sitagliptin-phosphate and Diabetic-Retinopathy

Diabetic retinopathy (DR), one of the leading causes of preventable blindness, is associated with many systemic factors that contribute to the development and progression of this microvascular complication of diabetes. While the duration of diabetes is the major risk factor for the development of DR, the main modifiable systemic risk factors for development and progression of DR are hyperglycemia, hypertension, and dyslipidemia. This review article looks at the evidence that control of these systemic factors has significant benefits in delaying the onset and progression of DR.

Topics: Blood Glucose; Blood Pressure; Diabetes Mellitus; Diabetic Retinopathy; Glycated Hemoglobin; Glycemic Index; Humans; Hypoglycemic Agents; Renin-Angiotensin System; Risk Factors; Sitagliptin Phosphate; Thiazolidinediones; Vision Disorders

The earliest and most significant change in diabetic retinopathy (DR) is blood-retinal barrier (BRB) dysfunction, followed by two main pathologies that may cause severe visual impairment: Diabetic Macular Edema (DME) and Proliferative Diabetic Retinopathy (PDR). The pathological hallmarks of BRB dysfunction include loss of tight junction integrity, VEGF- and AGE-induced damage, oxidative stress, and inflammatory changes. Recently, several BRB protective factors have been reported. Our aim is to give a review of those protective factors and discuss new potential therapeutic targets for DR.

Topics: Animals; Blood-Retinal Barrier; Diabetic Retinopathy; Erythropoietin; Fenofibrate; Humans; Insulin-Like Growth Factor Binding Protein 3; Macular Edema; Protective Factors; Pyrazines; Sitagliptin Phosphate; Triazoles; Vascular Endothelial Growth Factor A

Synaptic dysfunction and neuronal damage have been extensively associated with diabetic retinopathy (DR). Our group evidenced that chronic hyperglycemia reduces the retinal expression of presynaptic proteins, which are crucial for proper synaptic function. The aim of the study was to explore the effect of topically administered sitagliptin, an inhibitor of the enzyme dipeptidyl peptidase-4, on the retinal expression patterns of an experimental model of DR. Transcriptome analysis was performed, comparing the retinas of 10 diabetic (db/db) mice randomly treated with sitagliptin eye drops (10 mg/mL) twice daily and the retinas of 10 additional db/db mice that received vehicle eye drops. Ten non-diabetic mice (db/+) were used as a control group. The Gene Ontology (GO) and Reactome databases were used to perform the gene set enrichment analysis (GSEA) in order to explore the most enriched biological pathways among the groups. The most differentiated genes of these pathways were validated through quantitative RT-PCR. Transcriptome analysis revealed that sitagliptin eye drops have a significant effect on retinal expression patterns and that neurotransmission is the most enriched biological process. Our study evidenced enriched pathways that contain genes involved in membrane trafficking, transmission across chemical synapses, vesicle-mediated transport, neurotransmitter receptors and postsynaptic signal transmission with negative regulation of signaling as a consequence of neuroprotector treatment with sitagliptin. This improves the modulation of the macromolecule biosynthetic process with positive regulation of cell communication, which provides beneficial effects for the neuronal metabolism. This study suggests that topical administration of sitagliptin ameliorates the abnormalities on presynaptic and postsynaptic signal transmission during experimental DR and that this improvement is one of the main mechanisms behind the previously demonstrated beneficial effects.

Topics: Animals; Diabetes Mellitus; Diabetic Retinopathy; Dipeptidyl-Peptidase IV Inhibitors; Gene Expression Profiling; Mice; Models, Theoretical; Neuroprotective Agents; Sitagliptin Phosphate; Transcriptome

This study examined whether dipeptidyl peptidase (DPP)-4 inhibitor use is beneficial or harmful to diabetic retinopathy (DR) compared with other glucose-lowering agents in patients with type 2 diabetes (T2D).. From a population-based cohort provided by the National Health Insurance Service in Korea, 67,743 adults with T2D were identified as having been treated with oral glucose-lowering agents between 2008 and 2013. Matching (1:1) was performed for two groups comparing ever-use (cases) and never-use (controls) of DPP-4 inhibitors (n=14,522 in each group). Cox regression analyses were used to assess risk of the following DR events: vitreous haemorrhage; vitrectomy or photocoagulation; intravitreal agent use; and blindness.. During a median follow-up of 28.4 (14.0-45.2) months, there were 305 (in controls) and 342 (in cases) composite DR events. DPP-4 inhibitor ever-use was not associated with overall risk of composite DR events [adjusted hazard ratio (HR): 1.08, 95% CI: 0.93-1.26] compared with never-use, nor was the risk of each DR outcome increased with DPP-4 inhibitor therapy either. However, DPP-4 inhibitor administration for<12 months was associated with a greater risk of composite DR events (adjusted HR: 1.31, 95% CI: 1.09-1.57) compared with other glucose-lowering agents over the same treatment period.. In comparison to other oral glucose-lowering agents, DPP-4 inhibitor treatment did not increase overall risk of DR. However, DPP-4 inhibitors may be associated with an increased risk of retinopathy events early in the treatment phase.

Topics: Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Male; Middle Aged; Retrospective Studies; Sitagliptin Phosphate; Young Adult

Moringa oleifera Lam. (Moringaceae) has gained awareness for its antidiabetic effect, and is used as alternative therapy or concurrently with orthodox medicines such as sitagliptin in diabetes mellitus. This is without ascertaining the possibility of drug-herb interactions, which could either lead to enhanced antidiabetic efficacy, increased toxicity, or compromised glycaemic control with negative consequence in diabetic retinopathy.. To investigate the effect, of sitagliptin (50mg/kg), Moringa oleifera (300mg/kg) leaf extract, and a combination of both on glycaemic control parameters, lenticular opacity and changes in retinal microvasculature in alloxan (150mg/kg i.p) induced diabetic rat model.. Seven groups of eight rats per group were used, with groups I, II and VII as normal (NC), diabetic (DC) and post-prandial controls (PPC). Groups III to VI were diabetic rats on sitagliptin (III), M. oleifera (IV), sitagliptin and M. oleifera (SM) (V), for 42 days with 2 weeks delayed treatment in a post-prandial hyperglycaemic group (PPSM) (VI). Glycaemic control parameters, insulin levels, body weights, and effects of retinal microvasculature on lenticular opacity/morphology were investigated.. A significant decrease in fasting blood glucose (FBG) levels was displayed in SM group from day 14(60%) (p<0.01) to day 28 (38%) (p<0.01) of treatment, compared to day 1. Thereafter, a steady increase of up to 57% on day 42 compared to day 28 was observed. A significant decrease in random blood glucose (RBG) levels, were demonstrated on day 42 (24%) (p<0.001), compared to day 1. No significant difference was seen in mean serum levels of insulin across groups. No significant changes in body weights. Evidence of mild lenticular opacity was observed, with no significant effect in pathologic lesions in the retina.. The chronic co-administration of sitagliptin and M. oleifera showed a progressive decrease in anti-hyperglycaemic effect of sitagliptin, and although it delayed the onset of lenticular opacity (i.e. cataract-like changes) it did not prevent the progression nor ameliorated pathologic lesions in the retina.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Ethanol; Female; Herb-Drug Interactions; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Moringa oleifera; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Retina; Sitagliptin Phosphate

Diabetic retinopathy, a leading cause of vision loss in working-age population, is often associated with inflammation and apoptosis. We have previously reported that sitagliptin, a DPP-IV inhibitor, exerts beneficial effects in the retina of type 2 diabetic animals. The present study aimed to evaluate whether sitagliptin can exert protective effects in the retina of type 1 diabetic animals by a mechanism independent of insulin secretion and glycemia normalization. Streptozotocin-induced diabetic rats were treated orally with sitagliptin (5mg/kg/day) for the last two weeks of 4 weeks of diabetes. Sitagliptin treatment did not change the weight and glucose, HbA1c or insulin levels. However, it prevented the diabetes-induced increase in DPP-IV/CD26 activity and levels in serum and retina. Sitagliptin also prevented the increase in blood-retinal barrier (BRB) permeability and inhibited the changes in immunoreactivity and endothelial subcellular distribution of occludin, claudin-5 and ZO-1 proteins induced by diabetes. Furthermore, sitagliptin decreased the retinal inflammatory state and neuronal apoptosis. Sitagliptin inhibited the BRB breakdown in a type 1 diabetic animal model, by a mechanism independent of normalization of glycemia, by preventing changes in tight junctions (TJs) organization. Sitagliptin also exerted protective effects against inflammation and pro-apoptotic state in the retina of diabetic rats. Altogether, these results suggest that sitagliptin might be envisaged to be used to prevent or delay some of the alterations associated with the development of diabetic retinopathy.

Topics: Animals; Apoptosis; Biomarkers; Blood-Retinal Barrier; Blotting, Western; Cell Death; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme-Linked Immunosorbent Assay; Immunoenzyme Techniques; Inflammation; Male; Neurons; Pyrazines; Rats; Rats, Wistar; Retina; Sitagliptin Phosphate; Triazoles

The aim of this study was to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV inhibitor (DPP-IV), in preventing the deleterious effects of diabetes on the blood-retinal barrier in male Zucker Diabetic Fatty (ZDF) rats.. ZDF rats at 20 weeks of age were treated with sitagliptin (10 mg/kg/day) during 6 weeks. The effect of the drug on glycaemia was assessed by evaluating glycated haemoglobin (HbA1c). The content and/or distribution of tight junction (TJ) proteins occludin and claudin-5, as well as nitrotyrosine residues, interleukin (IL)-1β, BAX and Bcl-2 was evaluated in the retinas by western blotting and/or immunohistochemistry. Retinal cell apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay. The number of CD34+ cells present in peripheral circulation was assessed by flow cytometry, and endothelial progenitor cells (EPC) adhesion ability to the retinal vessels was evaluated by immunohistochemistry.. Sitagliptin improved glycaemic control as reflected by a significant decrease in HbA1c levels by about 1.2%. Treatment with sitagliptin prevented the changes in the endothelial subcellular distribution of the TJ proteins induced by diabetes. Sitagliptin also decreased the nitrosative stress, the inflammatory state and cell death by apoptosis in diabetic retinas. Diabetic animals presented decreased levels of CD34+ cells in the peripheral circulation and decreased adhesion ability of EPC to the retinal vessels. Sitagliptin allowed a recovery of the number of CD34+ cells present in the bloodstream to levels similar to their number in controls and increased the adhesion ability of EPC to the retinal vessels.. Sitagliptin prevented nitrosative stress, inflammation and apoptosis in retinal cells and exerted beneficial effects on the blood-retinal barrier integrity in ZDF rat retinas.

Topics: Animals; Apoptosis; Blood-Retinal Barrier; Blotting, Western; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Immunohistochemistry; In Situ Nick-End Labeling; Male; Pyrazines; Rats; Rats, Zucker; Sitagliptin Phosphate; Triazoles