Seth Braunstein

Retinal vascular autoregulation in diabetes mellitus.

The blue field entoptic technique was used to study autoregulation of the macular retinal circulation in response to acute alterations of intraocular pressure in 71 diabetic eyes and 30 normals matched for age, systemic blood pressure, and ophthalmic artery diastolic pressure. IOPmax, the maximal intraocular pressure at which flow is maintained normal by autoregulation, was normal in eyes with no retinopathy (30 +/- 3.2 mm Hg) but decreased with progression of retinopathy, approaching the resting intraocular pressure in eyes with proliferative retinopathy. The hyperemia observed by normals to an acute reduction of intraocular pressure was not observed frequently in the diabetics with no retinopathy. The frequency of observation of the hyperemia decreased with progression of retinopathy and was uniformly absent in eyes with proliferative retinopathy. A group of eyes with minimal microangiopathy was found to have an abnormal IOPmax and no hyperemic response. The prognostic significance of these parameters remains to be established.

Diabetic Glycemic Control and Retinal Blood Flow

The effect of strict glycmic control on retinal volumetric blood flow rate (Q) was investigated in 13 insulin-dependent diabetic patients with laser Doppler velocimetry and monochromatic fundus photography. Strict glycemic control was achieved by glucose monitoring and four daily insulin injections. Q was determined in a major retinal vein at baseline and then 5days, 2 mo, and 6 mo after the institution of strict control. Level of retinopathy was assessed from stereocolor fundus photographs taken at baseline and 6 mo. After 6 mo of strict diabetic control, five eyes demonstrated progression (P) by one or more retinopathy levels, and eight eyes showed no progression (NP). At 5 days, there was a significant decrease in Q of 1.4 ± 0.9 μU/min (P < 0.005) in NP eyes and a nonsignificant increase in Q of 1.2 ± 1.7 μU/min in P eyes. Changes in Q from baseline observed at 5 days were strongly correlated with changes in retinopathy level at 6 mo (r = 0.79, P <0.005). No significant changes in Q from baseline were observed at 2 and 6 mo. A lack of decrease in Q at 5 days was associated with the progression of retinopathy that occurs in some patients after the institution of strict glycemic control and may serve as a predictor for progression of retinopathy.

Relation of plasma fatty acid binding proteins 4 and 5 with the metabolic syndrome, inflammation and coronary calcium in patients with type-2 diabetes mellitus.

Fatty acid-binding proteins (FABPs) 4 and 5 play coordinated roles in rodent models of inflammation, insulin resistance, and atherosclerosis, but little is known of their role in human disease. The aim of this study was to examine the hypothesis that plasma adipocyte and macrophage FABP4 and FABP5 levels would provide additive value in the association with metabolic and inflammatory risk factors for cardiovascular disease as well as subclinical atherosclerosis. Using the Penn Diabetes Heart Study (PDHS; n = 806), cross-sectional analysis of FABP4 and FABP5 levels with metabolic and inflammatory parameters and with coronary artery calcium, a measure of subclinical coronary atherosclerosis, was performed. FABP4 and FABP5 levels had strong independent associations with the metabolic syndrome (for a 1-SD change in FABP levels, odds ratio [OR] 1.85, 95% confidence interval [CI] 1.43 to 2.23, and OR 1.66, 95% CI 1.41 to 1.95, respectively) but had differential associations with metabolic syndrome components. FABP4 and FABP5 were also independently associated with C-reactive protein and interleukin-6 levels. FABP4 (OR 1.26, 95% CI 1.05 to 1.52) but not FABP5 (OR 1.13, 95% CI 0.97 to 1.32) was associated with the presence of coronary artery calcium. An integrated score combining FABP4 and FABP5 quartile data had even stronger associations with the metabolic syndrome, C-reactive protein, interleukin-6, and coronary artery calcium compared to either FABP alone. In conclusion, this study provides evidence for an additive relation of FABP4 and FABP5 with the metabolic syndrome, inflammatory cardiovascular disease risk factors, and coronary atherosclerosis in type 2 diabetes mellitus. These findings suggest that FABP4 and FABP5 may represent mediators of and biomarkers for metabolic and cardiovascular disease in type 2 diabetes mellitus.

Strict control of glycaemia: effects on blood flow in the large retinal vessels and in the macular microcirculation.

AIMS--The purpose of this study was to investigate the effect of instituting strict diabetic glycaemic control on the retinal macular microcirculation and to compare this effect with that observed in the main retinal veins. METHODS--In 28 insulin dependent diabetic patients with poor glycaemic control a regimen of strict diabetic control, consisting of four daily insulin injections was instituted and maintained for 6 months. Retinal haemodynamics were investigated in the macular microcirculation by the blue field simulation technique and in the major retinal veins by a combination of bidirectional laser Doppler velocimetry and monochromatic fundus photography. Progression of diabetic retinopathy was assessed from fundus photographs taken at baseline and at the end of the study. RESULTS--Institution of strict diabetic control resulted in a significant increase in leucocyte velocity in the macular circulation (p = 0.013). No significant difference in this increase was observed between eyes that showed progression (n = 8) and no progression (n = 20) of retinopathy during the study. Significant correlations were found between relative changes over time of blood flow measured in the main retinal veins and relative changes of leucocyte velocity determined in the macular microcirculation at 2 months (p = 0.008) and 6 months (p = 0.001) but not at 5 days (p = 0.49). In the eight eyes that showed progression of retinopathy, the product of leucocyte velocity and density at baseline was significantly higher than normal (p < 0.05). During the length of this study, this product was also significantly higher in the eight eyes that showed retinopathy progression than in the 20 eyes that did not show progression (p = 0.005). CONCLUSION--Our results suggest that increased flow in the macular microcirculation may be associated with progression of retinopathy, thus supporting the hypothesis that increased blood flow may play a role in the development of diabetic microangiopathy. Although there are correlations between the changes detected in the macular microcirculation and those measured in the main retinal vessels, there are also differences which need to be further investigated in order to better understand pathogenetic mechanisms.

Strict metabolic control and retinal blood flow in diabetes mellitus.

The effects of strict diabetic control on retinal haemodynamics were studied to elucidate whether such effects are associated with retinopathy changes. In 28 patients with poorly controlled insulin dependent diabetes mellitus and non-proliferative retinopathy, retinal haemodynamics were investigated at baseline, 5 days, 2 months, and 6 months after the institution of strict diabetic control using the bidirectional laser Doppler velocimetry technique and monochromatic fundus photography. Changes in retinal blood flow measured in a major retinal vein (Q) on the fifth day of strict diabetic control correlated significantly with changes in retinopathy level observed at the end of the 6 months of this study (rank correlation 0.65, p < 0.01). On the fifth day of strict diabetic control, 16 out of 20 eyes that showed no progression (NP) of retinopathy at the end of the study had decreases in Q, whereas six out of eight eyes that showed progression (P) had increases in Q. The difference in these changes in Q between P and NP eyes was statistically significant (one way analysis of variance, p = 0.001). No significant changes in Q were detected at 2 months or 6 months. Following the institution of strict diabetic control, no significant changes in time were detected in the regulatory response to 100% oxygen breathing characterised as the percentage decrease in Q at 4-6 minutes of oxygen breathing (analysis of variance, p = 0.36). Changes in Q following institution of strict diabetic control are associated with progression of retinopathy. Measurements described in this study may help identify diabetic patients at risk of progression when their metabolic control is improved.

Usefulness of Insulin Resistance Estimation and the Metabolic Syndrome in Predicting Coronary Atherosclerosis in Type 2 Diabetes Mellitus

Metabolic syndrome (MS) definitions predict cardiovascular events beyond traditional risk factors in patients with type 2 diabetes mellitus (DM) as well as subjects without DM. It has been shown that apolipoprotein B (apoB) and non-high-density lipoprotein cholesterol are associated with coronary artery calcification in DM. However, the relative value of MS, apoB lipoproteins, and estimates of insulin resistance is unknown in predicting atherosclerosis in DM. Cross-sectional analyses of white subjects in 2 community-based studies were performed (n = 611 patients with DM, n = 803 subjects without DM) using multivariate analysis of traditional risk factors and then adding MS, apoB, and homeostasis model assessment of insulin resistance (HOMA-IR). Incremental value was tested using likelihood ratio testing. Beyond traditional risk, HOMA-IR (tobit regression ratio 1.86, p = 0.002), apoB (tobit regression ratio 1.55, p = 0.001), and MS (tobit regression ratio 2.37, p = 0.007) were independently associated with coronary artery calcification in DM. In nested models, HOMA-IR added value to apoB (tobit regression ratio 1.72, p = 0.008), MS (tobit regression ratio 1.72, p = 0.011), and apoB and MS (tobit regression ratio 1.64, p = 0.021). ApoB showed a similar pattern when added to HOMA-IR (tobit regression ratio 1.51, p = 0.004), MS (tobit regression ratio 1.46, p = 0.005), and HOMA-IR and MS (tobit regression ratio 1.48, p = 0.006). MS added to apoB (tobit regression ratio 1.99, p = 0.032) but not HOMA-IR (tobit regression ratio 1.54, p = 0.221) or apoB and HOMA-IR (tobit regression ratio 1.32, p = 0.434). In conclusion, insulin resistance estimates add value to MS and apoB in predicting coronary artery calcification scores in DM and warrant further evaluation in clinic for identification of patients with DM at higher risk for atherosclerotic cardiovascular disease.

Economic Model of First-Line Drug Strategies to Achieve Recommended Glycaemic Control in Newly Diagnosed Type 2 Diabetes Mellitus

AbstractObjective: To assess the short-term direct medical costs and effectiveness associated with achieving recommended glycaemic goals using commonly prescribed first-line oral antihyperglycaemic medications in type 2 diabetes mellitus. Materials and Methods: A literature-based, decision-tree model was developed to project the number of patients achieving glycosylated haemoglobin values of <7% on oral therapies and the associated costs over a 3-year timeframe. For each first-line strategy, patients could progress to combination therapy using two or more agents prior to the introduction of insulin. The overall cost of treatment included costs (2001/2002 values;

Gender differences in the association of C-reactive protein with coronary artery calcium in type-2 diabetes.

US) of comprehensive medical care, laboratory tests, patient education, drug therapy, home glucose monitoring and adverse events. Results: At 3 years, the overall cost of treatment for the various first-line strategies was

New developments in type 2 diabetes mellitus: Combination therapy with a thiazolidinedione

US6106 for glipizide gastrointestinal therapeutic system,

Measurement of waist circumference predicts coronary atherosclerosis beyond plasma adipokines

US6727 for metformin immediate release,