Sustained low-grade inflammation in young participants with childhood onset type 1 diabetes: The Norwegian atherosclerosis and childhood diabetes (ACD) study.

BACKGROUND AND AIMS: Persons with type 1 diabetes (T1D) have increased mortality from cardiovascular disease. Early inflammation is important in the development of atherosclerosis. We aimed to evaluate the extent of inflammation and difference in mean over a five-year period in young persons with T1D compared to healthy controls. METHODS: The Norwegian Atherosclerosis and Childhood Diabetes (ACD) study is a prospective population-based cohort study on atherosclerosis development in childhood-onset T1D compared to healthy controls, with follow-ups every fifth year. The original study cohort consisted of 314 children with T1D on intensive insulin treatment and 120 healthy controls of similar age. Circulating levels of VCAM-1, TNA-α, P-selectin, E-selectin, CRP, IL-6, IL-18, MCP-1, MMP-9 and TIMP-1 were measured by ELISAs at baseline and at the five-year follow-up. RESULTS: The group with T1D had mean age 13.7 (SD = 2.8) years, disease duration 5.6 (SD = 3.4) years and HbA1c 68 (SD = 13.1) mmol/mol at baseline. Levels of almost all inflammatory markers were significantly increased in the group with T1D compared to controls, and significant mean-difference between the two groups over the five-year period was observed in four markers: IL-18, P-selectin, E-selectin and TIMP-1. CONCLUSIONS: The early low-grade inflammation present in young individuals with T1D five years after diagnosis is sustained at ten-year disease duration, with moderate changes for most markers of inflammation over time. The evolving inflammatory profile indicates an accelerated chain of events in the progression of early atheromatosis in T1D.

Retinal venular oxygen saturation is associated with non-proliferative diabetic retinopathy in young patients with type 1 diabetes.

PURPOSE: To determine the contribution of retinal vessel density (VD), central retinal vessel diameter and retinal oxygen (O2 ) saturation independently of other known risk factors in the development of non-proliferative diabetic retinopathy (NPDR). METHODS: Macular optical coherence tomography angiography (OCTA), central retinal artery/vein equivalent diameter (CRAE/CRVE) measurements and retinal oximetry were performed in a cross-sectional study of 166 eyes from 166 individuals with type 1 diabetes (T1D) aged 14-30 years. Multiple logistic regression analysis was used to investigate whether O2 saturation, retinal vessel diameters and vessel density in the deep capillary plexus (VD-DCP) were associated with NPDR, when adjusting for known risk factors. The individuals were allocated to one group without and one group with NPDR. RESULTS: Multiple logistic regression analysis showed that age (OR = 1.25, 95% CI: 1.04-1.49) and AV-difference in O2 saturation (OR = 0.85, 95% CI 0.77-0.93) were significantly associated with NPDR. CONCLUSION: Our findings suggest that age and lower AV-O2 saturation difference contribute to explaining the grade of NPDR independently of other well-known risk factors. Reduced delivery of O2 to the retinal tissue is associated with the development of NPDR in young patients with T1D and should be given appropriate weight in the risk stratification at early stages of the disease.

Associations between Macular OCT Angiography and Nonproliferative Diabetic Retinopathy in Young Patients with Type 1 Diabetes Mellitus.

METHODS: OCTA of both eyes was performed in a cross-sectional study of 14 to 30-year-old individuals with at least 10-year duration of T1D and controls recruited from the Norwegian Atherosclerosis and Childhood Diabetes (ACD) study. Vessel density (VD) and foveal avascular zone (FAZ) area in the superficial and deep capillary plexus (SCP and DCP), total retinal volume (TRV), and central macular thickness (CMT) were calculated using automated software. Univariate and multivariate ordered logistic regression (OLR) models were used accordingly. RESULTS: We included 168 control eyes and 315 T1D eyes. Lower VD in DCP (OR 0.65, 95% CI 0.51-0.83), longer diabetes duration (OR 1.51, 95% CI 1.22-1.87), and higher waist circumference (OR 1.08, 95% CI 1.02-1.14) were significantly associated with progression of NPDR. VD in SCP and DCP were significantly lower in T1D patients without diabetic retinopathy than in controls. CONCLUSIONS: Sparser VD in DCP is significantly associated with severity of NPDR, supporting that OCTA might detect the earliest signs of NPDR before it is visible by ophthalmoscopy.

Venular oxygen saturation is increased in young patients with type 1 diabetes and mild nonproliferative diabetic retinopathy.

PURPOSE: To clarify how early in the development of diabetic retinopathy (DR) can oxygen (O2 ) saturation changes be detected. METHODS: Retinal oximetry was performed in a cross-sectional study, involving 14- to 30-year-old individuals: 185 with type 1 diabetes (T1D) and 94 controls. The subjects were divided into four groups according to the grade of DR. One-way ANOVA and post hoc tests were used to test for differences in the mean O2 saturations between the groups. RESULTS: Fifty-eight (31 %) of the T1D patients had nonproliferative DR. There was no significant difference in O2 saturations between controls and T1D patients with no DR. Arteriolar and venular O2 saturations in T1D patients were significantly higher in moderate/severe DR than in no DR (p = 0.009 and p > 0.001), while venular O2 saturation was significantly higher in mild DR than in no DR (p = 0.013). CONCLUSION: Increase in venular O2 saturation could not be detected before mild retinopathy had developed, and the retinal O2 saturation increase was measurable on the venular side first. Our results suggest that the increase in O2 saturation is likely a consequence of DR.

pH-dependent interaction of psychotropic drug with glycerophospholipid monolayers studied by the Langmuir technique.

We have earlier investigated the interaction of the antipsychotic drugs chlorpromazine(CPZ) and olanzapine(OLP) with glycerophospholipid monolayers. These experiments were carried out at high and low temperatures and showed that OLP had a more pronounced effect on the packing of the phospholipid (PL) monolayers than CPZ. At pH 7.36, where OLP consists of one positive and one neutral species. In the present work we have studied the interaction of the drugs with monolayers of PLs by the Langmuir technique at pH 6.00 and 10.00 at 37°C. The PLs were palmitoylphosphatidyl-choline(DPPC), 1-stearoyl-2-arachinodonoylphoshatidylcholine(SAPC),dipalmitoylphosphatidyl-serine(DPPS) and 1-palmitoyl-2-oleoylphosphatidylserine(POPS). OLP has a pKa around 7.4, with one neutral and one positive species at pH 6.00 and pH 10.00, respectively. CPZ has pKa value around 9.4, and is positively charged at pH 6.00 and neutral at pH 10.00. Our studies revealed that the surface area of DPPC with CPZ in the subphase did not change at pH 6.00. In contrast, OLP increased the mean molecular area(MMA) of DPPC at pH 6.00, while CPZ caused distinct increase in MMA on the monolayer packing of all the other PLs, including monolayers of DPPC at pH 10.00. OLP, increased MMA of all PLs at both pHs. Further, OLP increased MMA of DPPC (pH 10.00), SAPC (pH 10.00), DPPS (pH 6.00) and POPS (pH 6.00) at 30mN/m, the expected MMA of biological membranes. CPZ had the more pronounced effect at lift-off and gave an effect of the monolayers with negatively charged head groups in accordance our earlier experiments. However, CPZ affected the packing of the SAPC monolayer both at pH 6.00 and 10.00, and DPPC at pH 10.00. Both these PLs have neutral choline head group. Our results suggest that both drugs intercalate in the PL monolayers, and that the intercalation might involve electrostatic interaction with the head groups or hydrophobic interaction with the acyl chains of the PLs, or both. Probably the drugs intercalate to different extents depending on charge of both the drugs and the PL head groups. Our investigation may suggest that the interaction of CPZ and OLP with membrane PLs could be linked to both the psychotropic and the side effects.