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Objective: To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at nearnormal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy.Methods: Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome.Results: After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conven-tional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; PϽ.001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (PϽ.001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. Conclusion:The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning.

Purpose-To compare two laser photocoagulation techniques for treatment of diabetic macular edema (DME): modified-ETDRS direct/grid photocoagulation (mETDRS) and a, potentially milder, but potentially more extensive, mild macular grid (MMG) laser technique in which small mild burns are placed throughout the macula, whether or not edema is present, and microaneurysms are not treated directly.Methods-263 subjects (mean age 59 years) with previously untreated DME were randomly assigned to receive laser photocoagulation by mETDRS (N=162 eyes) or MMG (N=161 eyes) technique. Visual acuity, fundus photographs and OCT measurements were obtained at baseline and after 3.5, 8, and 12 months. Treatment was repeated if DME persisted.Main Outcome Measure-Change in OCT measures at 12-months follow up.Results-From baseline to 12 months, among eyes with baseline central subfield thickness ≥ 250 microns, central subfield thickening decreased by an average of 88 microns in the mETDRS group and decreased by 49 microns in the MMG group (adjusted mean difference: 33 microns, 95% confidence interval 5 to 61 microns, P=0.02). Weighted inner zone thickening by OCT decreased by 42 and 28 microns, respectively (adjusted mean difference: 14 microns, 95% confidence interval 1 to 27 microns, P=0.04), maximum retinal thickening (maximum of the central and four inner subfields) decreased by 66 and 39 microns, respectively (adjusted mean difference: 27 microns, 95% confidence interval 6 to 47 microns, P=0.01), and retinal volume decreased by 0.8 and 0.4 mm 3 , respectively (adjusted mean difference: 0.3 mm 3 , 95% confidence interval 0.02 to 0.53 mm 3 , P=0.03). At 12 months, the mean change in visual acuity was 0 letters in the mETDRS group and 2 letters worse in the MMG group (adjusted mean difference: 2 letters, 95% confidence interval −0.5 to 5 letters, P=0.10).Conclusions-At 12 months after treatment, the MMG technique is less effective at reducing OCT measured retinal thickening than the more extensively evaluated current mETDRS laser photocoagulation approach. However, the visual acuity outcome with both approaches is not substantially different. Given these findings a larger long-term trial of the MMG technique is not justified. Application to Clinical Practice-ModifiedETDRS focal photocoagulation should continue as a standard approach for treating diabetic macular edema. Clinical Sites that Participated in this Protocol Sites are listed in order by number of subjects randomized into the study. The number of subjects randomized is noted in parenthesis preceded by the site location and the site name. Personnel are listed as (I) for Investigator, (C) for Coordinator, (V) for Visual Acuity Tester, and (P) for Photographer. Southeastern Retina Associates, PC (3): Howard L. Cummings (I); D. Allan Couch (I); Gail Darnell (C); Deanna Jo Long (C); Stacy Carpenter (V); Rachel Mallard (V); Julie P. Berry (P); Melissa Sturgill (P); Los Angeles, CA -Doheny Eye Institute (3): Jennifer I. Lim (I); Christina J. Flaxel (I); Margaret Padilla (C); Jesus M....

Statins may have favorable effects on endothelial barrier function. The effect of rosuvastatin and simvastatin therapy (10 mg/kg) for 5 weeks on blood-brain barrier (BBB), blood-retinal barrier (BRB), and cardiac muscle permeability of streptozotocin-induced diabetic rats was studied. The size-selective permeability of different vascular beds to a group of fluorescein isothiocyanate dextrans of varying molecular weights was measured. The volume of distribution of 250-, 70-, and 40-kDa dextrans in the cerebral tissue of diabetic rats were significantly increased. The volume of distribution of these dextrans in cerebral tissue was normalized by both statins. Diabetes did not significantly alter the BRB, but both statins decreased the volume of distribution of 70-and 40-kDa dextrans in the retina. The volume of distribution of 40 kDa in cardiac muscle was increased in diabetes, and this change was prevented with statin treatment. Treatment with rosuvastatin and mevalonate (150 mg/kg in drinking water for 5 weeks) did not alter the volume of distribution measurements. We concluded that 1) diabetes in rats is associated with significant changes in the BBB permeability; 2) statin treatment improves the endothelial barrier function in cerebral tissue, retina, and cardiac muscle; and 3) this statin effect could not be attributed to HMGCoA reductase inhibition. Diabetes 54: [2977][2978][2979][2980][2981][2982] 2005 O ne of the sentinel features of atherosclerosis is endothelial cell dysfunction that manifests itself in a variety of ways including poor nitric oxide production, poor vasodilatory response, and increased adhesiveness to leukocytes (1). Another potential endothelial dysfunction commonly observed in diabetes is altered permeability to macromolecules.Diabetes in humans and in animal models has been found to cause significant alterations in endothelial permeability in various vascular beds (2-5). Potential mechanisms underlying the diabetes-related changes in the blood-brain barrier (BBB) include altered expression of key structural and enzymatic proteins, alterations in the lipid composition and fluidity of the membranes, alterations in the neurotransmitter activity, and increased oxidative damage of the endothelial cells (2,6). Another likely contributor to these changes is the activation of protein kinase C that is shown to play an important role in increased permeability of the peripheral and cerebral circulation (7,8). Finally, recent studies have shown that inactivation of the rho-GTPase has a critical role in endothelial barrier function (9,10).Statins are known to have many pleiotropic effects (11). However, the effect of statins on the functional integrity of the microvasculature of diabetic animals has not been well studied. Statins are known to alter endothelial cell function, smooth muscle cell migration and proliferation, and some aspects of vascular inflammation (11). In addition, statins have been shown to improve endothelial barrier permeability in the aorta of Watanabe hyperlipidimic rabbits ...

It has been speculated that platelet activation may contribute to the evolution of vascular complications in patients with Type I diabetes mellitus. To address this hypothesis, we measured the plasma and urinary metabolites of thromboxane, presumably of platelet origin, and of prostacyclin, derived from endothelial cells, in addition to more conventional indexes of platelet function. Urinary excretion of the metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha did not differ between diabetics with or without retinopathy and nondiabetic controls. Furthermore, measurement of platelet granule constituents, the aggregation responses to ADP or arachidonic acid, and levels of serum thromboxane B2 failed to discriminate between the groups. The institution of tight diabetic control with multiple daily injections of insulin failed to alter either urinary metabolite excretion or plasma levels of 11-dehydro-thromboxane B2. Conversely, insulin-induced hypoglycemia failed to alter the concentrations of plasma or urinary thromboxane metabolites in nondiabetic volunteers, despite a mean 60-fold increase in plasma epinephrine. These studies suggest that platelet activation does not precede the development of microvascular complications in patients with Type I diabetes who lack clinical evidence of macrovascular disease and have normal renal function. Furthermore, it is unlikely that platelet activation due to intermittent hypoglycemia contributes to the reportedly accelerated development of retinopathy in such patients, when they are subject to tight diabetic control.