Diabetic retinopathy in type 1 diabetes-a contemporary analysis of 8,784 patients

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 7.0% (53 mmol/mol) (1.499, p 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

High-glucose toxicity is mediated by AICAR-transformylase/ IMP cyclohydrolase and mitigated by AMP-activated protein kinase in Caenorhabditis elegans.

The enzyme AICAR-transformylase/IMP cyclohydrolase (ATIC) catalyzes the last two steps of purine de novo synthesis. It metabolizes 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), which is an AMP analogue, leading to activation of AMP-activated kinase (AMPK). We investigated whether the AICAR-ATIC pathway plays a role in the high glucose (HG)-mediated DNA damage response and AICAR-mediated AMPK activation, explaining the detrimental effects of glucose on neuronal damage and shortening of the lifespan. HG up-regulated the expression and activity of the Caenorhabditis elegans homologue of ATIC, C55F2.1 (atic-1), and increased the levels of reactive oxygen species and methylglyoxal-derived advanced glycation end products. Overexpression of atic-1 decreased the lifespan and head motility and increased neuronal damage under both standard and HG conditions. Inhibition of atic-1 expression, by RNAi, under HG was associated with increased lifespan and head motility and reduced neuronal damage, reactive oxygen species, and methylglyoxal-derived advanced glycation end product accumulation. This effect was independent of an effect on DNA damage or antioxidant defense pathways, such as superoxide dismutase (sod-3) or glyoxalase-1 (glod-4), but was dependent on AMPK and accumulation of AICAR. Through AMPK, AICAR treatment also reduced the negative effects of HG. The mitochondrial inhibitor rotenone abolished the AICAR/AMPK-induced amelioration of HG effects, pointing to mitochondria as a prime target of the glucotoxic effects in C. elegans. We conclude that atic-1 is involved in glucotoxic effects under HG conditions, either by blocked atic-1 expression or via AICAR and AMPK induction

The angiotensin II type 2 receptors protect renal tubule mitochondria in early stages of diabetes mellitus

Diabetic nephropathy correlates more closely to defective mitochondria and increased oxidative stress in the kidney than to hyperglycemia. A key driving factor of diabetic nephropathy is angiotensin II acting via the G-protein-coupled cell membrane type 1 receptor. The present study aimed to investigate the role of the angiotensin II type 2 receptor (AT2R) at the early stages of diabetic nephropathy. Using receptor binding studies and immunohistochemistry we found that the mitochondria in renal tubules contain high-affinity AT2Rs. Increased renal mitochondrial AT2R density by transgenic overexpression was associated with reduced superoxide production of isolated mitochondria from non-diabetic rats. Streptozotocin-induced diabetes (28 days) caused a drop in the ATP/oxygen ratio and an increase in the superoxide production of isolated renal mitochondria from wild-type diabetic rats. This correlated with changes in the renal expression profile and increased tubular epithelial cell proliferation. AT2R overexpression in tubular epithelial cells inhibited all diabetes-induced renal changes including a drop in mitochondrial bioenergetics efficiency, a rise in mitochondrial superoxide production, metabolic reprogramming, and increased proliferation. Thus, AT2Rs translocate to mitochondria and can contribute to reno-protective effects at early stages of diabetes. Hence, targeted AT2R overexpression in renal cells may open new avenues to develop novel types of drugs preventing diabetic nephropathy

Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair.

The integrity of genome is a prerequisite for healthy life. Indeed, defects in DNA repair have been associated with several human diseases, including tissue-fibrosis, neurodegeneration and cancer. Despite decades of extensive research, the spatio-mechanical processes of double-strand break (DSB)repair, especially the auxiliary factor(s) that can stimulate accurate and timely repair, have remained elusive. Here, we report an ATM-kinase dependent, unforeseen function of the nuclear isoform of the Receptor for Advanced Glycation End-products (nRAGE) in DSB-repair. RAGE is phosphorylated at Serine(376) and Serine(389) by the ATM kinase and is recruited to the site of DNA-DSBs via an early DNA damage response. nRAGE preferentially colocalized with the MRE11 nuclease subunit of the MRN complex and orchestrates its nucleolytic activity to the ATR kinase signaling. This promotes efficient RPA2(S4-S8) and CHK1(S345) phosphorylation and thereby prevents cellular senescence, IPF and carcinoma formation. Accordingly, loss of RAGE causatively linked to perpetual DSBs signaling, cellular senescence and fibrosis. Importantly, in a mouse model of idiopathic pulmonary fibrosis (RAGE(-/-)), reconstitution of RAGE efficiently restored DSB-repair and reversed pathological anomalies. Collectively, this study identifies nRAGE as a master regulator of DSB-repair, the absence of which orchestrates persistent DSB signaling to senescence, tissue-fibrosis and oncogenesis

CaM kinase II-δ is required for diabetic hyperglycemia and retinopathy but not nephropathy.

Type 2 diabetes has become a pandemic and leads to late diabetic complications of organs including kidney and eye. Lowering hyperglycemia is the typical therapeutic goal in clinical medicine. However, hyperglycemia may only be a symptom of diabetes but not the sole cause of late diabetic complications, Instead, other diabetes-related alterations could be causative. Here, we studied the role of CaM Kinase II δ (CaMKIIδ) that is known to be activated through diabetic metabolism. CaMKIIδ is expressed ubiquitously and might therefore affect several different organ systems. We crossed diabetic leptin receptor mutant mice to mice lacking CaMKIIδ globally. Remarkably, CaMKIIδ-deficient diabetic mice did not develop hyperglycemia. As potential underlying mechanisms, we provide evidence for improved insulin sensing with increased glucose transport into skeletal muscle but also reduced hepatic glucose production. Despite normoglycemia, CaMKIIδ-deficient diabetic mice developed the full picture of diabetic nephropathy but diabetic retinopathy was prevented. We also unmasked a retina-specific gene expression signature that might contribute to CaMKII-dependent retinal diabetic complications. These data challenge the clinical concept of normalizing hyperglycemia in diabetes as a causative treatment strategy for late diabetic complications and call for a more detailed analysis of intracellular metabolic signals in different diabetic organs

A hepatic GAbp-AMPK axis links inflammatory signaling to systemic vascular damage.

Increased pro-inflammatory signaling is a hallmark of&nbsp;metabolic dysfunction in obesity and diabetes. Although both inflammatory and energy substrate handling processes represent critical layers of metabolic control, their molecular integration sites remain largely unknown. Here, we identify the heterodimerization interface between the &alpha; and &beta; subunits of transcription factor GA-binding protein (GAbp) as a negative target of tumor necrosis factor alpha (TNF-&alpha;) signaling. TNF-&alpha; prevented GAbp&alpha; and &beta; complex formation via reactive oxygen species (ROS), leading to the non-energy-dependent transcriptional inactivation of AMP-activated kinase (AMPK) &beta;1, which was identified as a direct hepatic GAbp target. Impairment of AMPK&beta;1, in turn, elevated downstream cellular cholesterol biosynthesis, and hepatocyte-specific ablation of GAbp&alpha; induced systemic hypercholesterolemia and early macro-vascular lesion formation in mice. As GAbp&alpha; and AMPK&beta;1 levels were also found to correlate in obese human patients, the ROS-GAbp-AMPK pathway may represent a key component of a hepato-vascular axis in diabetic long-term complications

Wytyczne ESC dotyczace cukrzycy, stanu przedcukrzycowego i chorob ukladu sercowo-naczyniowego opracowane we wspolpracy z EASD.

[No abstract available