How the diabetic eye loses vision.

The objective is to review the most common causes of vision loss in patients with diabetes with the goal of better managing patients with diabetic eye disease. In this review, the causes of vision loss, and the clinical evaluation and management of diabetic retinopathy (DR) and diabetic macular edema (DME) are outlined. Patients with diabetes mellitus have an increased risk of vision loss and blindness. In patients with diabetes, the primary mechanism responsible for vision loss is centrally involved DME or clinically significant macular edema (CSME), defined as vascular leakage resulting in fluid accumulation that affects the center of the macula. DR and DME are thought to result from the effects of excessive blood glucose on the vessels that produces microvascular damage. The progression of DR can be slowed by intensive glycemic and blood pressure control. Severe visual loss from proliferative DR and moderate visual loss from DME can be reduced by laser photocoagulation. DR and DME are diagnosed on dilated retinal examination and confirmed with diagnostic testing. Many experts and associations recommend that patients with diabetes have an yearly, thorough, dilated eye exam. This manuscript describes the case history of a patient with diabetes and vision loss.

fMLP induces Hsp27 expression, attenuates NF-kappaB activation, and confers intestinal epithelial cell protection.

Sustained expression of cytoprotective intestinal epithelial heat shock proteins (Hsps), particularly Hsp27, depends on stimuli derived from bacterial flora. In this study, we examined the role of the bacterial chemotactic peptide fMLP in stimulating colonic epithelial Hsp expression at concentrations encountered in a physiological milieu. Treatment of the polarized human intestinal epithelial cell line Caco2bbe with physiological concentrations of fMLP (10-100 nM) induced expression of Hsp27, but not Hsp72, in a time- and concentration-dependent manner. Induction of Hsp27 by fMLP was specific since the fMLP analogs MRP and MLP were not effective. Hsp27 induction by fMLP was blocked by the fMLP-receptor antagonist BOC-FLFLF and was blocked when the dipeptide transporter PepT1, an entry pathway for fMLP, was silenced. fMLP activated both the p38 and ERK1/2 MAP kinase pathways in Caco2bbe cells, but not the SAPK/JNK pathway. The p38 inhibitor SB203580, but not the MEK-1 inhibitor PD98059, blocked Hsp27 induction by fMLP. fMLP treatment inhibited actin depolymerization and decreased transepithelial resistance caused by the oxidant monochloramine, and this inhibition was reversed by silencing Hsp27 expression. fMLP pretreatment also inhibited activation of proinflammatory transcription factor NF-kappaB by TNF-alpha in Caco2bbe cells, reducing induction of NF-kappaB target genes by TNF-alpha both in human intestinal biopsies and Caco2bbe cells. In conclusion, fMLP may contribute to the maintenance of intestinal homeostasis by mediating physiological expression of Hsp27, enhancing cellular protection, and negatively regulating the inflammatory response.

Role of protein kinase C inhibition in the development of diabetic microvascular complications.

Diabetes mellitus affects millions of people in the USA and throughout the world. The global epidemic may be attributed to both the increasing age of the population and the increasing rates of obesity. Diabetes is associated with chronic microvascular (diabetic neuropathy, retinopathy and nephropathy) and macrovascular complications (heart disease, stroke and peripheral vascular disease). Patients with diabetes benefit from a comprehensive approach to prevent complications, including weight loss, smoking cessation, antiplatelet agents, and glycemic and blood pressure control. However, all of these are difficult for patients to achieve and maintain on a daily basis and there is still a risk of developing vascular complications. Specific therapies for diabetic complications targeting molecules that are activated by hyperglycemia are emerging. The aim of this review is to highlight the role of protein kinase Cß in the development of diabetic microvascular complications while briefly describing clinical experience with the protein kinase Cß inhibitor ruboxistaurin.

Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy.

OBJECTIVE: To evaluate the effect of ruboxistaurin, an orally administered protein kinase C beta (PKC beta) isozyme-selective inhibitor, on vision loss in patients with diabetes. DESIGN: Thirty-six-month, randomized, double-masked, placebo-controlled, parallel, multicenter trial. PARTICIPANTS: Six hundred eighty-five patients randomized at 70 clinical sites. METHODS: Ophthalmologic examination was performed at screening and at each 3-month visit. Retinopathy status was assessed every 6 months with Early Treatment Diabetic Retinopathy Study (ETDRS) standard 7-field 30 degrees color stereoscopic fundus photography. Levels of diabetic retinopathy and diabetic macular edema were determined by 2 independent graders masked to site and treatment assignment, with additional independent adjudication as required. Eligible patients had a best-corrected visual acuity (VA) score of > or =45 letters, retinopathy level > or = 47A and < or = 53E, and no prior panretinal photocoagulation in at least one eye. MAIN OUTCOME MEASURE: Effect of oral ruboxistaurin (32 mg/day) on reduction of sustained moderate visual loss (> or =15-letter decrease in ETDRS VA score maintained > or = 6 months) in patients with moderately severe to very severe nonproliferative diabetic retinopathy. RESULTS: Sustained moderate visual loss occurred in 9.1% of placebo-treated patients versus 5.5% of ruboxistaurin-treated patients (40% risk reduction, P = 0.034). Mean VA was better in the ruboxistaurin-treated patients after 12 months. Baseline-to-end point visual improvement of > or =15 letters was more frequent (4.9% vs. 2.4%) and > or =15-letter worsening was less frequent (6.7% vs. 9.9%) in ruboxistaurin-treated patients relative to placebo (P = 0.005). When clinically significant macular edema was >100 microm from the center of the macula at baseline, ruboxistaurin treatment was associated with less frequent progression of edema to within 100 microm (68% vs. 50%, P = 0.003). Initial laser treatment for macular edema was 26% less frequent in eyes of ruboxistaurin-treated patients (P = 0.008). CONCLUSION: Oral ruboxistaurin treatment reduced vision loss, need for laser treatment, and macular edema progression, while increasing occurrence of visual improvement in patients with nonproliferative retinopathy.