Cardiovascular morbidity and all-cause mortality in patients with retinal vein occlusion: a Danish nationwide cohort study.

BACKGROUND/AIMS: Associations between retinal vein occlusion (RVO) and subsequent cardiovascular disease (CVD) or mortality have not been evaluated in a recent cohort, after novel therapeutic options have increased referrals for treatment of the condition. We aimed to evaluate overall and subtype-stratified risk of CVD and all-cause mortality following RVO and assess any alterations after the introduction of angiostatic therapy in Denmark in 2011. METHODS: This nationwide, registry-based cohort study from 1998 to 2018 evaluated 4 194 781 individuals. Hazard ratios (HRs) were reported for RVO as an overall measure and subclassified as branch and central RVO. RESULTS: Patients with RVO (n=15 665) were median 71.8 years old at the time of exposure and 50.7% were women. RVO associated with incident CVD (adjusted HR 1.13, 95% CI 1.09 to 1.17) but not mortality (adjusted HR 1.00, 95% CI 0.97 to 1.03). Almost similar risks of CVD were found for patients with branch and central RVO (adjusted HRs 1.14, 95% CI 1.03 to 1.25, and 1.12, 95% CI 1.00 to 1.25, respectively), but only patients with central RVO exhibited increased mortality (adjusted HR 1.12, 95% CI 1.04 to 1.21). Risk of CVD, especially non-ischaemic, was higher for patients diagnosed after 2011 (adjusted HRs 1.24, 95% CI 1.15 to 1.33 vs 1.06, 95% CI 1.01 to 1.12). CONCLUSION: In a cohort of the Danish population aged 40 years or more, patients with RVO had a 13% increased risk of incident CVD compared with unexposed individuals. Risk of CVD was increased after 2011, when intravitreal angiostatic treatment was introduced and referral practices altered.

Lack of differences in the regional variation of oxygen saturation in larger retinal vessels in diabetic maculopathy and proliferative diabetic retinopathy.

BACKGROUND: Diabetic retinopathy is characterised by morphological lesions in the ocular fundus related to disturbances in retinal blood flow. The two vision threatening forms of retinopathy show specific patterns of distribution of retinal lesions with proliferative diabetic retinopathy (PDR) developing secondary to ischaemia and hypoxia in the retinal periphery and diabetic maculopathy (DM) developing secondary to hyperperfusion and increased vascular permeability in the macular area. These differences in the distribution of retinal lesions might be reflected in regional differences in oxygen saturation in the larger retinal vessels. METHODS: Dual-wavelength retinal oximetry was performed in 30 normal persons, 30 patients with DM and 30 patients with PDR, and the oxygen saturation was measured in peripapillary vessels supplying the four retinal quadrants and in branches from the upper temporal arcades supplying, respectively, the macular area and the retinal periphery. RESULTS: The overall oxygen saturation was significantly higher in diabetic patients than in normal persons and the arteriovenous (AV) saturation difference significantly lower in the patients with DM. The regional variation in oxygen saturation was similar in the three studied groups with a decreasing saturation from the upper nasal through the lower nasal, lower temporal and the upper temporal peripapillary vessels, and with a significantly higher oxygen saturation in venules draining the macular area than in venules draining the retinal periphery. CONCLUSIONS: The regional differences in retinal lesions in vision threatening diabetic retinopathy are not reflected in regional differences in the oxygen saturation of larger retinal vessels. The development of vision threatening diabetic retinopathy depends on other factors, such as, for example, regional differences in the retinal microcirculation.

The Systemic Blood Pressure and Oxygen Saturation in Retinal Arterioles Predict the Effect of Intravitreal Anti-VEGF Treatment on Diabetic Maculopathy.

PURPOSE: The advent of vascular endothelial VEGF antagonists has increased the therapeutic options for diabetic maculopathy considerably. However, there is a need to identify patients who respond favorably to the treatment from those in whom the treatment is less effective. The purpose of the present study was to test the hypothesis that the oxygen saturation in retinal vessels together with other risk factors can predict the effect of anti-VEGF treatment on diabetic maculopathy. METHODS: In 73 eyes from 53 patients with center-involving diabetic macular edema, multiple linear regression was used to evaluate the predictive value of oxygen saturation in larger retinal vessels together with age, diabetes duration, diabetes type, hemoglobin A1c (HbA1c), mean arterial blood pressure (MAP), body mass index (BMI), previous retinal photocoagulation, visual acuity (VA), and central retinal thickness (CRT) before treatment as explanatory variables for VA and CRT after three monthly injections of anti-VEGF medication. RESULTS: Anti-VEGF treatment induced a significant increase in VA and a significant decrease in CRT, but no significant changes in the overall oxygen saturation of larger retinal vessels. Visual acuity and CRT before treatment contributed significantly to predicting the same variable after treatment. Additionally, MAP and the oxygen saturation in retinal arterioles before treatment contributed significantly to predicting VA and CRT after treatment. CONCLUSIONS: The MAP and oxygen saturation in retinal arterioles might potentially be included as parameters in risk models predicting the effect of anti-VEGF treatment in patients with diabetic maculopathy.

Increasing oxygen saturation in larger retinal vessels after photocoagulation for diabetic retinopathy.

PURPOSE: Diabetic retinopathy is characterized by retinal vascular impairment resulting in retinal hypoxia. The disease can be treated by retinal photocoagulation, but the mechanism of action of this treatment is unknown. Therefore, it is of interest to investigate whether the effects of retinal photocoagulation are related to changes in oxygen saturation. METHODS: Retinal oximetry and diameter measurements were performed on larger retinal arterioles and venules in 220 eyes from 149 patients with diabetic maculopathy (DM) and proliferative diabetic retinopathy (PDR) before, immediately after, and 3 months after photocoagulation treatment. RESULTS: Before treatment oxygen saturation was increased in retinal venules in DM patients to result in reduced arteriovenous (AV) saturation difference, and was increased in arterioles and venules in PDR patients to result in a normal AV saturation difference. Immediately after treatment the oxygen saturation in both groups was unchanged in retinal arterioles and increased in retinal venules resulting in a reduced AV saturation difference. Three months after treatment arterial and venous saturations were increased, but the AV saturation difference was not different from the pretreatment level. In both patient groups vascular diameters had decreased 3 months after treatment, which was significant for venules in the PDR group. CONCLUSIONS: The effects of retinal photocoagulation on diabetic retinopathy are not correlated with changes in oxygen saturation in larger retinal vessels.

The oxygen saturation in retinal vessels from diabetic patients depends on the severity and type of vision-threatening retinopathy.

PURPOSE: Diabetic retinopathy is characterized by morphological lesions in the retina secondary to disturbances in retinal blood flow which may influence the supply of oxygen to the retinal metabolism. Using retinal oximetry, it has been shown that the oxygen saturation is increased in retinal arterioles and venules from diabetic patients with retinopathy, but oxygenation before the development of retinopathy and possible differences in retinal oxygenation between diabetic maculopathy and proliferative diabetic retinopathy patients have not been evaluated. METHODS: One-hundred and fifty-six consecutive patients referred for specialist evaluation of diabetic retinopathy, and eighty normal control persons were subjected to retinal oximetry of the larger retinal arterioles and venules. The diabetic patients were allocated to one of four groups with severity of retinopathy ranging from no retinopathy to vision-threatening retinopathy, and the oxygen saturation in arterioles and venules was compared between these groups. RESULTS: Increasing severity of retinal changes from no retinopathy to diabetic maculopathy was accompanied with increasing oxygen saturation in retinal venules and decreasing oxygen extraction, whereas proliferative diabetic retinopathy showed increased oxygen saturation in both retinal arterioles and venules to result in a normal oxygen extraction. CONCLUSION: Prospective observational and interventional studies are needed to show whether changes in retinal oxygen saturation precede or follow the development of diabetic retinopathy. Additionally, studies of regional variations in haemodynamic parameters in patients with vision-threatening diabetic retinopathy might improve the understanding of the pathophysiology of diabetic retinopathy. This is a precondition for improving the prevention and treatment of the disease.

Intuitiveness, instruction time, and patient acceptance of a prefilled insulin delivery device and a reusable insulin delivery device in a randomized, open-label, crossover handling study in patients with type 2 diabetes.

BACKGROUND: Because the use of insulin therapy can place a substantial burden on patients with diabetes, insulin administration should be as simple as possible. OBJECTIVES: The primary aim of this trial was to compare the use of 2 insulin delivery devices-one prefilled (NovoMix 30 FlexPen [FP]; Novo Nordisk, Copenhagen, Denmark) and the other reusable (HumaPen Luxura [HL]; Eli Lilly and Company, Indianapolis, Indiana)-in patients with type 2 diabetes in terms of intuitiveness and training time. A secondary aim was to evaluate the ease of use and overall acceptance of the 2 devices. METHODS: This was a randomized, open-label, comparative, crossover handling study in adult patients with type 2 diabetes who had been treated with oral antidiabetic drugs for >or=2 years and had no previous experience with insulin injection devices. Patients were randomly allocated to the intuitiveness group (no instruction in the use of the devices provided) or the instruction group (instruction provided). The time taken to deliver an injection into a cushion was measured for each device in both groups. Patients answered questionnaires concerning the intuitiveness and ease of use of the 2 devices, their trust and confidence in the devices to deliver the insulin dose, and their overall pen preference. RESULTS: Sixty-one patients were enrolled in the study (70.5% male; mean [SD] age, 61.80 [7.60] years), 30 in the intuitiveness group and 31 in the instruction group. When all handling steps for the HL device were included, the mean (SD) injection time was significantly shorter for the FP device compared with the HL device in the intuitiveness group (1.21 [1.04] vs 1.74 [0.79] minutes, respectively; P = 0.035). The outcome was similar in the instruction group (0.71 [0.29] vs 1.09 [0.49] minutes; P < 0.001). When the time for cartridge insertion in the HL device was excluded, there was no significant difference in injection time for the respective devices in either group (intuitiveness group: 1.21 [1.04] and 1.07 [0.91] minutes; instruction group: 0.63 [0.35] and 0.71 [0.29] minutes). Twenty-two patients preferred the FP device in terms of ease of learning, compared with 8 patients preferring the HL device (P = 0.007). CONCLUSIONS: In this study, when all handling steps were included, the FP device was associated with significantly greater intuitiveness and a shorter injection time compared with the HL device. Further research is needed to determine whether these differences between devices are clinically meaningful.

Overnight versus 24 hours of continuous subcutaneous insulin infusion as supplement to oral antidiabetic drugs in type 2 diabetes.

BACKGROUND: Basal continuous subcutaneous insulin infusion (CSII) therapy at a fixed rate may effectively improve glycemic control in patients with type 2 diabetes when oral antidiabetic treatment fails. Regimens of simple constant subcutaneous delivery of insulin may provide theoretical advantages in type 2 diabetes. METHODS: Ten subjects with type 2 diabetes who obtained insufficient glycemic control on oral antidiabetic drugs were included. Following an initial control day, two periods of 3 days with CSII of a rapid-acting insulin analogue, 1.5 IU/h (dose obtained from a preceding study), for 8 hours overnight and for 24 hours, respectively, were carried out in random order. Profiles of serum insulin aspart, serum endogenous insulin, and plasma glucose were recorded. RESULTS: Compared to the control day, an 8-hour overnight insulin infusion during a 3-day period improved fasting plasma glucose (FPG) (mean differences +/- SEM; Delta59.0 +/- 10.1 mg/dl; p < 0.01) and 2-hour postprandial plasma glucose (PPPG) (Delta57.8 +/- 10.6 mg/dl; p < 0.01) after breakfast. Compared to an 8-hour overnight infusion, a 24-hour infusion further improved all three PPPG values after breakfast, lunch, and dinner (Delta28.8 +/- 8.1 mg/dl, Delta30.6 +/- 8.1 mg/dl, and Delta35.1 +/- 7.9 mg/dl; p < 0.01). During insulin infusion, only one hypoglycemic episode with PG <55.8 mg/dl and mild symptoms was recorded. CONCLUSION: Continuous subcutaneous insulin infusion with a rapid-acting insulin analogue at a fixed rate of 1.5 IU/h, either overnight or for 24 hours, improved glycemic control without safety concerns in patients with type 2 diabetes who had secondary failure to oral antidiabetic drugs. The effect on FPG was similar for both treatments, whereas the effect on PPPG was superior when insulin was infused during the entire 24 hours.

Regulation of insulin receptor substrate 1 pleckstrin homology domain by protein kinase C: role of serine 24 phosphorylation.

Phosphorylation of insulin receptor substrate (IRS) proteins on serine residues is an important posttranslational modification that is linked to insulin resistance. Several phosphoserine sites on IRS1 have been identified; the majority are located proximal to the phosphotryosine-binding domain or near key receptor tyrosine kinase substrate- and/or Src-homology 2 domain-binding sites. Here we report on the characterization of a serine phosphorylation site in the N-terminal pleckstrin homology (PH) domain of IRS1. Bioinformatic tools identify serine 24 (Ser24) as a putative substrate site for the protein kinase C (PKC) family of serine kinases. We demonstrate that this site is indeed a bona fide substrate for conventional PKC. In vivo, IRS-1 is also phosphorylated on Ser24 after phorbol 12-myristate 13-acetate treatment of cells, and isoform-selective inhibitor studies suggest the involvement of PKCalpha. By comparing the pharmacological characteristics of phorbol 12-myristate 13-acetate-stimulated Ser24 phosphorylation with phosphorylation at two other sites previously linked to PKC activity (Ser307 and Ser612), we show that PKCalpha is likely to be directly involved in Ser24 phosphorylation, but indirectly involved in Ser307 and Ser612 phosphorylation. Using Ser24Asp IRS-1 mutants to mimic the phosphorylated residue, we demonstrate that the phosphorylation status of Ser24 does play an important role in regulating phosphoinositide binding to, and the intracellular localization of, the IRS1-PH domain, which can ultimately impinge on insulin-stimulated glucose uptake. Hence we provide evidence that IRS1-PH domain function is important for normal insulin signaling and is regulated by serine phosphorylation in a manner that could contribute to insulin resistance.