Decreased endostatin in db/db retinas is associated with optic disc intravitreal vascularization.

Endostatin, a naturally cleaved fragment of type XVIII collagen with antiangiogenic activity, has been involved in the regulation of neovascularization during diabetic retinopathy. Here, the intracellular distribution of endostatin in healthy mouse and human neuroretinas has been analyzed. In addition, to study the effect of experimental hyperglycemia on retinal endostatin, the db/db mouse model has been used. Endostatin protein expression in mouse and human retinas was studied by immunofluorescence and Western blot, and compared with db/db mice. Eye fundus angiography, histology, and immunofluorescence were used to visualize mouse retinal and intravitreal vessels. For the first time, our results revealed the presence of endostatin in neurons of mouse and human retinas. Endostatin was mainly expressed in bipolar cells and photoreceptors, in contrast to the optic disc, where endostatin expression was undetectable. Diabetic mice showed a reduction of endostatin in their retinas associated with the appearance of intravitreal vessels at the optic disc in 50% of db/db mice. Intravitreal vessels showed GFAP positive neuroglia sheath, basement membrane thickening by collagen IV deposition, and presence of MMP-2 and MMP-9 in the vascular wall. All together, these results point that decreased retinal endostatin during experimental diabetes is associated with optic disc intravitreal vascularization. Based on their phenotype, these intravitreal vessels could be neovessels. However, it cannot be ruled out the possibility that they may also represent persistent hyaloid vessels.

TIM2 modulates retinal iron levels and is involved in blood-retinal barrier breakdown.

Careful control of iron availability in the retina is central to maintenance of iron homeostasis, as its imbalance is associated with oxidative stress and the progression of several retinopathies. Ferritin, known for its role in iron storage and detoxification, has also been proposed as an iron-transporter protein, through its binding to Scara5 and TIM2 membrane receptors. In this study, the presence and iron-related functions of TIM2 in the mouse retina were investigated. Our results revealed for the first time the presence of TIM2 receptors in the mouse retina, mainly in Müller cells. Experimental TIM2 downregulation in the mouse retina promoted, probably due to a compensatory mechanism, Scara5 overexpression that increased retinal ferritin uptake and induced iron overload. Consecutive reactive oxygen species (ROS) overproduction and vascular endothelial growth factor (VEGF) overexpression led to impaired paracellular and transcellular endothelial transport characterized by tight junction degradation and increased caveolae number. In consequence, blood-retinal barrier (BRB) breakdown and retinal edema were observed. Altogether, these results point to TIM2 as a new modulator of retinal iron homeostasis and as a potential target to counteract retinopathy.

Ferritin But Not Iron Increases in Retina Upon Systemic Iron Overload in Diabetic and Iron-Dextran Injected Mice.

Purpose: Iron overload causes oxidative damage in the retina, and it has been involved in the pathogeny of diabetic retinopathy, which is one of the leading causes of blindness in the adult population worldwide. However, how systemic iron enters the retina during diabetes and the role of blood retinal barrier (BRB) in this process remains unclear. Methods: The db/db mouse, a well-known model of type 2 diabetes, and a model of systemic iron overload induced by iron dextran intraperitoneal injection, were used. Perls staining and mass spectrophotometry were used to study iron content. Western blot and immunohistochemistry of iron handling proteins were performed to study systemic and retinal iron metabolism. BRB function was assessed by analyzing vascular leakage in fundus angiographies, whole retinas, and retinal sections and by studying the status of tight junctions using transmission electron microscopy and Western blot analysis. Results: Twenty-week-old db/db mice with systemic iron overload presented ferritin overexpression without iron increase in the retina and did not show any sign of BRB breakdown. These findings were also observed in iron dextran-injected mice. In those animals, after BRB breakdown induced by cryopexy, iron entered massively in the retina. Conclusions: Our results suggested that BRB protects the retina from excessive iron entry in early stages of diabetic retinopathy. Furthermore, ferritin overexpression before iron increase may prepare the retina for a potential BRB breakdown and iron entry from the systemic circulation.

Effects of weight stigma on BMI and inflammatory markers among people living with obesity.

OBJECTIVE: Weight stigma (WS) and prejudice are one of the most prevalent ways of discrimination among adults, comparable with rates of racial discrimination. Exposure to WS among patients with obesity (PWO) may make the adoption of healthy dietary patterns and regular physical activity even more challenging and, therefore, the achievement of weight loss. Additionally, WS could also induce physiological responses such as increased levels of inflammatory markers, due to stress exposure. METHOD: Subjects attending two obesity clinics were evaluated at baseline and after a minimum follow-up of six months. The weight Bias Internalization Scale (WBIS) and the Stigmatizing Situations Inventory (SSI) were administered to evaluate WS. Also, anthropometric and inflammatory markers, including cortisol, ferritin and C-reactive protein (CRP), were recorded at baseline. RESULTS: 79 PWO (87.3%♀, 45.5 ± 1.3 years, 35.9 ± 6.3 kg/m2) were included. At baseline, 72.2% started liraglutide as anti-obesity drug. Baseline body mass index (BMI) correlated positively with both WBIS (r = 0.23; p = 0.03) and SSI (r = 0.25; p = 0.02) scores. Mean percentual weight loss after a mean follow-up of six months was -7.28%. However, there was a negative, but not statistically significant, correlation between weight loss and both WBIS (r=-0.14; p = 0.2) and SSI (r=-0.19; p = 0.08). Regarding inflammatory markers, plasma cortisol levels at baseline correlated positively with WBIS (p = 0.005) and SSI (p = 0.02). CRP at baseline also presented a positive correlation with SSI (p = 0.03). No significant correlations were found for stigma tests and ferritin levels. DISCUSSION: As weight increases among PWO, so does stigma. Despite we did not find a significant negative association between the presence of WS and weight loss outcomes, there was an increase in inflammatory markers among PWO who experienced higher levels of WS.

Short term effects of semaglutide on emotional eating and other abnormal eating patterns among subjects living with obesity.

OBJECTIVE: Emotional eating (EE) and other abnormal eating patterns are highly prevalent among people living with obesity (PWO). In this sense, semaglutide, by acting on areas of the brain involved in the reward system and emotion regulation, could have the potential to ameliorate these eating patterns. METHOD: 69 PWO attending an obesity clinic were evaluated baseline and after 3 months since the beginning of semaglutide. To rule out abnormal EE, the Emotional Eating Questionnaire was administered, and a structured interview was conducted. RESULTS: 69 PWO (82.6%♀, 43.7 ± 1years, and 34.3 ± 6 kg/m2) were included. After 3 months of semaglutide, there was a significant reduction in weight (96.1 ± 20.9 vs 91.3 ± 19.7 kg; p < 0.001) and BMI (34.3 ± 6 vs 32.4 ± 5.6 kg/m2; p < 0.0001). The proportion of patients with EE (72.5% vs 11.5%; p < 0.001), external eating (27.5% vs 10.1%; p < 0.001) cravings (49.3% vs 21.7%; p < 0.001) and savory cravings (53.6% vs 14.5%; p < 0.001) was significantly reduced after 3 months of semaglutide. Also, the proportion of PWO with regular exercise was increased (15.9% vs 39.1%; p < 0.001). However, Logistic regression analysis showed that only sweet cravings at baseline were the only factor associated, although not significant, with a poorer weight loss (p = 0.05). DISCUSSION: Semaglutide is an effective weight-loss treatment in PWO at short term. Moreover, semaglutide was highly effective in ameliorating EE and other abnormal eating patterns that exert a negative influence on weight.

GLP1 analogues among patients with overweight or obesity during lockdown. / Análogos de GLP1 en los pacientes con sobrepeso u obesidad durante el confinamiento.

BACKGROUND AND OBJECTIVES: One of the potential negative effects of a lockdown are changes in dietary and lifestyle patterns, which can lead to weight gain. Our objective was to assess the changes on dietary habits and eating patterns in a lockdown situation and their impact on weight. We aimed to determine whether the treatment with GLP1 analogues (aGLP1) could impact on these parameters. MATERIAL AND METHODS: 100 overweight/obese patients were consecutively recruited for a review at the end of the lockdown. A structured interview was designed to see changes in dietary habits, routines and exercise. RESULTS: 52% patients gained weight during lockdown. The percentage of subjects with an active history of depression or anxiety was higher among the group of patients who gained weight. The percentage of patients who worsened their hyperphagia was higher in those who gained weight (71.2% vs. 10.6%; P<0.0001); similar results were observed with binge eating (92% vs. 10.6%; p<0.0001) and cravings, both sweet and salty (69.2% vs. 21.3% and 69.2% vs. 14.9%; p<0.0001 and p<0.0001 respectively). Of the 48 patients who did not gain weight, 30 were under aGLP1 treatment (61.7%). The worsening of abnormal eating patterns was lower among patients treated with aGLP-1. CONCLUSIONS: A lockdown is a vulnerable period to gain weight, especially in those patients with a psychopathological history. aGLP1 manage to control emotional eating, making them a valuable therapeutic option.

Novel Use of PLGA Microspheres to Create an Animal Model of Glaucoma with Progressive Neuroretinal Degeneration.

Progressive degeneration of neuroretinal tissue with maintained elevated intraocular pressure (IOP) to simulate chronic glaucoma was produced by intracameral injections of poly (lactic-co-glycolic) acid (PLGA) microspheres (Ms) in rat eyes. The right eye of 39 rats received different sizes of PLGA-Ms (2 µL suspension; 10% w/v): 14 with 38-20 µm Ms (Ms38/20 model) and 25 with 20-10 µm particles (Ms20/10 model). This novel glaucoma animal model was compared to the episcleral vein sclerosis (EPI) model (25 eyes). Injections were performed at baseline, two, four and six weeks. Clinical signs, IOP, retina and optic nerve thicknesses (using in vivo optical coherence tomography; OCT), and histological studies were performed. An IOP increment was observed in all three groups, however, the values obtained from the PLGA-Ms injection resulted lower with a better preservation of the ocular surface. In fact, the injection of Ms20/10 created a gentler, more progressive, and more sustained increase in IOP. This IOP alteration was correlated with a significant decrease in most OCT parameters and in histological ganglion-cell count for the three conditions throughout the eight-week follow-up. In all cases, progressive degeneration of the retina, retinal ganglion cells and optic nerve, simulating chronic glaucoma, was detected by OCT and corroborated by histological study. Results showed an alternative glaucoma model to the well-known episcleral vein model, which was simpler to perform, more reproducible and easier to monitor in vivo.

Long-Term Prevalence of Food Addiction Among Bariatric Surgery Patients: Influence on Metabolic and Psychological Outcomes.

Background: We wanted to assess the prevalence of individuals with food addiction (FA) among bariatric surgery (BS) patients at long term and to determine if there was any relationship between FA and both clinical and psychological outcomes at the time of the evaluation. Methods: Participants were evaluated for the presence of FA with the Yale Food Addiction Scale 2.0. Results: Of 134 subjects, 32 (23.9%) included met criteria for FA. The frequency of patients with depression at the time of the evaluation was greater among subjects with FA (34.4% vs. 11.8%; P = 0.006). The score obtained with the Beck Depression Inventory at the time of the evaluation was greater among subjects with FA (14.8 ± 11.5 vs. 6 ± 6.5; P < 0.0001). The frequency of subjects with FA who had criteria for binge eating disorder at the time of the evaluation was significantly greater (56.3% vs. 20.5%; P < 0.001). Patients with FA scored higher in the Lattinen index for chronic pain at the time of the evaluation (8.7 ± 5.9 vs. 5.8 ± 5.4; P = 0.014). However, clinical outcomes were similar between the two groups. Conclusions: Routine screening for FA at long term postoperatively should be recommended to improve psychological outcomes of BS.

Associations of food addiction with metabolic control, medical complications and depression among patients with type 2 diabetes.

AIMS: Food addiction (FA) is conceptualized as a behavioral pattern that is similar in some ways to addictions to alcohol and other substances. This disorder has not been well studied among patients with type 2 diabetes (T2DM). We aimed to analyze if there is any relationship between FA and clinical or psychological variables among patients with T2DM. METHODS: Three hundred patients with T2DM were analyzed cross-sectionally. Participants were evaluated for the presence of FA by completing the Yale Food Addiction Scale 2.0 questionnaire. RESULTS: 29.3% of patients screened positive for FA. Patients with FA had a greater BMI (33.41 ± 7.5 vs. 31.6 ± 5.9 kg/m2; p = 0.04). HbA1c was higher among individuals with FA (7.9 ± 4.4 vs. 7.6 ± 1.4%, p = 0.008). The proportion of subjects with diabetic retinopathy, neuropathy and nephropathy was greater among patients with criteria for FA compared with patients without this condition (25% vs. 13.2%, 29.5% vs. 21.8% and 32% vs. 22.3%; p = 0.03, p = 0.05 and p = 0.05, respectively). The percentage of patients with FA with significant depressive symptoms was also greater (36.4% vs. 18.5%; p = 0.002). CONCLUSIONS: The presence of FA among T2DM patients implied a worse glycaemic control. Microvascular complications and depressive symptoms were higher among these patients.

Vascular Interstitial Cells in Retinal Arteriolar Annuli Are Altered During Hypertension.

Purpose: It has been suggested that arteriolar annuli localized in retinal arterioles regulate retinal blood flow acting as sphincters. Here, the morphology and protein expression profile of arteriolar annuli have been analyzed under physiologic conditions in the retina of wild-type, ß-actin-Egfp, and Nestin-gfp transgenic mice. Additionally, to study the effect of hypertension, the KAP transgenic mouse has been used. Methods: Cellular architecture has been studied using digested whole mount retinas and transmission electron microscopy. The profile of protein expression has been analyzed on paraffin sections and whole mount retinas by immunofluorescence and histochemistry. Results: The ultrastructural analysis of arteriolar annuli showed a different cell population found between endothelial and muscle cells that matched most of the morphologic criteria established to define interstitial Cajal cells. The profile of protein expression of these vascular interstitial cells (VICs) was similar to that of interstitial Cajal cells and different from the endothelial and smooth muscle cells, because they expressed ß-actin, nestin, and CD44, but they did not express CD31 and α-SMA or scarcely express F-actin. Furthermore, VICs share with pericytes the expression of NG2 and platelet-derived growth factor receptor beta (PDGFR-ß). The high expression of Ano1 and high activity of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase observed in VICs was diminished during hypertensive retinopathy suggesting that these cells might play a role on the motility of arteriolar annuli and that this function is altered during hypertension. Conclusions: A novel type of VICs has been described in the arteriolar annuli of mouse retina. Remarkably, these cells undergo important molecular modifications during hypertensive retinopathy and might thus be a therapeutic target against this disease.