Diabetes is characterized by accelerated atherosclerosis with widely distributed vascular lesions. An important mechanism by which hyperglycaemia contributes to vascular injury is through the extensive intracellular and extracellular formation of AGEs (advanced glycation end products). AGEs represent a heterogeneous group of proteins, lipids and nucleic acids, irreversibly cross-linked with reducing sugars. AGEs are implicated in the atherosclerotic process, either directly or via receptor-mediated mechanisms, the most extensively studied receptor being RAGE (receptor for AGEs). The AGE-RAGE interaction alters cellular signalling, promotes gene expression and enhances the release of pro-inflammatory molecules. It elicits the generation of oxidative stress in numerous cell types. The importance of the AGE-RAGE interaction and downstream pathways leading to injurious effects as a result of chronic hyperglycaemia in the development, progression and instability of diabetic atherosclerotic lesions has been amply demonstrated in animal studies. Moreover, the deleterious link of AGEs with diabetic vascular complications has been suggested in many human studies. In the present review, our current understanding of their role as an important mediator of vascular injury through the various stages of atherosclerosis in diabetes will be reviewed and critically assessed.
The adiponectin-leptin ratio is associated with insulin resistance, measured with the euglycemic hyperinsulinemic clamp, in Caucasians with T2D. The association with clamp derived sensitivity index is even stronger than that of HOMA, QUICKI, fasting glucose/insulin ratio or McAuley index and is independent of body mass index or glycemic control. The adiponectin-leptin ratio promises to become a new laboratory marker of insulin resistance in T2D.
Abstract-To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria Ͻ200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; nϭ126), delapril (30 mg/d; nϭ127), or placebo (nϭ127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range ) on placebo (Pϭ0.87 and Pϭ0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 Pϭ0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0. Pϭ0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24 -0.87; Pϭ0.017) and 0.52 (0.27-0.99; Pϭ0.048), respectively. Glucose disposal rate decreased from 5.8Ϯ2.4 to 5.3Ϯ1.9 mg/kg per min on placebo (Pϭ0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity. (Hypertension. 2011;58:776-783.) • Online Data Supplement Key Words: ACE inhibitors Ⅲ calcium channel blockers Ⅲ manidipine Ⅲ diabetic nephropathy Ⅲ cardiovascular complications Ⅲ diabetic neuropathy Ⅲ diabetic retinopathy Received April 11, 2011; first decision April 26, 2011; revision accepted August 25, 2011. From the Mario Negri Institute for Pharmacological Research (P.R., I.P.I., A.F., A.P.I., S.R., C.C., N.R., G.N., N.M., B.E.-I., F.G., A.P., G.R.), Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Bergamo, Italy; Unit of Nephrology (P.R., S.R., G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy; Neuromuscular Diseases Unit (G.L., A.S., R.L., P.P.), Istituto Di Ricovero e Cura a Carattere Scientifico Foundation "Carlo Besta" Neurological Institute, Milan, Italy; Department for Endocrinology, Diabetes and Metabolic Diseases (P.B., J.Z.), University Medical Centre, Ljubljana, Slovenia; Department of Neuroscience and Biomedical Technologies (G.C. A ngiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists are the antihypertensive agents that more effectively reduce macrovascular disease 1 and limit the onset and progression o...
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