Andreea Ciudin

Neurodegeneration: An early event of diabetic retinopathy

Diabetic retinopathy (DR) has been classically considered to be a microcirculatory disease of the retina caused by the deleterious metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyperglycemia. However, retinal neurodegeneration is already present before any microcirculatory abnormalities can be detected in ophthalmoscopic examination. In other words, retinal neurodegeneration is an early event in the pathogenesis of DR which predates and participates in the microcirculatory abnormalities that occur in DR. Therefore, the study of the mechanisms that lead to neurodegeneration will be essential to identify new therapeutic targets in the early stages of DR. Elevated levels of glutamate and the overexpression of the renin- angiotensin-system play an essential role in the neurodegenerative process that occurs in diabetic retina. Among neuroprotective factors, pigment epithelial derived factor, somatostatin and erythropoietin seem to be the most relevant and these will be considered in this review. Nevertheless, it should be noted that the balance between neurotoxic and neuroprotective factors rather than levels of neurotoxic factors alone will determine the presence or absence of retinal neurodegeneration in the diabetic eye. New strategies, based on either the delivery of neuroprotective agents or the blockade of neurotoxic factors, are currently being tested in experimental models and in clinical pilot studies. Whether these novel therapies will eventually supplement or prevent the need for laser photocoagulation or vitrectomy awaits the results of additional clinical research.

Non-invasive methods of glucose measurement: current status and future perspectives.

Diabetes mellitus (DM) is a very common disease which, if a good glycemic control is not achieved, can lead to serious chronic complications such as cardiovascular disease, retinopathy, nephropathy and neuropathy. Selfmonitoring of blood glucose is a fundamental tool for the proper adjustment of the treatment of diabetes and, at present, it is based mainly on capillary blood obtained by finger-prick (the classical glucometers). Since this method is painful and the strips are expensive, investigators have been attracted by the idea of using a non-invasive device for determining blood glucose which would permit more frequent testing and a tighter control of diabetes. The non-invasive measurement of blood glucose is based on the ability of the glucose molecule to interact with various chemical or physical methods. Nevetheless, in spite of some encouraging results and the efforts made over the past 30-40 years, there is no device available at present for use in clinical practice. A possible explanation might be the combination between the specific features of each method and the specific characteristics of diabetic patients, which make them respond differently to physical and chemical methods when compared to their healthy counterparts. In this paper we will give an overview of the noninvasive devices tested so far and their implications for the clinical management of the diabetic patient.

Cognitive impairment and dementia: a new emerging complication of type 2 diabetes-The diabetologist's perspective.

Type 2 diabetes mellitus (T2D) and Alzheimer’s disease (AD) are two of the most common diseases of aging around the world. Given the frequency with which T2D and AD occur, the notion that people with T2D may be at increased risk for AD has large societal consequences, and understanding the mechanistic links between these diseases is imperative for the development of effective AD prevention and treatment strategies. Apart from being an accelerator of AD, T2D is associated with a progressive cognitive decline. Impaired insulin signaling, inflammation, the accumulation of advanced glycation end-products and oxidative stress all play an essential role in the pathogenesis of both AD and diabetic complications. Therefore, it is reasonable to postulate that these pathways are involved in the increased risk of dementia that occurs in the T2D population. The early diagnosis of cognitive impairment and the identification of the subset of patients at a higher risk of developing AD is a challenge for healthcare providers, and meeting it will permit us to implement a personalized medicine, which is an essential issue in diabetes care with significant therapeutic implications. The main gaps that should be filled to achieve this objective are examined.

Update on cardiovascular safety of PPARgamma agonists and relevance to medicinal chemistry and clinical pharmacology.

Peroxisome proliferator-activator receptors (PPARs) are now known as members of the nuclear hormonereceptor superfamily of ligand-activated transcription factors that regulate gene expression in response to nutritional and physiological stimuli. PPARγ plays a crucial role in glucose homeostasis and it is involved in the regulation of lipid metabolism and adipocyte differentiation and function. From all the PAARγ ligands, the thiazolidindiones (TZDs) are of most clinical importance. Rosiglitazone and pioglitazone have been largely used so far in the clinical practice. They provide similar effects on glycemic control, as well as a range of similar adverse effects, such as weight gain, fluid retention, and increased risk of hearth failure, which seem to be PPARγ mediated. Interestingly, they differ on their effect on lipid and cardiovascular safety profile, indicating a PPARγ-independent mechanism. Indeed, rosiglitazone was recently withdrawn in Europe and its use has been restricted in USA as a consequence of increased risk of cardiovascular events in type 2 diabetic patients. This review is focused on the cardiovascular effects of rosiglitazone and pioglitazone as representative members of PPARγ ligands, because they were widely evaluated in many clinical trials and experimental studies and data obtained from these studies are relevant from medicinal chemistry and clinical pharmacology point of view. Finally, an overview on the development of selective PPARγ modulators and/or dual PPARα/γ agonists will be given. These new approaches might provide anti-hyperglycemic efficacy without the associated undesirable side-effects. However, further experimental and clinical studies evaluating the theoretical benefit and safety of this therapeutic strategy are needed.

Iron overload in diabetic retinopathy: a cause or a consequence of impaired mechanisms?

Iron is an essential ion for life, playing a central role in many metabolic processes. The most important property of free iron is its capacity to be reversibly oxidized and reduced, but at same time this make it highly pro-oxidant molecule. In this regard, iron is able to generate powerful reactive oxygen species (ROS). For this reason, careful control on iron availability is central to the maintenance of normal cell function in the retina. In the diabetic eye there is an impairment of iron homeostasis, thus leading to iron overload. The mechanisms involved in this process include: (1) Destruction of heme molecules induced by hyperglycemia (2) Intraretinal and vitreal hemorrhages (3) Overexpression of the renin-angiotensin system. The main consequences of iron overload are the following: (1) Retinal neurodegeneration due to the increase of oxidative stress (2) Increase of AGE-RAGE binding (3) Defective phagocytosis of retinal pigment epithelium, which generates the accumulation of autoantigens and the synthesis of proinflammatory cytokines. Further studies addressed to explore not only the role of iron in the pathogenesis of diabetic retinopathy, but also to design novel therapeutic strategies based on the regulation of iron homeostasis are needed.

Measurement of waist circumference for retrospective studies – Prospective validation of use of CT images to assess abdominal circumference ☆

INTRODUCTION To validate the use of supine position and CT images for assessing abdominal circumference (AC). METHOD A prospective study in consecutive patients undergoing scheduled abdominal CT at our center between 17 and 25 September 2012. AC was measured four times: Measurements 1 and 2 were sequentially done by the same trained nurse before abdominal CT just above the iliac crest, while measurements 3 and 4 were done on the last abdominal CT slice not showing the iliac bone. Students t tests and Q-Q and Bland-Altman plots were used for statistical analysis. RESULTS A total of 102 patients were recruited. Mean age, 60 (35-78) years. Mean BMI, 25 (18-39) kg/m(2). Mean AC, 93.2 (73-135) cm. No significant differences were found between the four ACs measured (Students t test, P=0.83). Q-Q and Bland-Altman plots showed good overlapping for the low and central values (73-110 cm) with a greater scatter for extremely high values. For the ellipse estimation, R(2) was 0.987 with a mean error of 0.4 cm and a stretch dispersion between 1.1 and -0.3 cm. CONCLUSION Supine (either measured or estimated on CT images by free hand elliptical ROI or ellipse formula) and standing measurements appear to be equivalent for abdominal circumferences <110 cm.

Successful treatment for the Dunnigan-type familial partial lipodystrophy with Roux-en-Y gastric bypass

painless thyroiditis from those with Graves’ disease or toxic nodular goitre. Patients with painless thyroiditis are usually asymptomatic and require no therapy but follow up is important as more than a half may subsequently develop hypothyroidism. LiAT patients with Graves’ disease or toxic nodular goitre are best initially treated with carbimazole, and later many may require ablative therapy.

Molecular Implications of the PPARs in the Diabetic Eye.

Diabetic retinopathy (DR) remains as the leading cause of blindness among working age individuals in developed countries. Current treatments for DR (laser photocoagulation, intravitreal corticosteroids, intravitreal anti-VEGF agents, and vitreoretinal surgery) are applicable only at advanced stages of the disease and are associated with significant adverse effects. Therefore, new pharmacological treatments for the early stages of the disease are needed. Emerging evidence indicates that peroxisome proliferator-activator receptors (PPARs) agonists (in particular PPARα) are useful for the treatment of DR. However, the underlying molecular mechanisms are far from being elucidated. This paper mainly focuses on PPARs expression in the diabetic eye, its molecular implications, and the effect of PPAR agonists as a new approach for the treatment of DR. The availability of this new strategy will not only be beneficial in treating DR but may also result in a shift towards treating earlier stages of diabetic retinopathy, thus easing the burden of this devastating disease (Cheung et al. (2010)).

Variables Involved in the Discordance between HbA1c and Fructosamine: The Glycation Gap Revisited

Aims Glycation gap (GG) is defined as the difference between the measured level of HbA1c and the level that would be predicted from its regression on the fructosamine level. The aims of the study were: 1) To determine the reproducibility and consistency of GC; 2) To discover factors related to GG value. Given that metformin might increase glucose transport through the erythrocyte membrane, this treatment was also considered in the analyses of the results. Methods GG was calculated in two blood samples separated 30.6 (SD 7.3) weeks, obtained in 508 type 2 diabetic patients. The following variables were considered: HbA1c, fructosamine, glucose, creatinine, hematological parameters and treatment with metformin. Multivariate and logistic regression analyses were performed to explore the variables independently related to CG. Results GG was reproducible and consistent over time. Creatinine, mean corpuscular hemoglobin concentration (MCHC), and glycemia (inverse relationship); and HbA1c and treatment with metformin (direct relationship) were independently related to GG. Patients treated with metformin showed higher HbA1c values, despite similar fructosamine concentrations, than patients not treated with the drug. Conclusions GG is independently related to serum levels of creatinine, MCHC and treatment with metformin. The spurious effect of metformin on Hb glycation could have serious clinical implications and should be considered when interpreting the results of clinical trials.

Type 2 diabetes is an independent risk factor for dementia conversion in patients with mild cognitive impairment

AIMS To explore whether type 2 diabetes (T2D) is a risk factor for dementia conversion in patients with mild cognitive impairment (MCI). METHODS A longitudinal nested case-control study in which 101 T2D patients and 101 non-diabetic patients with MCI matched by age and gender were included. RESULTS The dementia conversion rate was 57.4% in T2D patients vs. 42.6% in non-diabetic subjects (p=0.02). T2D and APOE ε4 allele were independent risk factors for developing dementia. CONCLUSION T2D is an independent risk factor for dementia conversion in MCI patients. This finding has significant clinical implications.