Dicarbonyl Stress Mimics Diabetic Neurovascular Damage in the Retina.

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.

Protective Effects of Liraglutide and Linagliptin in C. elegans as a New Model for Glucose-Induced Neurodegeneration.

Liraglutide and linagliptin are novel drugs for the treatment of diabetes. Antioxidative and neuroprotective effects have been described for both compounds. However, it is not yet known, whether these mechanisms are also protective against diabetic retinal neurodegeneration. We assessed the antioxidative and neuroprotective capabilities of liraglutide and linagliptin as well as the signaling pathways involved, by using C. elegans as a model for glucose-induced neurodegeneration. C. elegans were cultivated under conditions, which mimic clinical hyperglycemia, and treated with 160 µmol/l liraglutide or 13 µmol/l linagliptin. Oxidative stress was reduced by 29 or 78% and methylglyoxal-derived advanced glycation endproducts (AGEs) by 33 or 22%, respectively. This resulted in an improved neuronal function by 42 or 60% and an extended mean lifespan by 9 or 11%, respectively. Antioxidative and AGE reducing effects of liraglutide and linagliptin were not dependent on v-akt murine thymoma viral oncogene homologue 1/forkhead box O1 (AKT1/FOXO). Neuroprotection by liraglutide was AKT1/FOXO dependent, yet AKT1/FOXO independent upon linagliptin treatment. Both liraglutide and linagliptin exert neuroprotective effects in an experimental model for glucose-induced neurodegeneration, however, the signaling pathways differ in the present study. Further pharmacological intervention with these pathways may help to delay the clinical onset of diabetic retinopathy by preserving neuronal integrity.

Understanding diabetic polyneuropathy and longevity: what can we learn from the nematode Caenorhabditis elegans?

Pathogenesis of late diabetic complications is influenced by a complex interplay of multiple exogenous and intrinsic factors. The well characterised nematode Caenorhabditis elegans is an ideal model to study causes of diabetic polyneuropathy because of its easily accessible nervous system. A repertoire of methods allows the assessment of both morphological and functional glucotoxic damages as well as reduction of lifespan, thereby helping to examine the influence of different pathways and mechanisms on neurodegeneration. Its insulin signalling system allows to directly visualize effects of insulin on high glucose induced neuronal damage, leading to a better understanding of diabetic polyneuropathy.

The -174G>C IL-6 gene promoter polymorphism and diabetic microvascular complications.

This study examined a possible association of the G>C polymorphism at nucleotide -174 in the promoter region of the interleukin-6 (IL-6) gene (rs1800795) with the prevalence of diabetic complications in 235 patients with type 1 and 498 patients with type 2 diabetes. Genotyping was performed using polymerase chain reaction (PCR) and subsequent cleavage by Nla III restriction endonuclease. Analyzing all diabetic patients together demonstrated that 301 patients (41.1%) carried the GG genotype, 114 (15.6%) the CC genotype, and 318 (43.3%) were heterozygous for the GC genotype. However, there was no correlation of any of the genotypes with the prevalence of diabetic nephropathy or diabetic neuropathy, but subjects with the CC genotype had a significantly higher prevalence of diabetic retinopathy compared to patients with the GC and GG genotype (p=0.016). This association was mainly lost when a logistic regression model was adjusted for diabetes duration (p=0.07). Consistently, a weak but not significant association of the polymorphism with diabetic retinopathy was observed when type 1 and type 2 diabetic patients were analyzed separately (patients with type 1 diabetes: p=0.12; patients with type 2 diabetes: p=0.09). Analogically, no association of the polymorphism was found for diabetic nephropathy or diabetic neuropathy in these groups. In conclusion these data suggest no major influence of the -174G>C variant in the promoter region of the IL-6 gene on the development of microvascular complications in patients with diabetes.

Rosiglitazone reduces angiotensin II and advanced glycation end product-dependent sustained nuclear factor-kappaB activation in cultured human proximal tubular epithelial cells.

Tubular damage is a major feature in the development of diabetic nephropathy. This study investigates the effects of the thiazolidindione rosiglitazone on angiotensin II and advanced glycation end product-induced tubular activation in human proximal tubular epithelial cells IN VITRO. Angiotensin II and advanced glycation end products, both induced a dose-dependent sustained activation of the redox-sensitive transcription factor, Nuclear Factor KAPPA B (NF-kappaB). Nuclear translocation of NF-kappaB was evident already after one hour and persistent for more than four days. Co-incubation of proximal tubular epithelial cells with rosiglitazone significantly reduced angiotensin II and advanced glycation end product-mediated generation of reactive oxygen species, angiotensin II-dependent advanced glycation end product formation, NF-kappaB activation, and NF-kappaB-dependent pro inflammatory gene expression. Most importantly, rosiglitazone effects on NFkappaB activation were maximal at later time points, indicating that rosiglitazone treatment confers long lasting renoprotective effects.

A M55V polymorphism in the SUMO4 gene is associated with a reduced prevalence of diabetic retinopathy in patients with Type 1 diabetes.

AIMS: We studied the association between a functionally relevant M55V polymorphism in the SUMO4 gene with microvascular diabetic complications in patients with type 1 diabetes. METHODS: 223 patients with type 1 diabetes were studied using polymerase chain reaction and subsequent cleavage by restriction endonucleases for the M55V SUMO4 gene variant. RESULTS: No effect of the polymorphism on diabetic neuropathy or diabetic nephropathy was found, but heterozygous or homozygous patients for the M55V polymorphism in the SUMO4 gene had a markedly reduced prevalence of diabetic retinopathy (odds ratio 0.37, 95%-confidence interval (CI) [0.32;0.43]; p=0.004). Furthermore, a multiple logistic regression model showed an age and diabetes duration independent effect of the M55V polymorphisms on the prevalence of diabetic retinopathy (p=0.03), but not of diabetic neuropathy or nephropathy. CONCLUSIONS: Our data indicate that the M55V polymorphism in the SUMO4 gene is associated with a reduced risk of diabetic retinopathy in type 1 diabetes. Thus, the results of our study suggest that posttranslational modification of proteins via SUMO4 could contribute to the development of certain diabetic complications.

No association of the 94T/G polymorphism in the adiponectin gene with diabetic complications.

AIM: This study examined a possible association of the T/G polymorphism at nucleotide 94 in the adiponectin gene with the prevalence of diabetic complications. METHODS: The study was performed in 696 patients with type 1 diabetes and type 2 diabetes. Genotyping was performed by means of polymerase chain reaction and subsequent cleavage by using SmaI restriction endonuclease. RESULTS: The 94G/G genotype was significantly more prevalent in patients with type 2 diabetes (2.2%) than in type 1 diabetics (0.0%) (p = 0.02), whereas no differences were found for frequencies of the 94T/T and the 94G/T genotypes, respectively. In patients with type 1 diabetes, 45 of 239 patients were heterozygous for the 94T/G polymorphism (carrier rate (CR): 18.8%; allele frequency (AF): 0.094). In type 2 diabetics, 71 of 457 patients were heterozygous and 10 patients were homozygous for the 94G/G genotype (CR: 17.7%; AF: 0.10). No association with diabetic nephropathy, diabetic neuropathy or diabetic retinopathy was found for either genotype in patients with type 1 and type 2 diabetes. CONCLUSIONS: The 94T/G polymorphism in the adiponectin gene is not associated with diabetic complications. The significance of a higher prevalence of the G allele in type 2, compared to type 1 diabetes remains to be clarified.