Retinal and Neuropathic Diseases in Diabetes

Friday, June 10, 2005
4:15-6:15 PM

Chair:
Hans-Peter Hammes, MD

Presentations in this session (25-OR to 32-OR) covered novel clinical and preclinical findings relevant to the  diabetic microvascular complications (DMC), diabetic retinopathy (DR) and diabetic neuropathy (DN). A broad range of topics were covered.

Reported by Kimberly McFarland, PhD

25-OR: Retinal blood flow (RBF) has been considered a surrogate endpoint for diabetic retinopathy (DR). The current study measured RBF in well-controlled type 1 diabetes patients (mean A1C = 7.75±1.33) with diabetes duration < 15 years and no or minimal (ETDRS 10-20) retinopathy. Contrary to previous reports, there were no significant differences in RBF between patients and age-matched controls. The results were similar in a subgroup of patients with longer disease duration. These results could reflect changes in retinopathy epidemiology among type 1 diabetes patients due to implementation of DCCT guidelines. The findings also suggest that RBF abnormalities may not be a good surrogate for retinopathy progression in this patient population.

26-OR: Genetic variants of the the aldose reductase gene, AKR1B1, differentially affect DMC. The (CA)n dinucleotide repeat allele, Z-2, and the -106C allele are associated with increased transcriptional activity and DMC risk. To the contrary, the Z+2 and -106T alleles result in reduced transcriptional activity and DMC risk. A longitudinal study in adolescent, type 1 diabetes patients was designed to determine which AKR1B1 allele has a greater effect on autonomic and peripheral neuropathy. Patients were followed for a minimum of 5 years. Autonomic function and peripheral sensory thresholds were assessed, and patient genotypes were determined using PCR-RFLP. Peripheral and autonomic function declined over time, but significantly better outcomes were associated with the Z+2 allele. The data indicate that patients with specific genotypes might derive greater benefit from aldose reductase inhibitors (ARIs).

27-OR: The authors of this study explored the effect of insulin on the hippocampus. In particular, the authors studied the effect of intrahippocampal insulin injection on spatial working memory, as measured by performance in a 4-choice maze test. The authors reported an inverted-U dose response to insulin, with optimal memory enhancement at 100uU insulin. The effects were not due to insulin effects on anxiety or motor activity, were specific to the hippocampus, were not due to action at the IGF-1 receptor, and could be abolished by a variety of PI3 kinase inhibitors. Finally, microdialysis demonstrated decreased hippocampal lactate and decreased hippocampal glucose, suggesting that insulin might mediate memory through local metabolism effects in the hippocampus.

28-OR: Stroma derived factor-1 (SDF-1) signals endothelial progenitor cells (EPCs) to migrate into sites of vascular injury and mediate repair. This process appears to be impaired in patients with diabetes. EPCs collected from diabetes patients did not migrate in response to SDF-1 alpha as EPCs from normal individuals do. The authors first determined that the activity of CD26 dipeptidyl peptidase, an enzyme that cleaves SDF-1, was higher in EPCs from diabetic patients than in those from nondiabetic individuals. However, the effect did not completely account for the loss of SDF-1 responsiveness. The nitric oxide (NO) donor, DETE-NO, reversed the EPC nonresponsiveness and rendered the cells more deformable. The increased flexibility and migration were attributed to increased recruitment of the cytoskeletal protein, VASP, to lamellopodia. Lack of SDF-1 responsiveness in EPCs of diabetes patients, and the resulting migration defect, could result in acellular capillaries. NO donors may provide a pharmacologic solution.

29-OR: Somatostatin (SST) is decreased in the vitreous fluid of diabetes patients with proliferative diabetic retinopathy. SST has two forms, SST-14 and SST-28. This study utilized radioimmunoassay and HPLC were used to determine that SS-28 is the form that predominates in human retinal fluid. Interestingly, while SST-28 levels are decreased in the vitreous fluid of diabetes patients, relative to individuals without diabetes, plasma levels of SST-28 are higher in diabetes patients.

30-OR: Male, type 1 diabetes patients from DCCT/EDIC completed a voluntary questionnaire regarding sexual dysfunction (erectile dysfunction, orgasmic disorder, decreased libido) at year 10 of the EDIC study. Only 1/3 of the men had erectile dysfunction (ED) more than 20 years after diagnosis of type 1 diabetes. Current A1C and presence of neuropathy were the greatest predictors of ED. Prior randomization to the intensive control arm of DCCT did not improve ED risk.

31-OR:   Homocysteine (Hc) is frequently elevated in patients with diabetes. The purpose of this study was to determine whether a relationship exists between elevated Hc and peripheral neuropathy (PN). In a group of 140 type 2 diabetes patients, 39.7% had hyperhomocysteinemia (Hc>15 micromol/L). Hc levels were higher in patients with neuropathy than in those without, and the rate of neuropathy was higher in patients with hyperhomocysteinemia (38.3%) than in patients without (13.9%, p<0.002). Statistical analysis (receiver operating curve, ROC) indicated a discrimination cut off of 14.4 micromol/L for neuropathy. The results suggest that elevated Hc may be associated with PN.

32-OR: The authors explored the relationship between diabetic retinopathy (DR), and coronary artery disease (CAD) in urban Asian Indian diabetic subjects. Participants were part of the Chennai Urban Rural Epidemiology Study (CURES). DR was present in 17.1% of the patients, and 17.7% had CAD. The prevalence of CAD was significantly higher in patients with DR than in those without. Increasing CAD prevalence had a direct relationship with increasing DR severity. CAD was present in 19.5% of patients with mild, non-proliferative DR (NPDR), 33.3% of those with moderate NPDR, 33.3% of those with severe NPDR, and 42.9% of those with proliferative DR (PDR). The association between DR and CAD was lost when the data were adjusted for A1C and disease duration.