3-DG with hemoglobin.. The erythrocyte levels of sorbitol, 3-DG, imidazolone, and CML were significantly elevated in diabetic HD patients as compared with healthy subjects. The erythrocyte levels of 3-DG significantly decreased after HD, but sorbitol, imidazolone or CML did not. The administration of ARI significantly decreased the erythrocyte levels of sorbitol, 3-DG and imidazolone, and tended to decrease the CML level. Imidazolone was rapidly produced in vitro by incubating 3-DG with hemoglobin, and CML was also produced, but less markedly as compared with imidazolone.. The erythrocyte levels of 3-DG and AGEs are elevated in diabetic HD patients. The administration of ARI reduces the erythrocyte levels of 3-DG and AGEs, especially imidazolone, as well as sorbitol. Thus, 3-DG and AGEs, especially imidazolone, in the erythrocytes are produced mainly via the polyol pathway. ARI may prevent diabetic and uremic complications associated with AGEs.

Topics: Adult; Aged; Aldehyde Reductase; Arginine; Creatinine; Deoxyglucose; Diabetic Nephropathies; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Female; Glycation End Products, Advanced; Hemoglobins; Humans; Imidazoles; In Vitro Techniques; Lysine; Male; Middle Aged; Polymers; Renal Dialysis; Sorbitol; Uremia