Incipient diabetic retinopathy is characterized by increased vascular permeability and progressive vascular occlusion. Pericyte loss precedes capillary occlusion in the diabetic retina, but its cause ...remains unclear. One concept proposes that pericyte loss is the result of toxic product accumulation and induction of destructive cellular signals generated within the pericyte. Alternatively, new experimental data indicate that pericyte dropout may result from regulations which induce pericyte elimination as an active process. Pericytes are critical for the development of a proper retinal network, and appear protective for endothelial cells under hyperglycemic conditions. The unifying hypothesis of hyperglycemia-induced microvascular damage centers around hyperglycemia-induced mitochondrial overproduction of reactive oxygen species. The pharmacological prevention of acellular capillaries without the rescue of pericyte loss in experimental diabetic retinopathy suggests that the endothelium is the primary therapeutic target.
Aims/hypothesis
The aim of this study was to analyse the risk profile for diabetic retinopathy under real-life conditions in a large cohort of patients with type 1 diabetes.
Methods
Patients (
n
= ...18,891) with childhood, adolescent or adult onset of type 1 diabetes from the prospective German Diabetes Documentation System survey were analysed. A total of 8,784 patients fulfilled the inclusion criterion, which was availability of retinopathy status. Retinopathy grading (any retinopathy, advanced retinopathy), treatment regimens and risk factors were prospectively recorded and tested as covariates by Kaplan–Meier analysis and logistic regression.
Results
Any retinopathy was present in 27.4% and advanced retinopathy (severe non-proliferative or proliferative diabetic retinopathy) in 8.0% of the cohort. After 40 years of diabetes, the cumulative proportion of patients with any retinopathy and advanced retinopathy was 84.1% and 50.2%, respectively. In multiple regression analysis, risk factors for any retinopathy were diabetes duration (OR 1.167 per year), HbA
1c
>7.0% (53 mmol/mol) (OR 2.225), smoking (OR 1.295) and male sex (OR 1.187) (
p
< 0.0001 for all). Young age at onset (5 vs 15 years at disease onset) was protective (0.410,
p
< 0.0001). No glycaemic threshold was detected for retinopathy protection. Risk factors for advanced retinopathy were duration (1.124 per year,
p
< 0.0001), male sex (1.323,
p
= 0.0020), HbA
1c
>7.0% (53 mmol/mol) (1.499,
p
< 0.0001), triacylglycerol >1.7 mmol/l (1.398,
p
= 0.0013) and blood pressure >140/90 mmHg (1.911,
p
< 0.0001).
Conclusions/interpretation
The prevalence of retinopathy remains significant in type 1 diabetes. Any improvement of metabolic control and non-smoking is protective, while hypertension affects progression to severe levels under real-life conditions. These data reinforce the validity of multifactorial concepts for morbidity protection in type 1 diabetes.
In humans, we reported an association of a certain allele of carnosinase gene with reduced carnosinase activity and absence of nephropathy in diabetic patients. CN1 degrades histidine dipeptides such ...as carnosine and anserine. Further, we and others showed that treatment with carnosine improves renal function and wound healing in diabetic mice and rats. We now investigated the effects of carnosine treatment alone and in combination with ACE inhibition, a clinically established nephroprotective drug in diabetic nephropathy.
Male Sprague–Dawley rats were injected i.v. with streptozotocin (STZ) to induce diabetes. After 4weeks, rats were unilaterally nephrectomized and randomized for 24weeks of treatment with carnosine, lisinopril or both.
Renal CN1 protein concentrations were increased under diabetic conditions which correlated with decreased anserine levels. Carnosine treatment normalized CN1 abundance and reduced glucosuria, blood concentrations of glycosylated hemoglobin (HbA1c), carboxyl-methyl lysine (CML), N-acetylglucosamine (GlcNac; all p<0.05 vs. non-treated STZ rats), reduced cataract formation (p<0.05) and urinary albumin excretion (p<0.05), preserved podocyte number (p<0.05) and normalized the increased renal tissue CN1 protein concentration. Treatment with lisinopril had no effect on HbA1C, glucosuria, cataract formation and CN1 concentration, but reduced albumin excretion rate more effectively than carnosine treatment (p<0.05). Treatment with both carnosine and lisinopril combined the effects of single treatment, albeit without additive effect on podocyte number or albuminuria.
Increased CN1 amount resulted in decreased anserine levels in the kidney. Both carnosine and lisinopril exert distinct beneficial effects in a standard model of diabetic nephropathy. Both drugs administered together combine the respective effects of single treatment, albeit without exerting additive nephroprotection.
•Carnosine treatment has renoprotective function in diabetic rats.•Renoprotection differs from the effect of the ACE inhibitor lisinopril.•Carnosinase activity correlates with anserine levels in the kidney.•Carnosine and lisinopril together combine the effect of single treatment.
Aims/hypothesis
Diabetic retinopathy is the result of increased oxidative and nitrosative stress induced by chronic hyperglycaemia, and affects the vasculature and the neuroglia. Erythropoietin is a ...neuroprotective and an endothelial survival factor. We assessed the effect of suberythropoietic epoetin delta doses on variables of oxidative stress in target tissues of diabetic complications and on pericyte loss in the diabetic retina.
Methods
We administered epoetin delta to streptozotocin-induced diabetic Wistar rats at doses of 384 IU/kg body weight once weekly or 128 IU/kg body weight three times a week. The treatment lasted for 3 months. Oxidative stress and formation of AGEs were assessed by immunoblotting, expression of
Ang-2
(also known as
Angpt2
) by RT-PCR, activation of protein kinase B (AKT) and heat shock protein (HSP)-27 levels by immunofluorescence, and incipient retinal vascular changes by quantitative morphometry of retinal digest preparations.
Results
Diabetes increased variables of oxidative stress and nitrosative stress (
N
ε
-carboxymethyl-lysine, nitrotyrosine and methylglyoxal-type AGEs) in retina, kidney and heart of diabetic rats. Epoetin delta reduced oxidative and nitrosative stress in all tissues, and AGEs in the retina. It also reduced increased retinal
Ang-2
expression and pericyte loss, and ameliorated p-AKT and HSP-27 levels.
Conclusions/interpretation
Epoetin delta has antioxidative properties in organs affected by diabetes and may prevent incipient microvascular damage in the diabetic retina.
Diabetic hyperglycaemia causes a variety of pathological changes in small
vessels, arteries and peripheral nerves. Vascular endothelial
cells are an important target of hyperglycaemic damage, but the ...mechanisms
underlying this damage are not fully understood. Three seemingly independent
biochemical pathways are involved in the pathogenesis: glucose-induced activation
of protein kinase C isoforms; increased formation of glucose-derived
advanced glycation end-products; and increased glucose flux
through the aldose reductase pathway. The relevance of each
of these pathways is supported by animal studies in which pathway-specific
inhibitors prevent various hyperglycaemia-induced abnormalities.
Hyperglycaemia increases the production of reactive oxygen species inside
cultured bovine aortic endothelial cells. Here we show that
this increase in reactive oxygen species is prevented by an inhibitor of electron
transport chain complex II, by an uncoupler of oxidative phosphorylation,
by uncoupling protein-1 and by manganese superoxide dismutase. Normalizing
levels of mitochondrial reactive oxygen species with each of these agents
prevents glucose-induced activation of protein kinase C, formation of advanced
glycation end-products, sorbitol accumulation and NFκB activation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The murine VEGF gene is alternatively transcribed to yield the VEGF(120), VEGF(164), and VEGF(188) isoforms, which differ in their potential to bind to heparan sulfate and neuropilin-1 and to ...stimulate endothelial growth. Here, their role in retinal vascular development was studied in mice selectively expressing single isoforms. VEGF(164/164) mice were normal, healthy, and had normal retinal angiogenesis. In contrast, VEGF(120/120) mice exhibited severe defects in vascular outgrowth and patterning, whereas VEGF(188/188) mice displayed normal venular outgrowth but impaired arterial development. It is noteworthy that neuropilin-1, a receptor for VEGF(164), was predominantly expressed in retinal arterioles. These findings reveal distinct roles of the various VEGF isoforms in vascular patterning and arterial development in the retina.
Pituitary carcinomas are rare and neurosurgically challenging lesions, as they commonly relapse after surgical removal. Their prognosis is dismal due to their limited response to radiotherapy and ...chemotherapy. In recent studies, temozolomide was administered in very few patients with partial effects. We report a patient with an ACTH-secreting pituitary carcinoma and widespread intracranial, spinal and systemic metastases despite repeated surgical treatment, bilateral adrenalectomy, medical treatment and radiotherapy. Additionally to chemotherapy with temozolomide, the patient received SOM230 as salvage therapy with an improvement of the patient's clinical status, and a reduction of ACTH levels. After 12 months of combination therapy a sustained tumor control was achieved and persisted upon monotherapy with SOM230 for more than 9 months thereafter. Thus, temozolomide in combination with SOM230 seems to be promising in patients with ACTH-secreting metastasized pituitary carcinoma.
The net effect of euglycemic treatment is grossly overestimated in diabetes mellitus and retinopathy, similar to what is observed in diabetic individuals, is found in the absence of chronic ...hyperglycemia. Explanations of this clinical paradox include the excess generation of reactive intermediates of metabolism. Excess formation or impaired detoxification of reactive intermediates can also result in multiple posttranslational modifications with a wide range of cellular dysfunctions. The multicellular neurovascular unit represents the response element of the retina which is crucial for the development of diabetic retinopathy. Current evidence suggests that increased reactive intermediates in the retina induce (micro-)glial activation, neurodegeneration and vasoregression similar to alterations found in the diabetic retina. Reactive metabolites can be lowered by metabolic signal blockade, by an activation of detoxification pathways and by quenching. The translation of these novel findings into treatment of patients with complications is important to reduce individual suffering and financial burden for societies.Quick Summary:Increased levels of reactive intermediates, independent of blood glucose levels, are linked to damage of the neurovascular unit of the diabetic retina.
Diabetic retinopathy shares important features with neurodegenerative retinal diseases, including loss of ganglion cells and retinal thinning. The impact on vasoregression and subsequent ...ischemia-driven changes such as macular edema and proliferative retinopathy are not established. Studies using adult neurodegenerative animal models such as the transgenic TGR(CMV-PKD2(1/703)HA) rat imply early activation of the innate immunity system and the complement system as well as microglia playing a role in the damage of the retinal neurovascular unit.
Hyperglycaemia-induced mitochondrial overproduction of reactive oxygen species (ROS) is central to the pathogenesis of endothelial damage in diabetes. R-(+)-alpha-lipoic acid has advantages over ...classic antioxidants, as it distributes to the mitochondria, is regenerated by glycolytic flux, and has a low redox potential.
To assess the effect of R-(+)-alpha-lipoic acid on experimental diabetic retinopathy, three groups of male Wistar rats were studied: non-diabetic controls, untreated diabetic controls, and diabetic rats treated with 60 mg/kg bodyweight R-(+)-alpha-lipoic acid i.p. for 30 weeks. Quantitative retinal morphometry included acellular occluded capillaries and pericyte numbers. The effects of R-(+)-alpha-lipoic acid on parameters of oxidative and nitrative stress, AGE and its receptor and nuclear factor kappa B (NFkappaB) were assessed by immunoblotting, and NFkappaB activation by electrophoretic mobility shift assay. Angiopoietin-2 and vascular endothelial growth factors were also determined by immunoblotting.
After 30 weeks of diabetes, the number of acellular capillaries was significantly elevated in diabetic rats (57.1+/-10.6 acellular capillary segments ac/mm(2) of retinal area) compared with non-diabetic (19.8+/-5.1 ac/mm(2); p<0.001). Treatment with 60 mg/kg R-(+)-alpha-lipoic acid reduced the numbers by 88% (p<0.001 vs diabetic). Pericyte loss was also significantly inhibited in diabetic rats treated with R-(+)-alpha-lipoic acid (non-diabetic: 1,940+/-137 pericytes/mm(2)capillary area; untreated diabetic: 1,294+/-94 pericytes/mm(2)capillary area vs treated diabetic: 1,656+/-134 pericytes/mm(2); p<0.01). R-(+)-alpha-lipoic acid treatment reduced oxidative stress, normalised NFkappaB activation and angiopoietin-2 expression, and reduced vascular endothelial growth factor in the diabetic retina by 43% (p<0.0001).
R-(+)-alpha-lipoic acid prevents microvascular damage through normalised pathways downstream of mitochondrial overproduction of ROS, and preserves pericyte coverage of retinal capillaries, which may provide additional endothelial protection.
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