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Hoshiyama K, Hirano T, Takahashi Y, Chiku Y, Murata T. Longitudinal evaluation of cotton wool spot following rapid glycemic improvement using wide-field multimodal imaging. Am J Ophthalmol Case Rep 2025; 37:102245. [PMID: 39834875 PMCID: PMC11743899 DOI: 10.1016/j.ajoc.2024.102245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 12/10/2024] [Accepted: 12/23/2024] [Indexed: 01/22/2025] Open
Abstract
Purpose To report a case of a diabetic patient undergoing rapid glycemic improvement characterized by the development and resolution of cotton wool spot (CWS), with detailed structural and vascular assessment using wide-field multimodal imaging, including wide-field color fundus photography and wide-field optical coherence tomography angiography (OCTA). Observations A 47-year-old man with poorly controlled Type 2 diabetes mellitus developed CWS in his right eye 3 months after initiating insulin therapy, which coincided with a significant reduction in HbA1c levels. Wide-field color fundus photography and wide-field OCTA were performed before, during, and after CWS appeared. OCTA images revealed an absence of blood flow in the area of CWS during its presence, followed by reperfusion after its resolution. No pre-existing microvascular damage was observed in the area before the development of CWS. Conclusions and Importance This case illustrates the potential the utility of multimodal imaging, combining wide-field color fundus photography and wide-field OCTA, as a powerful toolset for the follow-up and management of retinal changes in patients undergoing rapid glycemic improvement. These techniques provide comprehensive insights into retinal vascular and structural changes in diabetic retinopathy, with significant implications for both clinical practice and research.
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Affiliation(s)
- Ken Hoshiyama
- Department of Ophthalmology, Shinshu University School of Medicine, Japan
| | - Takao Hirano
- Department of Ophthalmology, Shinshu University School of Medicine, Japan
| | - Yoshiaki Takahashi
- Department of Ophthalmology, Shinshu University School of Medicine, Japan
| | - Yoshiaki Chiku
- Department of Ophthalmology, Shinshu University School of Medicine, Japan
| | - Toshinori Murata
- Department of Ophthalmology, Shinshu University School of Medicine, Japan
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Lin TY, Kang EYC, Shao SC, Lai ECC, Wang NK, Garg SJ, Chen KJ, Kang JH, Wu WC, Lai CC, Hwang YS. Association of sodium-glucose cotransporter-2 inhibitors and the risk of retinal vascular occlusion: A real-world retrospective cohort study in Taiwan. Diabetes Metab Res Rev 2024; 40:e3773. [PMID: 38598767 DOI: 10.1002/dmrr.3773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 12/03/2023] [Accepted: 01/04/2024] [Indexed: 04/12/2024]
Abstract
AIMS Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are proposed to alleviate the development of inflammatory eye diseases. However, the association between SGLT2i and retinal vascular occlusion remains unclear. Therefore, this study aims to explore the effects of SGLT2i on the incidence of retinal vascular occlusion. MATERIALS AND METHODS This retrospective cohort study analysed electronic medical records data from the largest multi-institutional database in Taiwan. Individuals who initiated SGLT2is and dipeptidyl peptidase 4 inhibitors (DPP4is) between 2016 and 2019 were included in our analysis. To conduct a homogenous comparison, inverse probability of treatment weighting with propensity scoring was employed. The primary outcome was retinal vascular occlusion, and the secondary outcomes were retinal vascular occlusion-related complications (macular oedema, vitreous haemorrhage, and tractional retinal detachment) and conditions requiring vitreoretinal intervention (intravitreal injection, retinal laser therapy, and vitrectomy). RESULTS In total, 12,074 SGLT2i users and 39,318 DPP4i users were included. The incidence rate of retinal vascular occlusion in the SGLT2i and DPP4i groups was 1.2 (95% confidence interval [CI], 0.9-1.4) and 1.6 (95% CI, 1.3-1.8) events per 1000 person-years, respectively, which yielded a subdistribution hazard ratio (SHR) of 0.74 (95% CI, 0.55-0.99). Similar risk reductions were observed in the retinal vascular occlusion-related complications (SHR, 0.76; 95% CI, 0.69-0.84) and conditions requiring vitreoretinal intervention (SHR, 0.84; 95% CI, 0.77-0.94). CONCLUSIONS In this multi-institutional study in Taiwan, SGLT2i use was associated with a reduced risk of retinal vascular occlusion. Further prospective studies are required to ascertain this association.
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Affiliation(s)
- Tzu-Yi Lin
- Department of Education, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Eugene Yu-Chuan Kang
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shih-Chieh Shao
- Department of Pharmacy, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Edward Chia-Cheng Lai
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Nan-Kai Wang
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, New York, USA
| | - Sunir J Garg
- Mid Atlantic Retina, The Retina Service of Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Kuan-Jen Chen
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Je-Ho Kang
- Department of Nephrology, Yang Ming Hospital, Taoyuan, Taiwan
| | - Wei-Chi Wu
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Chi-Chun Lai
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Yih-Shiou Hwang
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- Department of Ophthalmology, Jen-Ai Hospital Dali Branch, Taichung, Taiwan
- Department of Ophthalmology, Xiamen Chang Gung Memorial Hospital, Xiamen, China
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Li JX, Hung YT, Bair H, Hsu SB, Hsu CY, Lin CJ. Sodium-glucose co-transporter 2 inhibitor add-on therapy for metformin delays diabetic retinopathy progression in diabetes patients: a population-based cohort study. Sci Rep 2023; 13:17049. [PMID: 37816862 PMCID: PMC10564914 DOI: 10.1038/s41598-023-43893-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 09/29/2023] [Indexed: 10/12/2023] Open
Abstract
To investigate how sodium-glucose co-transporter 2 inhibitors (SGLT2is) add-on therapy for metformin affects diabetic retinopathy (DR) progression in patients with type 2 diabetes mellitus (T2DM). This nationwide population-based study conducted from January 1, 2016, to December 31, 2018 involved 3,432,911 adults with T2DM in Taiwan. To adjust for potential confounders, data on sex, age, income, comorbidities, diabetes complication severity index score, staging of kidney disease, anti-diabetic medications, and index year were included. The outcome was DR progression, determined by procedure codes or the addition of ICD-9-CM or ICD-10-CM codes to the medical records of the patients during the study. Sensitivity analyses were performed to validate the findings. The adjusted hazard ratio (aHR) of DR progression was 0.89 for the SGLT2is add-on group, relative to the control group [95% confidence interval (CI) 0.81-0.99, P = 0.026]. The Kaplan-Meier curve of the cumulative incidence rate showed that the cumulative incidence of DR progression was considerably decreased in the SGLT2is cohort (log-rank P = 0.0261). The use of SGLT2is for less than 1 year and 1-2 years were associated with a significant increase in the risk of DR progression (aHR 1.56 and 1.88, respectively); however, the risk markedly reduced if the SGLT2is regimen was used for more than 2 years (aHR 0.41, 95% Cl 0.35-0.48; P < 0.001). The serial sensitivity analysis showed consistent findings. The aHR of DR progression was 0.82 for the SGLT2is cohort relative to the non-SGLT2is cohort based on the fundoscopy or indirect ophthalmoscopy findings within 1 year before the outcome date (95% Cl 0.71-0.95; P = 0.009). Co-administration of metformin and SGLT2is may reduce the risk of DR progression. Short-term use of SGLT2is may markedly increase the risk of DR, whereas prolonged use SGLT2is may significantly decrease it.
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Affiliation(s)
- Jing-Xing Li
- Department of Internal Medicine, Taipei Veteran General Hospital, Taipei, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
- Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Yu-Tung Hung
- Institute of Public Health, China Medical University Hospital, Taichung, Taiwan
| | - Henry Bair
- Department of Ophthalmology, China Medical University Hospital, Taichung, Taiwan
- Byers Eye Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Shu-Bai Hsu
- Department of Nursing, China Medical University Hospital, Taichung, Taiwan
- School of Nursing, China Medical University, Taichung, Taiwan
| | - Chung-Yi Hsu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Chun-Ju Lin
- School of Medicine, China Medical University, Taichung, Taiwan.
- Department of Ophthalmology, China Medical University Hospital, Taichung, Taiwan.
- Department of Optometry, Asia University, Taichung, Taiwan.
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Cigrovski Berkovic M, Strollo F. Semaglutide-eye-catching results. World J Diabetes 2023; 14:424-434. [PMID: 37122431 PMCID: PMC10130900 DOI: 10.4239/wjd.v14.i4.424] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/08/2023] [Accepted: 03/20/2023] [Indexed: 04/12/2023] Open
Abstract
Semaglutide is a glucagon-like peptide-1 receptor agonist used either orally every day or subcutaneously once a week for the treatment of type 2 diabetes mellitus and, more recently, at higher doses, for the treatment of obesity. Both diseases are reaching epidemic proportions and often coexist, posing patients with a high risk for cardiovascular disease and death. Therefore, an agent such as semaglutide, which offers clinically significant weight loss and cardiovascular benefits, is essential and will be increasingly used in high-risk patients. However, during the SUSTAIN clinical trial program (Semaglutide Unabated Sustainability in treat-ment of type 2 diabetes), a safety issue concerning the progression and worsening of diabetic retinopathy emerged. The existing explanation so far mainly supports the role of the magnitude and speed of HbA1c reduction, a phenomenon also associated with insulin treatment and bariatric surgery. Whether and to which extent the effect is direct is still a matter of debate and an intriguing topic to investigate for suitable preventative and rehabilitative purposes. In this minireview, we will summarize the available data and suggest guidelines for a comprehensive semaglutide clinical utilization until new evidence becomes available.
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Affiliation(s)
| | - Felice Strollo
- Department of Endocrinology and Metabolism, IRCCS San Raffaele Pisana, Rome 00163, Italy
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Huang YH, Kuo CH, Peng IC, Chang YS, Tseng SH, Conway EM, Wu HL. Recombinant thrombomodulin domain 1 rescues pathological angiogenesis by inhibition of HIF-1α-VEGF pathway. Cell Mol Life Sci 2021; 78:7681-7692. [PMID: 34705054 PMCID: PMC11072095 DOI: 10.1007/s00018-021-03950-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 08/12/2021] [Accepted: 09/21/2021] [Indexed: 12/24/2022]
Abstract
Pathological angiogenesis (PA) contributes to various ocular diseases, including age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity, which are major causes of blindness over the world. Current treatments focus on anti-vascular endothelial growth factor (VEGF) therapy, but persistent avascular retina, recurrent intravitreal neovascularization, and general adverse effects are reported. We have previously found that recombinant thrombomodulin domain 1 (rTMD1) can suppress vascular inflammation. However, the function of rTMD1 in VEGF-induced PA remains unknown. In this study, we found that rTMD1 inhibited VEGF-induced angiogenesis in vitro. In an oxygen induced retinopathy (OIR) animal model, rTMD1 treatment significantly decreased retinal neovascularization but spared normal physiological vessel growth. Furthermore, loss of TMD1 significantly promoted PA in OIR. Meanwhile, hypoxia-inducible factor-1α, the transcription factor that upregulates VEGF, was suppressed after rTMD1 treatment. The levels of interleukin-6, and intercellular adhesion molecule-1 were also significantly suppressed. In conclusion, our results indicate that rTMD1 not only has dual effects to suppress PA and inflammation in OIR, but also can be a potential HIF-1α inhibitor for clinical use. These data bring forth the possibility of rTMD1 as a novel therapeutic agent for PA.
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MESH Headings
- Animals
- Apoptosis
- Cell Movement
- Cell Proliferation
- Cells, Cultured
- Female
- Gene Expression Regulation
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/prevention & control
- Retinal Neovascularization/genetics
- Retinal Neovascularization/metabolism
- Retinal Neovascularization/pathology
- Retinal Neovascularization/prevention & control
- Thrombomodulin/genetics
- Thrombomodulin/metabolism
- Vascular Endothelial Growth Factor A/antagonists & inhibitors
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Mice
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Affiliation(s)
- Yi-Hsun Huang
- Department of Ophthalmology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.
| | - Cheng-Hsiang Kuo
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
| | - I-Chen Peng
- Department of Ophthalmology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Sheng Chang
- Department of Ophthalmology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Sung-Huei Tseng
- Department of Ophthalmology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Edward M Conway
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
| | - Hua-Lin Wu
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan.
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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6
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Dascalu AM, Stoian AP, Cherecheanu AP, Serban D, Costea DO, Tudosie MS, Stana D, Tanasescu D, Sabau AD, Gangura GA, Costea AC, Nicolae VA, Smarandache CG. Outcomes of Diabetic Retinopathy Post-Bariatric Surgery in Patients with Type 2 Diabetes Mellitus. J Clin Med 2021; 10:jcm10163736. [PMID: 34442032 PMCID: PMC8396947 DOI: 10.3390/jcm10163736] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/13/2021] [Accepted: 08/19/2021] [Indexed: 12/23/2022] Open
Abstract
Bariatric surgery is an emerging therapeutic approach for obese type 2 diabetes mellitus (T2DM) patients, with proven benefits for achieving target glucose control and even remission of diabetes. However, the effect of bariatric surgery upon diabetic retinopathy is still a subject of debate as some studies show a positive effect while others raise concerns about potential early worsening effects. We performed a systematic review, on PubMed, Science Direct, and Web of Science databases regarding the onset and progression of diabetic retinopathy in obese T2DM patients who underwent weight-loss surgical procedures. A total of 6375 T2DM patients were analyzed. Most cases remained stable after bariatric surgery (89.6%). New onset of diabetic retinopathy (DR) was documented in 290 out of 5972 patients (4.8%). In cases with DR at baseline, progression was documented in 50 out of 403 (12.4%) and regression in 90 (22.3%). Preoperative careful preparation of hemoglobin A1c (HbA1c), blood pressure, and lipidemia should be provided to minimize the expectation of DR worsening. Ophthalmologic follow-up should be continued regularly in the postoperative period even in the case of diabetic remission. Further randomized trials are needed to better understand the organ-specific risk factors for progression and provide personalized counseling for T2DM patients planned for bariatric surgery.
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Affiliation(s)
- Ana Maria Dascalu
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania; (A.M.D.); (A.P.C.); (M.S.T.); (G.A.G.); (V.A.N.); (C.G.S.)
- Department of Ophthalmology, Emergency University Hospital Bucharest, 050098 Bucharest, Romania;
| | - Anca Pantea Stoian
- Department of Diabetes, Nutrition and Metabolic Diseases, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Alina Popa Cherecheanu
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania; (A.M.D.); (A.P.C.); (M.S.T.); (G.A.G.); (V.A.N.); (C.G.S.)
- Department of Ophthalmology, Emergency University Hospital Bucharest, 050098 Bucharest, Romania;
| | - Dragos Serban
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania; (A.M.D.); (A.P.C.); (M.S.T.); (G.A.G.); (V.A.N.); (C.G.S.)
- Fourth Department of General Surgery, Emergency University Hospital Bucharest, 050098 Bucharest, Romania
- Correspondence:
| | - Daniel Ovidiu Costea
- Faculty of Medicine, Ovidius University, 900470 Constanta, Romania;
- First Surgery Department, Emergency County Hospital, 900591 Constanta, Romania
| | - Mihail Silviu Tudosie
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania; (A.M.D.); (A.P.C.); (M.S.T.); (G.A.G.); (V.A.N.); (C.G.S.)
- ICU II Toxicology, Clinical Emergency Hospital, 014461 Bucharest, Romania
| | - Daniela Stana
- Department of Ophthalmology, Emergency University Hospital Bucharest, 050098 Bucharest, Romania;
| | - Denisa Tanasescu
- Fourth Department of Dental Medicine and Nursing, Faculty of Medicine, “Lucian Blaga” University, 550169 Sibiu, Romania;
| | - Alexandru Dan Sabau
- 3rd Clinical Department, Faculty of Medicine, “Lucian Blaga” University Sibiu, 550024 Sibiu, Romania;
| | - Gabriel Andrei Gangura
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania; (A.M.D.); (A.P.C.); (M.S.T.); (G.A.G.); (V.A.N.); (C.G.S.)
- Second Department of General Surgery, Emergency University Hospital Bucharest, 050098 Bucharest, Romania
| | | | - Vanessa Andrada Nicolae
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania; (A.M.D.); (A.P.C.); (M.S.T.); (G.A.G.); (V.A.N.); (C.G.S.)
- Department of Ophthalmology, Emergency University Hospital Bucharest, 050098 Bucharest, Romania;
| | - Catalin Gabriel Smarandache
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania; (A.M.D.); (A.P.C.); (M.S.T.); (G.A.G.); (V.A.N.); (C.G.S.)
- Fourth Department of General Surgery, Emergency University Hospital Bucharest, 050098 Bucharest, Romania
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7
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Abstract
Hypoxia can be defined as a relative deficiency in the amount of oxygen reaching the tissues. Hypoxia-inducible factors (HIFs) are critical regulators of the mammalian response to hypoxia. In normal circumstances, HIF-1α protein turnover is rapid, and hyperglycemia further destabilizes the protein. In addition to their role in diabetes pathogenesis, HIFs are implicated in development of the microvascular and macrovascular complications of diabetes. Improving glucose control in people with diabetes increases HIF-1α protein and has wide-ranging benefits, some of which are at least partially mediated by HIF-1α. Nevertheless, most strategies to improve diabetes or its complications via regulation of HIF-1α have not currently proven to be clinically useful. The intersection of HIF biology with diabetes is a complex area in which many further questions remain, especially regarding the well-conducted studies clearly describing discrepant effects of different methods of increasing HIF-1α, even within the same tissues. This Review presents a brief overview of HIFs; discusses the range of evidence implicating HIFs in β cell dysfunction, diabetes pathogenesis, and diabetes complications; and examines the differing outcomes of HIF-targeting approaches in these conditions.
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Affiliation(s)
- Jenny E Gunton
- Centre for Diabetes, Obesity and Endocrinology, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.,Westmead Hospital, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
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8
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Malan L, Hamer M, von Känel R, van Wyk RD, Sumner AE, Nilsson PM, Lambert GW, Steyn HS, Badenhorst CJ, Malan NT. A Stress Syndrome Prototype Reflects Type 3 Diabetes and Ischemic Stroke Risk: The SABPA Study. BIOLOGY 2021; 10:162. [PMID: 33670473 PMCID: PMC7922484 DOI: 10.3390/biology10020162] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/28/2021] [Accepted: 02/09/2021] [Indexed: 12/19/2022]
Abstract
Type 3 diabetes (T3D) accurately reflects that dementia, e.g., Alzheimer's disease, represents insulin resistance and neurodegeneration in the brain. Similar retinal microvascular changes were observed in Alzheimer's and chronic stressed individuals. Hence, we aimed to show that chronic stress relates to T3D dementia signs and retinopathy, ultimately comprising a Stress syndrome prototype reflecting risk for T3D and stroke. A chronic stress and stroke risk phenotype (Stressed) score, independent of age, race or gender, was applied to stratify participants (N = 264; aged 44 ± 9 years) into high stress risk (Stressed, N = 159) and low stress risk (non-Stressed, N = 105) groups. We determined insulin resistance using the homeostatic model assessment (HOMA-IR), which is interchangeable with T3D, and dementia risk markers (cognitive executive functioning (cognitiveexe-func); telomere length; waist circumference (WC), neuronal glia injury; neuron-specific enolase/NSE, S100B). Retinopathy was determined in the mydriatic eye. The Stressed group had greater incidence of HOMA-IR in the upper quartile (≥5), larger WC, poorer cognitiveexe-func control, shorter telomeres, consistently raised neuronal glia injury, fewer retinal arteries, narrower arteries, wider veins and a larger optic cup/disc ratio (C/D) compared to the non-Stressed group. Furthermore, of the stroke risk markers, arterial narrowing was related to glaucoma risk with a greater C/D, whilst retinal vein widening was related to HOMA-IR, poor cognitiveexe-func control and neuronal glia injury (Adjusted R2 0.30; p ≤ 0.05). These associations were not evident in the non-Stressed group. Logistic regression associations between the Stressed phenotype and four dementia risk markers (cognitiveexe-func, telomere length, NSE and WC) comprised a Stress syndrome prototype (area under the curve 0.80; sensitivity/specificity 85%/58%; p ≤ 0.001). The Stress syndrome prototype reflected risk for HOMA-IR (odds ratio (OR) 7.72) and retinal glia ischemia (OR 1.27) and vein widening (OR 1.03). The Stressed phenotype was associated with neuronal glia injury and retinal ischemia, potentiating glaucoma risk. The detrimental effect of chronic stress exemplified a Stress syndrome prototype reflecting risk for type 3 diabetes, neurodegeneration and ischemic stroke.
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Affiliation(s)
- Leoné Malan
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom 2520, South Africa; (R.v.K.); (N.T.M.)
| | - Mark Hamer
- Division of Surgery & Interventional Science, Faculty of Medical Sciences, University College London, London WC1E 6BT, UK;
| | - Roland von Känel
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom 2520, South Africa; (R.v.K.); (N.T.M.)
- Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Roelof D. van Wyk
- Surgical Ophthalmologist, 85 Peter Mokaba Street, Potchefstroom 2531, South Africa;
| | - Anne E. Sumner
- Section on Ethnicity and Health, Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA;
- National Institute of Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD 20892, USA
| | - Peter M. Nilsson
- Department of Clinical Sciences, Lund University, SE-205 02 Malmö, Sweden;
| | - Gavin W. Lambert
- Iverson Health Innovation Research Institute, Swinburne University of Technology, Hawthorn, VIC 3122, Australia;
- Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia
| | - Hendrik S. Steyn
- Statistical Consultation Services, North-West University, Potchefstroom 2520, South Africa;
| | - Casper J. Badenhorst
- Anglo American Corporate Services, Sustainable Development Department, Johannesburg 2017, South Africa;
| | - Nico T. Malan
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom 2520, South Africa; (R.v.K.); (N.T.M.)
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9
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Ji Z, Luo J, Su T, Chen C, Su Y. miR-7a Targets Insulin Receptor Substrate-2 Gene and Suppresses Viability and Invasion of Cells in Diabetic Retinopathy Mice via PI3K-Akt-VEGF Pathway. Diabetes Metab Syndr Obes 2021; 14:719-728. [PMID: 33623407 PMCID: PMC7896799 DOI: 10.2147/dmso.s288482] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/11/2021] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Diabetic retinopathy (DR) is one of the major leading causes for vision loss globally. Current study illustrates the role of miR-7a in DR. MATERIAL AND METHODS Retinal pericytes (RPs) and Endothelial cells (ECs) were isolated from mouse model of DR. qRT-PCR was done for expression of miR-7a and target gene mRNA, Western blot for protein expression. Identification of miR-7a target gene was done by TargetScan and Luciferase assay. Cell viability and invasion was done by MTT and Transwell chamber assay. RESULTS The expression of miR-7a was down-regulated whereas level of IRS-2 was unregulated in isolated RPs and ECs. Luciferase assay suggested correlation between miR-7a and IRS-2, over-expression of miR-7a using a mimic resulted in suppression in viability and invasion capacity of RPs and ECs and inhibited the protein levels of PI3K/Akt cascade and IRS-2, and however the inhibitor reversed them respectively. Transfection of siRNA targeting IRS-2 caused alteration in miR-7a mediated changes in ECs suggesting that miR-7a may decrease angiogenesis in DR by inhibiting the levels of IRS-2. CONCLUSION miR-7a suppresses PI3K/Akt cascade via targeting IRS-2, thus decreasing the viability and invasion capacity of RPs and ECs, suggesting an interesting treatment target for DR.
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Affiliation(s)
- Zhenyu Ji
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China
| | - Jinyuan Luo
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China
| | - Ting Su
- Eye Institute of Xiamen University, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
| | - Changzheng Chen
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China
| | - Yu Su
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China
- Correspondence: Yu Su Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of ChinaTel/Fax +86-2788041911 Email
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10
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Rudraraju M, Narayanan SP, Somanath PR. Regulation of blood-retinal barrier cell-junctions in diabetic retinopathy. Pharmacol Res 2020; 161:105115. [PMID: 32750417 PMCID: PMC7755666 DOI: 10.1016/j.phrs.2020.105115] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/22/2020] [Accepted: 07/27/2020] [Indexed: 12/15/2022]
Abstract
Loss of the blood-retinal barrier (BRB) integrity and subsequent damage to the neurovascular unit in the retina are the underlying reasons for diabetic retinopathy (DR). Damage to BRB eventually leads to severe visual impairment in the absence of prompt intervention. Diabetic macular edema and proliferative DR are the advanced stages of the disease where BRB integrity is altered. Primary mechanisms contributing to BRB dysfunction include loss of cell-cell barrier junctions, vascular endothelial growth factor, advanced glycation end products-induced damage, and oxidative stress. Although much is known about the involvement of adherens and tight-junction proteins in the regulation of vascular permeability in various diseases, there is a significant gap in our knowledge on the junctional proteins expressed in the BRB and how BRB function is modulated in the diabetic retina. In this review article, we present our current understanding of the molecular composition of BRB, the changes in the BRB junctional protein turnover in DR, and how BRB functional modulation affects vascular permeability and macular edema in the diabetic retina.
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Affiliation(s)
- Madhuri Rudraraju
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912, United States
| | - S Priya Narayanan
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States; Vascular Biology Center, Augusta University, Augusta, GA 30912, United States; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912, United States
| | - Payaningal R Somanath
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States; Vascular Biology Center, Augusta University, Augusta, GA 30912, United States; Department of Medicine, Augusta University, Augusta, GA 30912, United States.
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11
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Baliou S, Kyriakopoulos AM, Goulielmaki M, Panayiotidis MI, Spandidos DA, Zoumpourlis V. Significance of taurine transporter (TauT) in homeostasis and its layers of regulation (Review). Mol Med Rep 2020; 22:2163-2173. [PMID: 32705197 PMCID: PMC7411481 DOI: 10.3892/mmr.2020.11321] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 07/09/2020] [Indexed: 11/05/2022] Open
Abstract
Taurine (2‑aminoethanesulfonic acid) contributes to homeostasis, mainly through its antioxidant and osmoregulatory properties. Taurine's influx and efflux are mainly mediated through the ubiquitous expression of the sodium/chloride‑dependent taurine transporter, located on the plasma membrane. The significance of the taurine transporter has been shown in various organ malfunctions in taurine‑transporter‑null mice. The taurine transporter differentially responds to various cellular stimuli including ionic environment, electrochemical charge, and pH changes. The renal system has been used as a model to evaluate the factors that significantly determine the regulation of taurine transporter regulation.
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Affiliation(s)
- Stella Baliou
- National Hellenic Research Foundation, 11635 Athens, Greece
| | | | | | - Michalis I Panayiotidis
- Department of Electron Microscopy and Molecular Pathology, The Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Greece
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12
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Zarei R, Nikpour P, Rashidi B, Eskandari N, Aboutorabi R. Evaluation of Diabetes Effects on the Expression of Leukemia Inhibitory Factor and Vascular Endothelial Growth Factor A Genes and Proteins at the Time of Endometrial Receptivity after Superovulation in Rat Model. Adv Biomed Res 2020; 8:66. [PMID: 31897404 PMCID: PMC6909543 DOI: 10.4103/abr.abr_159_19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 08/21/2019] [Accepted: 08/26/2019] [Indexed: 12/20/2022] Open
Abstract
Background: Diabetes, a major metabolic disorder, seems to affect the fertility rates of women in various ways. Due to the uncertainty of the effects of diabetes along with superovulation treatment on the infertility, we investigate the effects of ovulation induction treatment as therapeutic approach on the expression of leukemia inhibitory factor (LIF) and vascular endothelial growth factor A (VEGFA) as two main factors which are involved in the implantation in the streptozotocin (STZ)-induced type 1 diabetic rats. Materials and Methods: Type 1 diabetes was induced by injections of STZ in Wistar rats. The animals were kept in diabetic conditions for 4 weeks, while some were treated with insulin for treatment. After treatment, the ovulation was induced by human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG). The rats were then sacrificed and the expression of LIF and VEGFA was checked by immunohistochemistry staining method, and the relative expression of LIF and VEGFA was measured by quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blotting methods. Results: It was observed that diabetes and insulin treatment for diabetes altered the expression of Lif and VEGFA in both mRNA and protein levels. However, superovulation treatment seems to ameliorate this alternation for both factors. Conclusion: According to our results, diabetes and insulin therapy could alter the expression of Lif and VEGFA genes and proteins that are effective in endometrial receptivity and implantation process. It seems in diabetic cases, the effect of hCG and hMG therapy by itself could regulate the level of expression and presence of these two genes and proteins.
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Affiliation(s)
- Ronak Zarei
- Department of Anatomical Sciences, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parvaneh Nikpour
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan, Iran.,Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Bahman Rashidi
- Department of Anatomical Sciences, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nahid Eskandari
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Roshanak Aboutorabi
- Department of Anatomical Sciences, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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13
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Coughlin BA, Guha-Niyogi P, Sikorskii A, Glazer LC, Mohr S. Ranibizumab Alters Levels of Intraocular Soluble Cytokine Receptors in Patients with Diabetic Macular Edema. Curr Eye Res 2019; 45:509-520. [DOI: 10.1080/02713683.2019.1665187] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Brandon A. Coughlin
- Department of Physiology, Michigan State University, East Lansing, Michigan, USA
| | - Pratim Guha-Niyogi
- Department of Statistics and Probability, Michigan State University, East Lansing, Michigan, USA
| | - Alla Sikorskii
- Department of Statistics and Probability, Michigan State University, East Lansing, Michigan, USA
- Department of Psychiatry, Michigan State University, East Lansing, Michigan, USA
| | | | - Susanne Mohr
- Department of Physiology, Michigan State University, East Lansing, Michigan, USA
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14
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Changes in VEGF-related factors are associated with presence of inflammatory factors in carbohydrate metabolism disorders during pregnancy. PLoS One 2019; 14:e0220650. [PMID: 31415573 PMCID: PMC6695137 DOI: 10.1371/journal.pone.0220650] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 07/19/2019] [Indexed: 11/19/2022] Open
Abstract
The aim of this study was to determine the action of molecules in carbohydrate metabolism disorders during pregnancy. The concentration of different types of cytokines and vascular endothelial growth factor (VEGF) in the plasma were measured in 4 groups of women: Group I, normal pregnancy (n = 10); Group II, patients with gestational DM (n = 12); Group III, pregnant patients with preexisting DM (n = 16); and Group IV, diabetic non-pregnant women (n = 22). The plasma VEGF concentration was significantly higher in the women in Group IV than in other groups (P <0.01). The concentration of the soluble form of the VEGF receptor-1 (sVEGFR-1) was significantly higher in Group I than in other groups (P <0.01). The concentration of soluble form of the VEGF receptor-2 (sVEGFR-2) was significantly lower in Groups I than in other groups (P <0.05). The concentrations of monocyte chemotactic protein-1 (MCP-1) and eotaxin were significantly lower in Group I than in Groups III and IV. The levels of interleukin (IL)-8, IL-6, and tumor necrosis factor-α (TNF-α) were significantly higher in Group I than in Group IV. Both the VEGF-related molecules and the Inflammatory cytokines are altered in pregnant women with the carbohydrate metabolism disorders.
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15
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Bain SC, Klufas MA, Ho A, Matthews DR. Worsening of diabetic retinopathy with rapid improvement in systemic glucose control: A review. Diabetes Obes Metab 2019; 21:454-466. [PMID: 30226298 PMCID: PMC6587545 DOI: 10.1111/dom.13538] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 09/11/2018] [Accepted: 09/13/2018] [Indexed: 12/13/2022]
Abstract
Worsening of diabetic retinopathy (DR) is associated with the initiation of effective treatment of glycaemia in some patients with diabetes. It has been associated with risk factors such as poor blood-glucose control and hypertension, and it manifests prior to the long-term benefits of optimizing glycaemic control. The majority of evidence supports an association of large and rapid reductions in blood-glucose levels with early worsening of DR. Despite a general awareness of early worsening within the diabetes community, mechanisms to explain the phenomenon remain speculative. We provide an overview of early worsening of DR and its pathophysiology based on current data. We describe the phenomenon in various settings, including in patients receiving insulin- or non-insulin-based treatments, in those undergoing bariatric surgery, and in pregnant women. We discuss various mechanisms and theories that have been suggested to explain this paradoxical phenomenon, and we summarize the implications of these in clinical practice.
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Affiliation(s)
| | | | - Allen Ho
- Wills Eye Hospital/Mid Atlantic RetinaPhiladelphiaPennsylvania
| | - David R. Matthews
- Oxford Centre for Diabetes, Endocrinology and Metabolism, and Harris Manchester CollegeUniversity of OxfordOxfordUK
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16
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Chakravarthy H, Devanathan V. Molecular Mechanisms Mediating Diabetic Retinal Neurodegeneration: Potential Research Avenues and Therapeutic Targets. J Mol Neurosci 2018; 66:445-461. [PMID: 30293228 DOI: 10.1007/s12031-018-1188-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 09/25/2018] [Indexed: 12/16/2022]
Abstract
Diabetic retinopathy (DR) is a devastating complication of diabetes with a prevalence rate of 35%, and no effective treatment options. Since the most visible clinical features of DR are microvascular irregularities, therapeutic interventions often attempt to reduce microvascular injury, but only after permanent retinal damage has ensued. However, recent data suggests that diabetes initially affects retinal neurons, leading to neurodegeneration as an early occurrence in DR, before onset of the more noticeable vascular abnormalities. In this review, we delineate the sequence of initiating events leading to retinal degeneration in DR, considering neuronal dysfunction as a primary event. Key molecular mechanisms and potential biomarkers associated with retinal neuronal degeneration in diabetes are discussed. In addition to glial reactivity and inflammation in the diabetic retina, the contribution of neurotrophic factors, cell adhesion molecules, apoptosis markers, and G protein signaling to neurodegenerative pathways warrants further investigation. These studies could complement recent developments in innovative treatment strategies for diabetic retinopathy, such as targeting retinal neuroprotection, promoting neuronal regeneration, and attempts to re-program other retinal cell types into functional neurons. Indeed, several ongoing clinical trials are currently attempting treatment of retinal neurodegeneration by means of such novel therapeutic avenues. The aim of this article is to highlight the crucial role of neurodegeneration in early retinopathy progression, and to review the molecular basis of neuronal dysfunction as a first step toward developing early therapeutic interventions that can prevent permanent retinal damage in diabetes. ClinicalTrials.gov: NCT02471651, NCT01492400.
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Affiliation(s)
- Harshini Chakravarthy
- Department of Biology, Indian Institute of Science Education and Research (IISER), Transit campus: C/o. Sree Rama Engineering College Campus, Karakambadi Road, Mangalam, Tirupati, 517507, India
| | - Vasudharani Devanathan
- Department of Biology, Indian Institute of Science Education and Research (IISER), Transit campus: C/o. Sree Rama Engineering College Campus, Karakambadi Road, Mangalam, Tirupati, 517507, India.
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17
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He H, Weir RL, Toutounchian JJ, Pagadala J, Steinle JJ, Baudry J, Miller DD, Yates CR. The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism. PLoS One 2017; 12:e0180808. [PMID: 28796787 PMCID: PMC5552119 DOI: 10.1371/journal.pone.0180808] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 06/21/2017] [Indexed: 12/03/2022] Open
Abstract
Retinal microaneurysms, an early disease manifestation of diabetic retinopathy, are associated with retinal endothelial cell (REC) death and macular edema. We previously demonstrated that a quinic acid (QA) analog, KZ-41, promoted REC survival by blunting stress-induced p38 MAPK activation. Herein, we sought to expand our understanding of the pro-survival signal transduction pathways actuated by KZ-41. Using human RECs exposed to high glucose (25 mM, 72 hours), we demonstrated that KZ-41 blocks caspase-3 activation by triggering phosphorylation of the PI3K regulatory subunit (p85; Tyr458) and its downstream target Akt (Ser473). Akt signal transduction was accompanied by autophosphorylation of the receptor tyrosine kinase, insulin growth factor-1 receptor (IGF-1R). IGF-1R knockdown using either the tyrosine kinase inhibitor AG1024 or silencing RNA abolished KZ-41’s pro-survival effect. Under high glucose stress, caspase-3 activation correlated with elevated ERK1/2 phosphorylation and decreased insulin receptor substrate-1 (IRS-1) levels. KZ-41 decreased ERK1/2 phosphorylation and reversed the glucose-dependent reduction in IRS-1. To gain insight into the mechanistic basis for IGF-1R activation by KZ-41, we used molecular modeling and docking simulations to explore a possible protein:ligand interaction between the IGF-1R kinase domain and KZ-41. Computational investigations suggest two possible KZ-41 binding sites within the kinase domain: a region with high homology to the insulin receptor contains one potential allosteric binding site, and another potential site on the other side of the kinase domain, near the hinge domain. These data, together with previous proof-of-concept efficacy studies demonstrating KZ-41 mitigates pathologic retinal neovascularization in the murine oxygen-induced retinopathy model, suggests that QA derivatives may offer therapeutic benefit in ischemic retinopathies.
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Affiliation(s)
- Hui He
- Department of Pharmaceutical Sciences, UTHSC College of Pharmacy, Memphis, Tennessee, United States of America
| | - Rebecca L. Weir
- Biochemistry and Cellular and Molecular Biology, The University of Tennessee, Knoxville, Tennessee, United States of America
| | - Jordan J. Toutounchian
- Department of Pharmaceutical Sciences, UTHSC College of Pharmacy, Memphis, Tennessee, United States of America
| | - Jayaprakash Pagadala
- Department of Pharmaceutical Sciences, UTHSC College of Pharmacy, Memphis, Tennessee, United States of America
| | - Jena J. Steinle
- Department of Anatomy, Wayne State University, Detroit, Michigan, United States of America
| | - Jerome Baudry
- Biochemistry and Cellular and Molecular Biology, The University of Tennessee, Knoxville, Tennessee, United States of America
- UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee, United States of America
| | - Duane D. Miller
- Department of Pharmaceutical Sciences, UTHSC College of Pharmacy, Memphis, Tennessee, United States of America
| | - Charles R. Yates
- Department of Pharmaceutical Sciences, UTHSC College of Pharmacy, Memphis, Tennessee, United States of America
- Department of Ophthalmology, UTHSC College of Medicine, Memphis, Tennessee, United States of America
- * E-mail:
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18
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Gupta A, Delhiwala KS, Raman RPG, Sharma T, Srinivasan S, Kulothungan V. Failure to initiate early insulin therapy - A risk factor for diabetic retinopathy in insulin users with Type 2 diabetes mellitus: Sankara Nethralaya-Diabetic Retinopathy Epidemiology and Molecular Genetics Study (SN-DREAMS, Report number 35). Indian J Ophthalmol 2017; 64:440-5. [PMID: 27488152 PMCID: PMC4991171 DOI: 10.4103/0301-4738.187668] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Context: Insulin users have been reported to have a higher incidence of diabetic retinopathy (DR). Aim: The aim was to elucidate the factors associated with DR among insulin users, especially association between duration, prior to initiating insulin for Type 2 diabetes mellitus (DM) and developing DR. Materials and Methods: Retrospective cross-sectional observational study included 1414 subjects having Type 2 DM. Insulin users were defined as subjects using insulin for glycemic control, and insulin nonusers as those either not using any antidiabetic treatment or using diet control or oral medications. The duration before initiating insulin after diagnosis was calculated by subtracting the duration of insulin usage from the duration of DM. DR was clinically graded using Klein's classification. SPSS (version 9.0) was used for statistical analysis. Results: Insulin users had more incidence of DR (52.9% vs. 16.3%, P < 0.0001) and sight threatening DR (19.1% vs. 2.4%, P < 0.0001) in comparison to insulin nonusers. Among insulin users, longer duration of DM (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.00–1.25, P = 0.044) and abdominal obesity (OR 1.15, 95% CI 1.02–1.29, P = 0.021) was associated with DR. The presence of DR was significantly associated with longer duration (≥5 years) prior to initiating insulin therapy, overall (38.0% vs. 62.0%, P = 0.013), and in subjects with suboptimal glycemic control (32.5% vs. 67.5%, P = 0.022). Conclusions: The presence of DR is significantly associated with longer duration of diabetes (>5 years) and sub-optimal glycemic control (glycosylated hemoglobin <7.0%). Among insulin users, abdominal obesity was found to be a significant predictor of DR; DR is associated with longer duration prior to initiating insulin therapy in Type 2 DM subjects with suboptimal glycemic control.
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Affiliation(s)
- Aditi Gupta
- Shri Bhagwan Mahavir Vitreoretinal Services, Chennai, Tamil Nadu, India
| | | | - Rajiv P G Raman
- Shri Bhagwan Mahavir Vitreoretinal Services, Chennai, Tamil Nadu, India
| | - Tarun Sharma
- Shri Bhagwan Mahavir Vitreoretinal Services, Chennai, Tamil Nadu, India
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19
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Fang S, Ma X, Guo S, Lu J. MicroRNA-126 inhibits cell viability and invasion in a diabetic retinopathy model via targeting IRS-1. Oncol Lett 2017; 14:4311-4318. [PMID: 28943945 DOI: 10.3892/ol.2017.6695] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 03/28/2017] [Indexed: 12/28/2022] Open
Abstract
Diabetic retinopathy (DR) is a sight-threatening complication of diabetes. IRS-1 was predicted to be the target gene of microRNA-126 (miR-126). The present study was designed to illustrate the involvement of miR-126 in the regulation of DR via targeting IRS-1. The present study revealed that the expression of miR-126 was significantly decreased while IRS-1 expression was increased in endothelial cells (ECs) and retinal pericytes (RPs) from a DR mouse model compared with healthy controls. Furthermore, a luciferase reporter assay confirmed the interaction between miR-126 and IRS-1. Following transfection with anmiR-126 mimic or miR-126 inhibitor, overexpression of miR-126 was demonstrated to suppress the invasion and viability of ECs and RPs and to inhibit the IRS-1 and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway protein expression levels, with inhibition of miR-126 leading to reverse results. Furthermore, transfection with small interfering RNA targeting IRS-1 altered the miR-126-induced effects observed in ECs, indicating that miR-126 may suppress angiogenesis in DR via inhibition of IRS-1 expression. Taken together, the results of the present study suggested that miR-126 affected the expression of IRS-1, resulting in downregulated expression of PI3K/Akt pathway proteins, and also suppressed cell invasion and viability. These results may provide a potential therapeutic strategy for DR.
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Affiliation(s)
- Shifeng Fang
- Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Xiang Ma
- Dalian Medical University, Dalian, Liaoning 116044, P.R. China.,Department of Ophthalmology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Suping Guo
- Department of Ophthalmology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Jianmin Lu
- Department of Ophthalmology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
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20
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Blair NP, Wanek J, Felder AE, Brewer KC, Joslin CE, Shahidi M. Inner Retinal Oxygen Delivery, Metabolism, and Extraction Fraction in Ins2Akita Diabetic Mice. Invest Ophthalmol Vis Sci 2017; 57:5903-5909. [PMID: 27802520 PMCID: PMC5096417 DOI: 10.1167/iovs.16-20082] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Purpose Retinal nonperfusion and hypoxia are important factors in human diabetic retinopathy, and these presumably inhibit energy production and lead to cell death. The purpose of this study was to elucidate the effect of diabetes on inner retinal oxygen delivery and metabolism in a mouse model of diabetes. Methods Phosphorescence lifetime and blood flow imaging were performed in spontaneously diabetic Ins2Akita (n = 22) and nondiabetic (n = 22) mice at 12 and 24 weeks of age to measure retinal arterial (O2A) and venous (O2V) oxygen contents and total retinal blood flow (F). Inner retinal oxygen delivery (DO2) and metabolism (MO2) were calculated as F ∗ O2A and F ∗ (O2A − O2V), respectively. Oxygen extraction fraction (OEF), which equals MO2/DO2, was calculated. Results DO2 at 12 weeks were 112 ± 40 and 97 ± 29 nL O2/min in nondiabetic and diabetic mice, respectively (NS), and 148 ± 31 and 85 ± 37 nL O2/min at 24 weeks, respectively (P < 0.001). MO2 were 65 ± 31 and 66 ± 27 nL O2/min in nondiabetic and diabetic mice at 12 weeks, respectively, and 79 ± 14 and 54 ± 28 nL O2/min at 24 weeks, respectively (main effects = NS). At 12 weeks OEF were 0.57 ± 0.17 and 0.67 ± 0.09 in nondiabetic and diabetic mice, respectively, and 0.54 ± 0.07 and 0.63 ± 0.08 at 24 weeks, respectively (main effect of diabetes: P < 0.01). Conclusions Inner retinal MO2 was maintained in diabetic Akita mice indicating that elevation of the OEF adequately compensated for reduced DO2 and prevented oxidative metabolism from being limited by hypoxia.
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Affiliation(s)
- Norman P Blair
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Justin Wanek
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Anthony E Felder
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Katherine C Brewer
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Charlotte E Joslin
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States 2Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, Illinois, United States 3University of Illinois Cancer Center, Population Health, Behavior, and Outcomes Program, Chicago, Illinois, United States
| | - Mahnaz Shahidi
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
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21
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Escudero CA, Herlitz K, Troncoso F, Guevara K, Acurio J, Aguayo C, Godoy AS, González M. Pro-angiogenic Role of Insulin: From Physiology to Pathology. Front Physiol 2017; 8:204. [PMID: 28424632 PMCID: PMC5380736 DOI: 10.3389/fphys.2017.00204] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 03/20/2017] [Indexed: 12/13/2022] Open
Abstract
The underlying molecular mechanisms involve in the regulation of the angiogenic process by insulin are not well understood. In this review article, we aim to describe the role of insulin and insulin receptor activation on the control of angiogenesis and how these mechanisms can be deregulated in human diseases. Functional expression of insulin receptors and their signaling pathways has been described on endothelial cells and pericytes, both of the main cells involved in vessel formation and maturation. Consequently, insulin has been shown to regulate endothelial cell migration, proliferation, and in vitro tubular structure formation through binding to its receptors and activation of intracellular phosphorylation cascades. Furthermore, insulin-mediated pro-angiogenic state is potentiated by generation of vascular growth factors, such as the vascular endothelial growth factor, produced by endothelial cells. Additionally, diseases such as insulin resistance, obesity, diabetes, and cancer may be associated with the deregulation of insulin-mediated angiogenesis. Despite this knowledge, the underlying molecular mechanisms need to be elucidated in order to provide new insights into the role of insulin on angiogenesis.
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Affiliation(s)
- Carlos A Escudero
- Group of Investigation in Tumor Angiogenesis, Vascular Physiology Laboratory, Basic Sciences Department, Universidad del Bío BíoChillán, Chile.,Group of Research and Innovation in Vascular Health, Department of Basic Sciences, Universidad del Bío-BíoChillán, Chile
| | - Kurt Herlitz
- Group of Investigation in Tumor Angiogenesis, Vascular Physiology Laboratory, Basic Sciences Department, Universidad del Bío BíoChillán, Chile
| | - Felipe Troncoso
- Group of Investigation in Tumor Angiogenesis, Vascular Physiology Laboratory, Basic Sciences Department, Universidad del Bío BíoChillán, Chile
| | - Katherine Guevara
- Group of Investigation in Tumor Angiogenesis, Vascular Physiology Laboratory, Basic Sciences Department, Universidad del Bío BíoChillán, Chile
| | - Jesenia Acurio
- Group of Investigation in Tumor Angiogenesis, Vascular Physiology Laboratory, Basic Sciences Department, Universidad del Bío BíoChillán, Chile
| | - Claudio Aguayo
- Group of Research and Innovation in Vascular Health, Department of Basic Sciences, Universidad del Bío-BíoChillán, Chile.,Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of ConcepciónConcepción, Chile
| | - Alejandro S Godoy
- Department of Physiology, Pontificia Universidad Católica de ChileSantiago, Chile.,Department of Urology, Roswell Park Cancer InstituteBuffalo, NY, USA
| | - Marcelo González
- Group of Research and Innovation in Vascular Health, Department of Basic Sciences, Universidad del Bío-BíoChillán, Chile.,Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad of ConcepciónConcepción, Chile
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Vascular endothelial growth factor-A 165b ameliorates outer-retinal barrier and vascular dysfunction in the diabetic retina. Clin Sci (Lond) 2017; 131:1225-1243. [PMID: 28341661 PMCID: PMC5450016 DOI: 10.1042/cs20170102] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 03/09/2017] [Accepted: 03/24/2017] [Indexed: 01/11/2023]
Abstract
Diabetic retinopathy (DR) is one of the leading causes of blindness in the developed world. Characteristic features of DR are retinal neurodegeneration, pathological angiogenesis and breakdown of both the inner and outer retinal barriers of the retinal vasculature and retinal pigmented epithelial (RPE)–choroid respectively. Vascular endothelial growth factor (VEGF-A), a key regulator of angiogenesis and permeability, is the target of most pharmacological interventions of DR. VEGF-A can be alternatively spliced at exon 8 to form two families of isoforms, pro- and anti-angiogenic. VEGF-A165a is the most abundant pro-angiogenic isoform, is pro-inflammatory and a potent inducer of permeability. VEGF-A165b is anti-angiogenic, anti-inflammatory, cytoprotective and neuroprotective. In the diabetic eye, pro-angiogenic VEGF-A isoforms are up-regulated such that they overpower VEGF-A165b. We hypothesized that this imbalance may contribute to increased breakdown of the retinal barriers and by redressing this imbalance, the pathological angiogenesis, fluid extravasation and retinal neurodegeneration could be ameliorated. VEGF-A165b prevented VEGF-A165a and hyperglycaemia-induced tight junction (TJ) breakdown and subsequent increase in solute flux in RPE cells. In streptozotocin (STZ)-induced diabetes, there was an increase in Evans Blue extravasation after both 1 and 8 weeks of diabetes, which was reduced upon intravitreal and systemic delivery of recombinant human (rh)VEGF-A165b. Eight-week diabetic rats also showed an increase in retinal vessel density, which was prevented by VEGF-A165b. These results show rhVEGF-A165b reduces DR-associated blood–retina barrier (BRB) dysfunction, angiogenesis and neurodegeneration and may be a suitable therapeutic in treating DR.
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Zhou J, Ni M, Liu X, Ren Z, Zheng Z. Curcumol Promotes Vascular Endothelial Growth Factor (VEGF)-Mediated Diabetic Wound Healing in Streptozotocin-Induced Hyperglycemic Rats. Med Sci Monit 2017; 23:555-562. [PMID: 28138126 PMCID: PMC5297326 DOI: 10.12659/msm.902859] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 01/10/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Wound healing in chronic diabetic mellitus is mainly associated with the management of angiogenesis. The angiogenic mechanism of vascular endothelial growth factor (VEGF) has been widely studied in the context of diabetic ulcers. The aim of this study was to investigate the wound-healing potential of curcumol in streptozotocin-induced diabetic rats. MATERIAL AND METHODS Sixty male SD (Sprague Dawley) rats were purchased and randomly assigned into four groups: a control group and a model group treated with blank ointment, a high-dose curcumol group, and a low-dose curcumol group. The number of animals in each group was 15. Diabetes was induced by an intraperitoneal injection of streptozotocin. Two cutaneous wounds were incised at the dorsal region of all the experimental animals. Wound healing was assessed for all animal groups by observing the rate of wound closure. The expression of VEGF at the wound sites was studied by immunohistochemical staining to evaluate the vascular endothelial cell reaction. VEGF protein and related mRNA levels were analyzed by Western blotting and RT-PCR (reverse transcription-polymerase chain reaction). RESULTS Curcumol treatment significantly increased the rates of wound closure in treated animals, and hence wound healing was drastically enhanced for treatment groups compared to control groups. Histological observations and related mRNA and protein levels showed a higher VEGF expression in the treatment groups. CONCLUSIONS Our analyses clearly suggested that the observed enhancement in wound healing as a result of curcumol administration was attributable to VEGF-mediated angiogenesis.
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Affiliation(s)
- Jie Zhou
- Development and Research Center of Official Silkworm Resources, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, P.R. China
| | - Maowei Ni
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, P.R. China
| | - Xia Liu
- Development and Research Center of Official Silkworm Resources, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, P.R. China
| | - Zeming Ren
- Development and Research Center of Official Silkworm Resources, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, P.R. China
| | - Zhiguo Zheng
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, P.R. China
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Rosa MD, Distefano G, Gagliano C, Rusciano D, Malaguarnera L. Autophagy in Diabetic Retinopathy. Curr Neuropharmacol 2017; 14:810-825. [PMID: 26997506 PMCID: PMC5333581 DOI: 10.2174/1570159x14666160321122900] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 11/08/2015] [Accepted: 11/10/2015] [Indexed: 12/19/2022] Open
Abstract
Autophagy is an important homeostatic cellular process encompassing a number of consecutive steps indispensable for degrading and recycling cytoplasmic materials. Basically autophagy is an adaptive response that under stressful conditions guarantees the physiological turnover of senescent and impaired organelles and, thus, controls cell fate by various cross-talk signals. Diabetic retinopathy (DR) is a serious microvascular complication of diabetes and accounts for 5% of all blindness. Although, various metabolic disorders have been linked with the onset of DR, due to the complex character of this multi-factorial disease, a connection between any particular defect and DR becomes speculative. Diabetes increases inflammation, advanced glycation end products (AGEs) and oxidative stress in the retina and its capillary cells. Particularly, a great number of evidences suggest a mutual connection between oxidative stress and other major metabolic abnormalities implicated in the development of DR. In addition, the intricate networks between autophagy and apoptosis establish the degree of cellular apoptosis and the progression of DR. Growing data underline the crucial role of reactive oxygen species (ROS) in the activation of autophagy. Depending on their delicate balance both redox signaling and autophagy, being detrimental or beneficial, retain opposing effects. The molecular mechanisms of autophagy are very complex and involve many signaling pathways cooperating at various steps. This review summarizes recent advances of the possible molecular mechanisms in autophagic process that are involved in pathophysiology of DR. In-depth analysis on the molecular mechanisms leading to autophagy in the retinal pigment epithelial (RPE) will be helpful to plan new therapies aimed at preventing or improving the progression of DR.
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Affiliation(s)
| | | | | | | | - Lucia Malaguarnera
- Department of Biomedical and Biotechnological Sciences, Faculty of Medicine, University of Catania, 95124 Catania, Italy
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D'Amico AG, Maugeri G, Bucolo C, Saccone S, Federico C, Cavallaro S, D'Agata V. Nap Interferes with Hypoxia-Inducible Factors and VEGF Expression in Retina of Diabetic Rats. J Mol Neurosci 2016; 61:256-266. [PMID: 27909871 DOI: 10.1007/s12031-016-0869-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 11/22/2016] [Indexed: 02/14/2023]
Abstract
The retinal microvascular damage is a complication of diabetic retinopathy (DR). Hyperglycemia and hypoxia are responsible of aberrant vessel's proliferation. The cellular response to hypoxia is mediated through activation of hypoxia-inducible factors (HIFs). Among these, HIF-1α modulates expression of its target gene, VEGF, whose upregulation controls the angiogenic event during DR development. In a previous study, we have demonstrated that a small peptide, NAP, is able to protect retina from hyperglycemic insult. Here, we have demonstrated that its intraocular administration in a rat model of diabetic retinopathy has reduced expression of HIF-1α, HIF-2α, and VEGF by increasing HIF-3α levels. These data have been also confirmed by immunolocalization study by confocal microscopy. Although these evidences need to be further deepened to understand the molecular mechanism involved in the protective NAP action, the present data suggest that this small peptide may be effective to prevent the development of this ocular pathology.
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Affiliation(s)
- Agata Grazia D'Amico
- San Raffaele Open University of Rome, Rome, Italy.,Department of Biomedical and Biotechnological Sciences, Section of Human Anatomy and Histology, University of Catania, Via S. Sofia, 87, 95123, Catania, Italy
| | - Grazia Maugeri
- Department of Biomedical and Biotechnological Sciences, Section of Human Anatomy and Histology, University of Catania, Via S. Sofia, 87, 95123, Catania, Italy
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Salvatore Saccone
- Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, Italy
| | - Concetta Federico
- Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, Italy
| | - Sebastiano Cavallaro
- Institute of Neurological Sciences, Italian National Research Council, Catania, Italy
| | - Velia D'Agata
- Department of Biomedical and Biotechnological Sciences, Section of Human Anatomy and Histology, University of Catania, Via S. Sofia, 87, 95123, Catania, Italy.
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Gast TJ, Fu X, Gens JS, Glazier JA. A Computational Model of Peripheral Photocoagulation for the Prevention of Progressive Diabetic Capillary Occlusion. J Diabetes Res 2016; 2016:2508381. [PMID: 27847828 PMCID: PMC5099465 DOI: 10.1155/2016/2508381] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 08/02/2016] [Accepted: 09/29/2016] [Indexed: 01/17/2023] Open
Abstract
We developed a computational model of the propagation of retinal ischemia in diabetic retinopathy and analyzed the consequences of various patterns and sizes of burns in peripheral retinal photocoagulation. The model addresses retinal ischemia as a phenomenon of adverse local feedback in which once a capillary is occluded there is an elevated probability of occlusion of adjacent capillaries resulting in enlarging areas of retinal ischemia as is commonly seen clinically. Retinal burns of different sizes and patterns, treated as local oxygen sources, are predicted to have different effects on the propagation of retinal ischemia. The patterns of retinal burns are optimized with regard to minimization of the sum of the photocoagulated retina and computer predicted ischemic retina. Our simulations show that certain patterns of retinal burns are effective at preventing the spatial spread of ischemia by creating oxygenated boundaries across which the ischemia does not propagate. This model makes no statement about current PRP treatment of avascular peripheral retina and notes that the usual spot sizes used in PRP will not prevent ischemic propagation in still vascularized retinal areas. The model seems to show that a properly patterned laser treatment of still vascularized peripheral retina may be able to prevent or at least constrain the propagation of diabetic retinal ischemia in those retinal areas with intact capillaries.
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Affiliation(s)
- Thomas J. Gast
- School of Optometry, Indiana University, Bloomington, IN 47405, USA
| | - Xiao Fu
- The Biocomplexity Institute, Indiana University, Bloomington, IN 47405, USA
- Physics Department, Indiana University, Bloomington, IN 47405, USA
| | - John Scott Gens
- The Biocomplexity Institute, Indiana University, Bloomington, IN 47405, USA
- Physics Department, Indiana University, Bloomington, IN 47405, USA
| | - James A. Glazier
- The Biocomplexity Institute, Indiana University, Bloomington, IN 47405, USA
- Physics Department, Indiana University, Bloomington, IN 47405, USA
- School of Informatics and Computing, Indiana University, Bloomington, IN 47408, USA
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27
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Fu X, Gens JS, Glazier JA, Burns SA, Gast TJ. Progression of Diabetic Capillary Occlusion: A Model. PLoS Comput Biol 2016; 12:e1004932. [PMID: 27300722 PMCID: PMC4907516 DOI: 10.1371/journal.pcbi.1004932] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 04/20/2016] [Indexed: 12/14/2022] Open
Abstract
An explanatory computational model is developed of the contiguous areas of retinal capillary loss which play a large role in diabetic maculapathy and diabetic retinal neovascularization. Strictly random leukocyte mediated capillary occlusion cannot explain the occurrence of large contiguous areas of retinal ischemia. Therefore occlusion of an individual capillary must increase the probability of occlusion of surrounding capillaries. A retinal perifoveal vascular sector as well as a peripheral retinal capillary network and a deleted hexagonal capillary network are modelled using Compucell3D. The perifoveal modelling produces a pattern of spreading capillary loss with associated macular edema. In the peripheral network, spreading ischemia results from the progressive loss of the ladder capillaries which connect peripheral arterioles and venules. System blood flow was elevated in the macular model before a later reduction in flow in cases with progression of capillary occlusions. Simulations differing only in initial vascular network structures but with identical dynamics for oxygen, growth factors and vascular occlusions, replicate key clinical observations of ischemia and macular edema in the posterior pole and ischemia in the retinal periphery. The simulation results also seem consistent with quantitative data on macular blood flow and qualitative data on venous oxygenation. One computational model applied to distinct capillary networks in different retinal regions yielded results comparable to clinical observations in those regions.
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Affiliation(s)
- Xiao Fu
- The Biocomplexity Institute, Indiana University, Bloomington, Indiana, United States of America
- Department of Physics, Indiana University, Bloomington, Indiana, United States of America
| | - John Scott Gens
- The Biocomplexity Institute, Indiana University, Bloomington, Indiana, United States of America
- Department of Physics, Indiana University, Bloomington, Indiana, United States of America
| | - James A. Glazier
- The Biocomplexity Institute, Indiana University, Bloomington, Indiana, United States of America
- Department of Physics, Indiana University, Bloomington, Indiana, United States of America
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, Indiana, United States of America
| | - Stephen A. Burns
- School of Optometry, Indiana University, Bloomington, Indiana, United States of America
| | - Thomas J. Gast
- School of Optometry, Indiana University, Bloomington, Indiana, United States of America
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Bhatta M, Ma JH, Wang JJ, Sakowski J, Zhang SX. Enhanced endoplasmic reticulum stress in bone marrow angiogenic progenitor cells in a mouse model of long-term experimental type 2 diabetes. Diabetologia 2015; 58:2181-90. [PMID: 26063198 PMCID: PMC4529381 DOI: 10.1007/s00125-015-3643-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 05/01/2015] [Indexed: 01/08/2023]
Abstract
AIMS/HYPOTHESIS Bone marrow-derived circulating angiogenic cells (CACs) play an important role in vascular repair. In diabetes, compromised functioning of the CACs contributes to the development of diabetic retinopathy; however, the underlying mechanisms are poorly understood. We examined whether endoplasmic reticulum (ER) stress, which has recently been linked to endothelial injury, is involved in diabetic angiogenic dysfunction. METHODS Flow cytometric analysis was used to quantify bone marrow-derived progenitors (Lin(-)/c-Kit(+)/Sca-1(+)/CD34(+)) and blood-derived CACs (Sca-1(+)/CD34(+)) in 15-month-old Lepr (db) (db/db) mice and in their littermate control (db/+) mice used as a model of type 2 diabetes. Markers of ER stress in diabetic (db/db) and non-diabetic (db/+) bone marrow-derived early outgrowth cells (EOCs) and retinal vascular density were measured. RESULTS The numbers of bone-marrow progenitors and CACs were significantly reduced in db/db mice. Vascular density was markedly decreased in the retinas of db/db mice, and this was accompanied by vascular beading. Microglial activation was enhanced, as was the production of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). The production of ER stress markers (glucose-regulated protein-78 [GRP-78], phosphorylated inositol-requiring enzyme-1α [p-IRE-1α], phosphorylated eukaryotic translation initiation factor-2α [p-eIF2α], activating transcription factor-4 [ATF4], C/EBP homologous protein [CHOP] and spliced X-box binding protein-1 [XBP1s]) was significantly increased in bone marrow-derived EOCs from db/db mice. In addition, mouse EOCs cultured in high-glucose conditions demonstrated higher levels of ER stress, reduced colony formation, impaired migration and increased apoptosis, all of which were largely prevented by the chemical chaperone 4-phenylbutyrate. CONCLUSIONS/INTERPRETATION Taken together, our results indicate that diabetes increases ER stress in bone marrow angiogenic progenitor cells. Thus, targeting ER stress may offer a new approach to improving angiogenic progenitor cell function and promoting vascular repair in diabetes.
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Affiliation(s)
- Maulasri Bhatta
- Department of Ophthalmology, University at Buffalo, State University of New York, 3435 Main Street, Buffalo, NY, 14214, USA
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Does Insulin Like Growth Factor-1 (IGF-1) Deficiency Have a "Protective" Role in the Development of Diabetic Retinopathy in Thalassamia Major Patients? Mediterr J Hematol Infect Dis 2015; 7:e2015038. [PMID: 26075045 PMCID: PMC4450649 DOI: 10.4084/mjhid.2015.038] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 05/08/2015] [Indexed: 01/19/2023] Open
Abstract
RATIONALE Both insulin and IGF-1 have been implicated in the control of retinal endothelial cell growth, neovascularization and diabetic retinopathy. Recent findings have established an essential role for IGF-1 in angiogenesis and demonstrated a new target for control of retinopathy that explains why diabetic retinopathy initially increases with the onset of insulin treatment. OBJECTIVE This cross-sectional study was designed to give insights into relationship between Insulin-Growth-Factor 1 (IGF-1) levels and diabetic retinopathy (DR) in a sample of thalassemia major (TM) patients with insulin dependent diabetes mellitus (IDDM). This relation was not previously evaluated, despite the fact that both diseases co-exist in the same patient. The study also describes the clinical and biochemical profile of the associated complications in TM patients with and without IDDM. DESIGN A population-based cross-sectional study. PARTICIPANTS The study includes 19 consecutive TM patients with IDDM and 31 age- and sex-matched TM patients without IDDM who visited our out-patient clinics for an endocrine assessment. METHODS An extensive medical history, with data on associated complications and current medications, was obtained. Blood samples were drawn in the morning after an overnight fast to measure the serum concentrations of IGF-1, glucose, fructosamine, free thyroxine (FT4), thyrotropin (TSH) and biochemical analysis. Serologic screening assays for hepatitis C virus seropositivity (HCVab and HCV-RNA) were also evaluated; applying routine laboratory methods. Plasma total IGF-1 was measured by a chemiluminescent immunometric assay (CLIA) method. Ophthalmology evaluation was done by the same researcher using stereoscopic fundus biomicroscopy through dilated pupils. DR was graded using the scale developed by the Global Diabetic Retinopathy Group. Iron stores were assessed by direct and indirect methods. RESULTS Eighteen TM patients with IDDM (94.7 %) and ten non-diabetic patients (32.2 %) had IGF-1 levels below the 2.5(th) percentile of the normal values for the Italian population. The mean serum IGF-1 concentrations were significantly lower in the diabetic versus the non-diabetic TM groups (p < 0.001). DR was present in 4 (21 %) of 19 TM patients with IDDM and was associated with the main classical risk factors, namely inefficient glycemic control and duration of the disease but not hypertension. Using the scale developed by the Global Diabetic Retinopathy Group, the DR in our patients was classified as non proliferative diabetic retinopathy (NPDR). Only a few numbers of microaneurysms [1-3] were detected. Our data also confirm the strong association of IDDM in TM patients with other endocrine and non-endocrine complications.
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Abu El-Asrar AM, Mohammad G, Nawaz MI, Abdelsaid M, Siddiquei MM, Alam K, Van den Eynde K, De Hertogh G, Opdenakker G, Al-Shabrawey M, Van Damme J, Struyf S. The Chemokine Platelet Factor-4 Variant (PF-4var)/CXCL4L1 Inhibits Diabetes-Induced Blood-Retinal Barrier Breakdown. Invest Ophthalmol Vis Sci 2015; 56:1956-64. [PMID: 25711636 DOI: 10.1167/iovs.14-16144] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
PURPOSE To investigate the expression of platelet factor-4 variant (PF-4var/CXCL4L1) in epiretinal membranes from patients with proliferative diabetic retinopathy (PDR) and the role of PF-4var/CXCL4L1 in the regulation of blood-retinal barrier (BRB) breakdown in diabetic rat retinas and human retinal microvascular endothelial cells (HRMEC). METHODS Rats were treated intravitreally with PF-4var/CXCL4L1 or the anti-vascular endothelial growth factor (VEGF) agent bevacizumab on the first day after diabetes induction. Blood-retinal barrier breakdown was assessed in vivo with fluorescein isothiocyanate (FITC)-conjugated dextran and in vitro in HRMEC by transendothelial electrical resistance and FITC-conjugated dextran cell permeability assay. Occludin, vascular endothelial (VE)-cadherin, hypoxia-inducible factor (HIF)-1α, VEGF, tumor necrosis factor (TNF)-α, receptor for advanced glycation end products (RAGE), caspase-3 levels, and generation of reactive oxygen species (ROS) were assessed by Western blot, enzyme-linked immunosorbent assays, or spectrophotometry. RESULTS In epiretinal membranes, vascular endothelial cells and stromal cells expressed PF-4var/CXCL4L1. In vitro, HRMEC produced PF-4var/CXCL4L1 after stimulation with a combination of interleukin (IL)-1β and TNF-α, and PF-4var/CXCL4L1 inhibited VEGF-mediated hyperpermeability in HRMEC. In rats, PF-4var/CXCL4L1 was as potent as bevacizumab in attenuating diabetes-induced BRB breakdown. This effect was associated with upregulation of occludin and VE-cadherin and downregulation of HIF-1α, VEGF, TNF-α, RAGE, and caspase-3, whereas ROS generation was not altered. CONCLUSIONS Our findings suggest that increasing the intraocular PF-4var/CXCL4L1 levels early after the onset of diabetes protects against diabetes-induced BRB breakdown.
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Affiliation(s)
- Ahmed M Abu El-Asrar
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia Dr Nasser Al-Rashid Research Chair in Ophthalmology, King Saud University, Riyadh, Saudi Arabia
| | - Ghulam Mohammad
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohd Imtiaz Nawaz
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed Abdelsaid
- Department of Oral Biology, Cellular Biology and Anatomy, Culver Vision Discovery Institute and Department of Ophthalmology, Georgia Regents University, Augusta, Georgia, United States
| | | | - Kaiser Alam
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Kathleen Van den Eynde
- Laboratory of Histochemistry and Cytochemistry, University of Leuven, KU Leuven, Leuven, Belgium
| | - Gert De Hertogh
- Laboratory of Histochemistry and Cytochemistry, University of Leuven, KU Leuven, Leuven, Belgium
| | - Ghislain Opdenakker
- Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium
| | - Mohamed Al-Shabrawey
- Department of Oral Biology, Cellular Biology and Anatomy, Culver Vision Discovery Institute and Department of Ophthalmology, Georgia Regents University, Augusta, Georgia, United States
| | - Jo Van Damme
- Laboratory of Molecular Immunology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium
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31
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Semeraro F, Cancarini A, dell'Omo R, Rezzola S, Romano MR, Costagliola C. Diabetic Retinopathy: Vascular and Inflammatory Disease. J Diabetes Res 2015; 2015:582060. [PMID: 26137497 PMCID: PMC4475523 DOI: 10.1155/2015/582060] [Citation(s) in RCA: 291] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 05/03/2015] [Accepted: 05/13/2015] [Indexed: 02/06/2023] Open
Abstract
Diabetic retinopathy (DR) is the leading cause of visual impairment in the working-age population of the Western world. The pathogenesis of DR is complex and several vascular, inflammatory, and neuronal mechanisms are involved. Inflammation mediates structural and molecular alterations associated with DR. However, the molecular mechanisms underlying the inflammatory pathways associated with DR are not completely characterized. Previous studies indicate that tissue hypoxia and dysregulation of immune responses associated with diabetes mellitus can induce increased expression of numerous vitreous mediators responsible for DR development. Thus, analysis of vitreous humor obtained from diabetic patients has made it possible to identify some of the mediators (cytokines, chemokines, and other factors) responsible for DR pathogenesis. Further studies are needed to better understand the relationship between inflammation and DR. Herein the main vitreous-related factors triggering the occurrence of retinal complication in diabetes are highlighted.
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Affiliation(s)
- F. Semeraro
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - A. Cancarini
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - R. dell'Omo
- Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy
| | - S. Rezzola
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - M. R. Romano
- Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples, Italy
| | - C. Costagliola
- Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy
- ICRRS Neuromed, Pozzilli, Isernia, Italy
- *C. Costagliola:
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32
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Matsuda S, Tam T, Singh RP, Kaiser PK, Petkovsek D, Zanella MT, Ehlers JP. Impact of insulin treatment in diabetic macular edema therapy in type 2 diabetes. Can J Diabetes 2014; 39:73-7. [PMID: 25444681 DOI: 10.1016/j.jcjd.2014.06.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 06/01/2014] [Accepted: 06/27/2014] [Indexed: 01/29/2023]
Abstract
OBJECTIVE To evaluate the impact of insulin therapy on the outcomes of diabetic macular edema (DME) treatment with vascular endothelial growth factor (VEGF) inhibitors in people with type 2 diabetes. METHODS A retrospective consecutive case series of 95 patients with type 2 diabetes and DME who were treated with anti-VEGF therapy. We examined 2 cohorts: patients taking only oral antidiabetic agents and patients on insulin therapy. The main outcome measures were change in visual acuity and change in central subfield macular thickness measured by spectral-domain optical coherence tomography. The additional variables analyzed included glycated hemoglobin (A1C), creatinine, blood pressure and body mass index and their correlations with clinical findings. RESULTS Both groups had a statistically significant improvement in visual acuity (oral antidiabetic agents group: 20/61 to 20/49, p=0.003; insulin therapy group: 20/76 to 20/56, p=0.005). There was no difference between groups at initial or 12-month examination (p=0.239 and p=0.489, respectively). From an anatomic standpoint, central subfield macular thickness also improved significantly in both groups: from 454.7 μm to 354.9 μm (p<0.001) in the oral antidiabetic agents group and from 471.5 μm to 368.4 μm (p<0.001) in the insulin therapy group. Again, there was no significant difference between groups at initial or 12-month follow-up examinations (p=0.586 and p=0.591, respectively). Mean A1C levels remained relatively stable during the follow up in both groups. CONCLUSION Anti-VEGF therapy is a useful treatment for DME. This study suggests that chronic insulin therapy, compared with oral antidiabetic agents, does not modify the anatomic or functional effectiveness of DME treatment.
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Affiliation(s)
- Simone Matsuda
- Ophthalmic Imaging Center, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America; Department of Medicine, Division of Endocrinology, Universidade Federal de São Paulo, Sao Paulo, SP, Brazil
| | - Tiffany Tam
- Ophthalmic Imaging Center, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America
| | - Rishi P Singh
- Ophthalmic Imaging Center, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America
| | - Peter K Kaiser
- Ophthalmic Imaging Center, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America
| | - Daniel Petkovsek
- Ophthalmic Imaging Center, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America
| | - Maria Teresa Zanella
- Department of Medicine, Division of Endocrinology, Universidade Federal de São Paulo, Sao Paulo, SP, Brazil
| | - Justis P Ehlers
- Ophthalmic Imaging Center, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America.
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Evans SM, Kim K, Moore CE, Uddin MI, Capozzi ME, Craft JR, Sulikowski GA, Jayagopal A. Molecular probes for imaging of hypoxia in the retina. Bioconjug Chem 2014; 25:2030-7. [PMID: 25250692 PMCID: PMC4240343 DOI: 10.1021/bc500400z] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Hypoxia has been associated with retinal diseases which lead the causes of irreversible vision loss, including diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration. Therefore, technologies for imaging hypoxia in the retina are needed for early disease detection, monitoring of disease progression, and assessment of therapeutic responses in the patient. Toward this goal, we developed two hypoxia-sensitive imaging agents based on nitroimidazoles which are capable of accumulating in hypoxic cells in vivo. 2-nitroimidazole or Pimonidazole was conjugated to fluorescent dyes to yield the imaging agents HYPOX-1 and HYPOX-2. Imaging agents were characterized in cell culture and animal models of retinal vascular diseases which exhibit hypoxia. Both HYPOX-1 and -2 were capable of detecting hypoxia in cell culture models with >10:1 signal-to-noise ratios without acute toxicity. Furthermore, intraocular administration of contrast agents in mouse models of retinal hypoxia enabled ex vivo detection of hypoxic tissue. These imaging agents are a promising step toward translation of hypoxia-sensitive molecular imaging agents in preclinical animal models and patients.
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Affiliation(s)
- Stephanie M Evans
- Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute , Nashville, Tennessee37232, United States
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Catrina SB. Impaired hypoxia-inducible factor (HIF) regulation by hyperglycemia. J Mol Med (Berl) 2014; 92:1025-34. [PMID: 25027070 DOI: 10.1007/s00109-014-1166-x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 05/06/2014] [Accepted: 05/08/2014] [Indexed: 12/13/2022]
Abstract
The mechanisms that contribute to the development of diabetes complications remain unclear. A defective reaction of tissues to hypoxia has recently emerged as a new pathogenic mechanism and consists of a complex repression of hypoxia-inducible factor (HIF), which is the main regulator of the adaptive response to hypoxia. This paper discusses the mechanisms by which hyperglycaemia contributes to HIF repression in diabetes. Furthermore, a comprehensive analysis of the functional relevance of these new findings to the development of chronic diabetes complications is provided, along with examples from animal models and clinics.
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Affiliation(s)
- Sergiu-Bogdan Catrina
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska University Hospital, L1:01, 17176, Stockholm, Sweden,
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Jindal V. Neurodegeneration as a primary change and role of neuroprotection in diabetic retinopathy. Mol Neurobiol 2014; 51:878-84. [PMID: 24826918 DOI: 10.1007/s12035-014-8732-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023]
Abstract
Diabetic retinopathy (DR) was earlier recognized as a vascular disease, but nowadays, it is considered as a neurovascular disorder. Neuronal death is the primary change which leads to various vascular changes which are visible to an ophthalmologist. But these changes are feature of an advanced disease and can affect vision at any moment of time. There are various evidences which suggests that glutamate excitotoxicity, hyperhomocysteinemia, kynurenic acid, and erythro-poietin plays important role in causation of retinal ganglionic cell apoptosis in diabetic patients. Adaptive optics, a new imaging technique, also showed that loss of photoreceptors (specialized neurons) is the early change in diabetic retinopathy. These changes suggest DR as a neurovascular disorder. Neuroprotective agents also showed good results in delaying progression of DR especially memantine, insulin receptor activation, and neurotrophic factors. More research in this field will help us to find novel therapeutic measures for DR, which can delay or even stop progression of DR at a very early stage.
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Affiliation(s)
- Vishal Jindal
- , H. No. 102 GHS 51 sector 20, Panchkula, Haryana, India,
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Gogula SV, Divakar C, Satyanarayana C, Kumar YP, Lavanaya VS. Computational investigation of pkcβ inhibitors for the treatment of diabetic retinopathy. Bioinformation 2013; 9:1040-3. [PMID: 24497733 PMCID: PMC3910362 DOI: 10.6026/97320630091040] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 12/19/2013] [Indexed: 01/17/2023] Open
Abstract
Diabetic Retinopathy (DR) is one of the attenuating complications of diabetes mellitus. The key gene responsible for causing
diabetic retinopathy is protein kinase C beta (PKCβ). Protein kinase C is a family of protein kinase enzymes which are involved in
controlling the function of other proteins through phosphorylation mechanism and plays a crucial role in signal transduction
mechanisms. Among all the PKC isoenzymes, PKCβ could be a significant isoenzyme involved in vascular dysfunction during
hyperglycemia. Studies show that oral administration of PKCβ inhibitor Ruboxistaurin (LY333531), decreases vessel permeability
and improves retinal condition. Thus compounds that decrease the PKCβ activation would be helpful in the treatment of diabetic
retinopathy. The compounds similar to Ruboxistaurin are taken from Super Target database and docking analysis was performed.
Maleimide derivative 3 showed highest binding affinities compared to Ruboxistaurin and so we advise that compound may be
utilized in the treatment of diabetic retinopathy.
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Affiliation(s)
| | - Ch Divakar
- Pydah College of Engineering and Technology, Gambheeram, Anandapuram (M); Visakhapatnam-531163
| | - Ch Satyanarayana
- Jawaharlal Nehru Technological University Kakinada, Kakinada, Andhra Pradesh-533003
| | - Yedla Phani Kumar
- Jawaharlal Nehru Technological University Kakinada, Kakinada, Andhra Pradesh-533003
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TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists. Cell Death Dis 2013; 4:e964. [PMID: 24336084 PMCID: PMC3877573 DOI: 10.1038/cddis.2013.506] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 11/11/2013] [Accepted: 11/13/2013] [Indexed: 01/06/2023]
Abstract
This article is addressed to endocrinologists treating patients with diabetic complications as well as to basic scientists studying an elusive link between diseases and aging. It answers some challenging questions. What is the link between insulin resistance (IR), cellular aging and diseases? Why complications such as retinopathy may paradoxically precede the onset of type II diabetes. Why intensive insulin therapy may initially worsen retinopathy. How nutrient- and insulin-sensing mammalian target of rapamycin (mTOR) pathway can drive insulin resistance and diabetic complications. And how rapamycin, at rational doses and schedules, may prevent IR, retinopathy, nephropathy and beta-cell failure, without causing side effects.
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Effects of Trigonella foenum-graecum (L.) on retinal oxidative stress, and proinflammatory and angiogenic molecular biomarkers in streptozotocin-induced diabetic rats. Mol Cell Biochem 2013; 388:1-9. [PMID: 24242137 DOI: 10.1007/s11010-013-1893-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 11/05/2013] [Indexed: 12/18/2022]
Abstract
The aim of the present study was to investigate the protective effects of Trigonella foenum-graecum Linn. (fenugreek) in Streptozotocin-induced diabetic rat retina. Fenugreek (100 and 200 mg/kg body weights) treatment was carried out for 24 weeks and evaluated for inflammatory [tumor necrosis factor (TNF)-α and interleukin (IL)-1β] and angiogenic [vascular endothelial growth factor (VEGF) and protein kinase C (PKC)-β] molecular biomarkers. Retinal oxidative stress was evaluated by estimating antioxidant (Glutathione, Superoxide dismutase, and Catalase) parameters. Fluorescein angiography was performed to detect retinal vascular leakage. Electron microscopy was performed to determine basement membrane thickness. In the present study, significant rises in the expressions of retinal inflammatory (TNF-α and IL-1β) and angiogenic (VEGF and PKC-β) molecular biomarkers were observed in diabetic retinae compared with normal retinae. However, fenugreek-treated retinae showed marked inhibition in the expression of inflammatory and angiogenic molecular biomarkers. Moreover, results from the present study showed positive modulatory effects of fenugreek on retinal oxidative stress. Fluorescein angiograms and fundus photographs obtained from diabetic retinae showed retinal vascular leakage. On the other hand, fenugreek-treated retinae did not show vascular leakage. Further, thickened BM was recorded in diabetic retina compared with normal retinae. However, fenugreek-treated retinae showed relatively lesser thickening of capillary BM. In conclusion, it may be postulated that fenugreek has great potential in preventing diabetes-induced retinal degeneration in humans after regular consumption in the specified dosage.
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Mysona BA, Al-Gayyar MMH, Matragoon S, Abdelsaid MA, El-Azab MF, Saragovi HU, El-Remessy AB. Modulation of p75(NTR) prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats. Diabetologia 2013; 56:2329-39. [PMID: 23918145 PMCID: PMC3791887 DOI: 10.1007/s00125-013-2998-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Accepted: 07/02/2013] [Indexed: 12/16/2022]
Abstract
AIMS/HYPOTHESIS Diabetic retinopathy is characterised by early blood-retina barrier (BRB) breakdown and neurodegeneration. Diabetes causes imbalance of nerve growth factor (NGF), leading to accumulation of the NGF precursor (proNGF), as well as the NGF receptor, p75 neurotrophin receptor (p75(NTR)), suggesting a possible pathological role of the proNGF-p75(NTR) axis in the diabetic retina. To date, the role of this axis in diabetes-induced retinal inflammation and BRB breakdown has not been explored. We hypothesised that modulating p75(NTR) would prevent diabetes- and proNGF-induced retinal inflammation and BRB breakdown. METHODS Diabetes was induced by streptozotocin in wild-type and p75(NTR) knockout (p75KO) mice. After 5 weeks, the expression of inflammatory mediators, ganglion cell loss and BRB breakdown were determined. Cleavage-resistant proNGF was overexpressed in rodent retinas with and without p75(NTR) short hairpin RNA or with pharmacological inhibitors. In vitro, the effects of proNGF were investigated in retinal Müller glial cell line (rMC-1) and primary Müller cells. RESULTS Deletion of p75(NTR) blunted the diabetes-induced decrease in retinal NGF expression and increases in proNGF, nuclear factor κB (NFκB), p-NFκB and TNF-α. Deletion of p75(NTR) also abrogated diabetes-induced glial fibrillary acidic protein expression, ganglion cell loss and vascular permeability. Inhibited expression or cleavage of p75(NTR) blunted proNGF-induced retinal inflammation and vascular permeability. In vitro, proNGF induced p75(NTR)-dependent production of inflammatory mediators in primary wild-type Müller and rMC-1 cultures, but not in p75KO Müller cells. CONCLUSIONS/INTERPRETATION The proNGF-p75(NTR) axis contributes to retinal inflammation and vascular dysfunction in the rodent diabetic retina. These findings underscore the importance of p75(NTR) as a novel regulator of inflammation and potential therapeutic target in diabetic retinopathy.
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Affiliation(s)
- Barbara A Mysona
- Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, 1120 15th Street HM-1200, Augusta, GA 30912, USA
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Platelet-derived growth factor/vascular endothelial growth factor receptor inactivation by sunitinib results in Tsc1/Tsc2-dependent inhibition of TORC1. Mol Cell Biol 2013; 33:3762-79. [PMID: 23878397 DOI: 10.1128/mcb.01570-12] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors are implicated in development and tumorigenesis and dual inhibitors like sunitinib are prescribed for cancer treatment. While mammalian VEGF and PDGF receptors are present in multiple isoforms and heterodimers, Drosophila encodes one ancestral PDGF/VEGF receptor, PVR. We identified PVR in an unbiased cell-based RNA interference (RNAi) screen of all Drosophila kinases and phosphatases for novel regulators of TORC1. PVR is essential to sustain target of rapamycin complex 1 (TORC1) and extracellular signal-regulated kinase (ERK) activity in cultured insect cells and for maximal stimulation by insulin. CG32406 (henceforth, PVRAP, for PVR adaptor protein), an Src homology 2 (SH2) domain-containing protein, binds PVR and is required for TORC1 activation. TORC1 activation by PVR involves Tsc1/Tsc2 and, in a cell-type-dependent manner, Lobe (ortholog of PRAS40). PVR is required for cell survival in vitro, and both PVR and TORC1 are necessary for hemocyte expansion in vivo. Constitutive PVR activation induces tumor-like structures that exhibit high TORC1 activity. Like its mammalian orthologs, PVR is inhibited by sunitinib, and sunitinib treatment phenocopies PVR loss in hemocytes. Sunitinib inhibits TORC1 in insect cells, and sunitinib-mediated TORC1 inhibition requires an intact Tsc1/Tsc2 complex. Sunitinib similarly inhibited TORC1 in human endothelial cells in a Tsc1/Tsc2-dependent manner. Our findings provide insight into the mechanism of action of PVR and may have implications for understanding sunitinib sensitivity and resistance in tumors.
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Hernandez D, Espejo-Gil A, Bernal-Lopez MR, Mancera-Romero J, Baca-Osorio AJ, Tinahones FJ, Armas-Padron AM, Ruiz-Esteban P, Torres A, Gomez-Huelgas R. Association of HbA1c and cardiovascular and renal disease in an adult Mediterranean population. BMC Nephrol 2013; 14:151. [PMID: 23865389 PMCID: PMC3720537 DOI: 10.1186/1471-2369-14-151] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 07/11/2013] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Increasing evidence suggests a mechanistic link between the glycemic environment and renal and cardiovascular events, even below the threshold for diabetes. We aimed to assess the association between HbA1c and chronic kidney disease (CKD) and cardiovascular disease (CVD). METHODS A cross-sectional study involving a random representative sample of 2270 adults from southern Spain (Malaga) was undertaken. We measured HbA1c, serum creatinine and albuminuria in fasting blood and urine samples. RESULTS Individuals without diabetes in the upper HbA1c tertile had an unfavorable cardiovascular and renal profile and shared certain clinical characteristics with the patients with diabetes. Overall, a higher HbA1c concentration was strongly associated with CKD or CVD after adjustment for traditional risk factors. The patients with known diabetes had a 2-fold higher odds of CKD or CVD. However, when both parameters were introduced in the same model, the HbA1c concentration was only significantly associated with clinical endpoints (OR: 1.4, 95% CI, 1.1-1.6, P = 0.002). An increase in HbA1c of one percentage point was associated with a 30% to 40% increase in the rate of CKD or CVD. This relationship was apparent in persons with and without known diabetes. ROC curves illustrated that a HbA1c of 37 mmol/mol (5.5%) was the optimal value in terms of sensitivity and specificity for predicting endpoints in this population. CONCLUSION HbA1c levels were associated with a higher prevalence of CKD and CVD cross-sectionally, regardless of diabetes status. These data support the value of HbA1c as a marker of cardiovascular and renal disease in the general population.
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Affiliation(s)
- Domingo Hernandez
- Nephrology Department, Hospital Regional Universitario Carlos Haya, Malaga, Spain
| | - Ana Espejo-Gil
- Internal Medicine Department, Hospital Regional Universitario Carlos Haya, Avenida Carlos Haya s/n, 29010 Malaga, Spain
| | - M Rosa Bernal-Lopez
- Biomedical Research Laboratory, Endocrinology Department, Hospital Virgen de la Victoria, Campus de Teatinos s/n., 29010 Malaga, Spain
- Ciber Fisiopatologia de la Obesidad y Nutricion, Instituto de Salud Carlos III, Madrid, Spain
| | | | | | - Francisco J Tinahones
- Ciber Fisiopatologia de la Obesidad y Nutricion, Instituto de Salud Carlos III, Madrid, Spain
- Endocrinology Department, Hospital Virgen de la Victoria, Malaga, Spain
| | | | - Pedro Ruiz-Esteban
- Nephrology Department, Hospital Regional Universitario Carlos Haya, Malaga, Spain
| | - Armando Torres
- Research Unit, Hospital Universitario de Canarias, Tenerife, Spain
| | - Ricardo Gomez-Huelgas
- Internal Medicine Department, Hospital Regional Universitario Carlos Haya, Avenida Carlos Haya s/n, 29010 Malaga, Spain
- Ciber Fisiopatologia de la Obesidad y Nutricion, Instituto de Salud Carlos III, Madrid, Spain
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Sugimoto M, Cutler A, Shen B, Moss SE, Iyengar SK, Klein R, Folkman J, Anand-Apte B. Inhibition of EGF signaling protects the diabetic retina from insulin-induced vascular leakage. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 183:987-95. [PMID: 23831329 DOI: 10.1016/j.ajpath.2013.05.017] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Revised: 05/02/2013] [Accepted: 05/14/2013] [Indexed: 02/03/2023]
Abstract
Diabetes mellitus is a disease with considerable morbidity and mortality worldwide. Breakdown of the blood-retinal barrier and leakage from the retinal vasculature leads to diabetic macular edema, an important cause of vision loss in patients with diabetes. Although epidemiologic studies and randomized clinical trials suggest that glycemic control plays a major role in the development of vascular complications of diabetes, insulin therapies for control of glucose metabolism cannot prevent long-term retinal complications. The phenomenon of temporary paradoxical worsening of diabetic macular edema after insulin treatment has been observed in a number of studies. In prospective studies on non-insulin-dependent (type 2) diabetes mellitus patients, a change in treatment from oral drugs to insulin was often associated with a significant increased risk of retinopathy progression and visual impairment. Although insulin therapies are critical for regulation of the metabolic disease, their role in the retina is controversial. In this study with diabetic mice, insulin treatment resulted in increased vascular leakage apparently mediated by betacellulin and signaling via the epidermal growth factor (EGF) receptor. In addition, treatment with EGF receptor inhibitors reduced retinal vascular leakage in diabetic mice on insulin. These findings provide unique insight into the role of insulin signaling in mediating retinal effects in diabetes and open new avenues for therapeutics to treat the retinal complications of diabetes mellitus.
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Affiliation(s)
- Masahiko Sugimoto
- Department of Ophthalmology, Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA
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Hale LJ, Hurcombe J, Lay A, Santamaría B, Valverde AM, Saleem MA, Mathieson PW, Welsh GI, Coward RJ. Insulin directly stimulates VEGF-A production in the glomerular podocyte. Am J Physiol Renal Physiol 2013; 305:F182-8. [PMID: 23698113 DOI: 10.1152/ajprenal.00548.2012] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Podocytes are critically important for maintaining the integrity of the glomerular filtration barrier and preventing albuminuria. Recently, it has become clear that to achieve this, they need to be insulin sensitive and produce an optimal amount of VEGF-A. In other tissues, insulin has been shown to regulate VEGF-A release, but this has not been previously examined in the podocyte. Using in vitro and in vivo approaches, in the present study, we now show that insulin regulates VEGF-A in the podocyte in both mice and humans via the insulin receptor (IR). Insulin directly increased VEGF-A mRNA levels and protein production in conditionally immortalized wild-type human and murine podocytes. Furthermore, when podocytes were rendered insulin resistant in vitro (using stable short hairpin RNA knockdown of the IR) or in vivo (using transgenic podocyte-specific IR knockout mice), podocyte VEGF-A production was impaired. Importantly, in vivo, this occurs before the development of any podocyte damage due to podocyte insulin resistance. Modulation of VEGF-A by insulin in the podocyte may be another important factor in the development of glomerular disease associated with conditions in which insulin signaling to the podocyte is deranged.
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Affiliation(s)
- L J Hale
- Academic and Children's Renal Unit, University of Bristol, Learning and Research building, Southmead Hospital, Bristol, United Kingdom
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Laroche S, Wucher H, Nguyen YL, Timsit J, Larger E. Case report: insulin edema and acute renal failure. Diabetes Care 2013; 36:e65. [PMID: 23613606 PMCID: PMC3631854 DOI: 10.2337/dc12-2137] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Suzanne Laroche
- Service de diabétologie, Hôtel Dieu, Assistance Publique-Hopitaux de Paris, Université Paris Descartes, Paris, France
| | - Hélène Wucher
- Service de diabétologie, Hôtel Dieu, Assistance Publique-Hopitaux de Paris, Université Paris Descartes, Paris, France
| | - Yên-Lan Nguyen
- Réanimation médicale, Hôpital Cochin, Assistance Publique-Hopitaux de Paris, Université Paris Descartes, Paris, France
| | - José Timsit
- Service de diabétologie, Hôtel Dieu, Assistance Publique-Hopitaux de Paris, Université Paris Descartes, Paris, France
| | - Etienne Larger
- Service de diabétologie, Hôtel Dieu, Assistance Publique-Hopitaux de Paris, Université Paris Descartes, Paris, France
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45
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Vitreous mediators in retinal hypoxic diseases. Mediators Inflamm 2013; 2013:935301. [PMID: 23365490 PMCID: PMC3556845 DOI: 10.1155/2013/935301] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2012] [Revised: 10/19/2012] [Accepted: 12/01/2012] [Indexed: 12/31/2022] Open
Abstract
The causes of retinal hypoxia are many and varied. Under hypoxic conditions, a variety of soluble factors are secreted into the vitreous cavity including growth factors, cytokines, and chemokines. Cytokines, which usually serve as signals between neighboring cells, are involved in essentially every important biological process, including cell proliferation, inflammation, immunity, migration, fibrosis, tissue repair, and angiogenesis. Cytokines and chemokines are multifunctional mediators that can direct the recruitment of leukocytes to sites of inflammation, promote the process, enhance immune responses, and promote stem cell survival, development, and homeostasis. The modern particle-based flow cytometric analysis is more direct, stable and sensitive than the colorimetric readout of the conventional ELISA but, similar to ELISA, is influenced by vitreous hemorrhage, disruption of the blood-retina barrier, and high serum levels of a specific protein. Finding patterns in the expression of inflammatory cytokines specific to a particular disease can substantially contribute to the understanding of its basic mechanism and to the development of a targeted therapy.
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Bharadwaj AS, Appukuttan B, Wilmarth PA, Pan Y, Stempel AJ, Chipps TJ, Benedetti EE, Zamora DO, Choi D, David LL, Smith JR. Role of the retinal vascular endothelial cell in ocular disease. Prog Retin Eye Res 2013; 32:102-80. [PMID: 22982179 PMCID: PMC3679193 DOI: 10.1016/j.preteyeres.2012.08.004] [Citation(s) in RCA: 129] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2012] [Revised: 08/23/2012] [Accepted: 08/24/2012] [Indexed: 12/14/2022]
Abstract
Retinal endothelial cells line the arborizing microvasculature that supplies and drains the neural retina. The anatomical and physiological characteristics of these endothelial cells are consistent with nutritional requirements and protection of a tissue critical to vision. On the one hand, the endothelium must ensure the supply of oxygen and other nutrients to the metabolically active retina, and allow access to circulating cells that maintain the vasculature or survey the retina for the presence of potential pathogens. On the other hand, the endothelium contributes to the blood-retinal barrier that protects the retina by excluding circulating molecular toxins, microorganisms, and pro-inflammatory leukocytes. Features required to fulfill these functions may also predispose to disease processes, such as retinal vascular leakage and neovascularization, and trafficking of microbes and inflammatory cells. Thus, the retinal endothelial cell is a key participant in retinal ischemic vasculopathies that include diabetic retinopathy and retinopathy of prematurity, and retinal inflammation or infection, as occurs in posterior uveitis. Using gene expression and proteomic profiling, it has been possible to explore the molecular phenotype of the human retinal endothelial cell and contribute to understanding of the pathogenesis of these diseases. In addition to providing support for the involvement of well-characterized endothelial molecules, profiling has the power to identify new players in retinal pathologies. Findings may have implications for the design of new biological therapies. Additional progress in this field is anticipated as other technologies, including epigenetic profiling methods, whole transcriptome shotgun sequencing, and metabolomics, are used to study the human retinal endothelial cell.
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Affiliation(s)
| | | | - Phillip A. Wilmarth
- Department of Biochemistry and Molecular Biology, Oregon Health & Science University
| | - Yuzhen Pan
- Casey Eye Institute, Oregon Health & Science University
| | | | | | | | | | - Dongseok Choi
- Department of Public Health and Preventive Medicine, Oregon Health & Science University
| | - Larry L. David
- Department of Biochemistry and Molecular Biology, Oregon Health & Science University
| | - Justine R. Smith
- Casey Eye Institute, Oregon Health & Science University
- Department of Cell & Developmental Biology, Oregon Health & Science University
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Meng D, Mei A, Liu J, Kang X, Shi X, Qian R, Chen S. NADPH oxidase 4 mediates insulin-stimulated HIF-1α and VEGF expression, and angiogenesis in vitro. PLoS One 2012; 7:e48393. [PMID: 23144758 PMCID: PMC3483150 DOI: 10.1371/journal.pone.0048393] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Accepted: 09/25/2012] [Indexed: 11/24/2022] Open
Abstract
Acute intensive insulin therapy causes a transient worsening of diabetic retinopathy in type 1 diabetes patients and is related to VEGF expression. Reactive oxygen species (ROS) have been shown to be involved in HIF-1α and VEGF expression induced by insulin, but the role of specific ROS sources has not been fully elucidated. In this study we examined the role of NADPH oxidase subunit 4 (Nox4) in insulin-stimulated HIF-1α and VEGF expression, and angiogenic responses in human microvascular endothelial cells (HMVECs). Here we demonstrate that knockdown of Nox4 by siRNA reduced insulin-stimulated ROS generation, the tyrosine phosphorylation of IR-β and IRS-1, but did not change the serine phosphorylation of IRS-1. Nox4 gene silencing had a much greater inhibitory effect on insulin-induced AKT activation than ERK1/2 activation, whereas it had little effect on the expression of the phosphatases such as MKP-1 and SHIP. Inhibition of Nox4 expression inhibited the transcriptional activity of VEGF through HIF-1. Overexpression of wild-type Nox4 was sufficient to increase VEGF transcriptional activity, and further enhanced insulin-stimulated the activation of VEGF. Downregulation of Nox4 expression decreased insulin-stimulated mRNA and protein expression of HIF-1α, but did not change the rate of HIF-1α degradation. Inhibition of Nox4 impaired insulin-stimulated VEGF expression, cell migration, cell proliferation, and tube formation in HMVECs. Our data indicate that Nox4-derived ROS are essential for HIF-1α-dependent VEGF expression, and angiogenesis in vitro induced by insulin. Nox4 may be an attractive therapeutic target for diabetic retinopathy caused by intensive insulin treatment.
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Affiliation(s)
- Dan Meng
- Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College, Shanghai, China.
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Xue M, Ge Y, Zhang J, Wang Q, Hou L, Liu Y, Sun L, Li Q. Anticancer properties and mechanisms of fucoidan on mouse breast cancer in vitro and in vivo. PLoS One 2012; 7:e43483. [PMID: 22916270 PMCID: PMC3423341 DOI: 10.1371/journal.pone.0043483] [Citation(s) in RCA: 138] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Accepted: 07/20/2012] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Fucoidan is a sulfated polysaccharide derived from brown algae that has been reported to perform multiple biological activities, including antitumor activity. In this study, we examined the influence of crude fucoidan on mouse breast cancer in vitro and in vivo. MATERIALS AND METHODS In vitro, fluorescent staining, flow cytometry and Western blot were performed to analyze apoptosis and vascular endothelial growth factor (VEGF) expression of mouse breast cancer 4T1 cells. In vivo, therapy experiments were conducted on Babl/c mice bearing breast cancer. The tumor volume and weight were measured. The number of apoptotic cells and microvascular density (MVD) in tumor tissues were assessed by TUNEL and CD34 immunostaining. Immunohistochemical assays and ELISA assay were used to detect the expression of VEGF in tissues. RESULTS In vitro studies showed that crude fucoidan significantly decreased the viable number of 4T1 cells, induced apoptosis and down-regulated the expression of VEGF. The expression of Bcl-2 was decreased, and the ratio of Bcl-2 to Bax was significantly decreased. The expression of Survivin and phosphorylated extracellular signal regulated protein kinases (ERKs) was decreased. Cytochrome C was released from mitochondria into cytosol, and the cleaved Caspase-3 protein rose after fucoidan treatment. Intraperitoneal injection of fucoidan in breast cancer models reduced the tumor volume and weight. The enhanced antitumor efficacy was associated with decreased angiogenesis and increased induction of apoptosis. CONCLUSION These findings indicated that crude fucoidan inhibited mouse breast cancer growth in vitro and in vivo. These data suggest that fucoidan may serve as a potential therapeutic agent for breast cancer.
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Affiliation(s)
- Meilan Xue
- Department of Biochemistry and Molecular Biology, Medical College, Qingdao University, Qingdao, China
| | - Yinlin Ge
- Department of Biochemistry and Molecular Biology, Medical College, Qingdao University, Qingdao, China
- * E-mail:
| | - Jinyu Zhang
- Department of Biochemistry and Molecular Biology, Medical College, Qingdao University, Qingdao, China
| | - Qing Wang
- Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lin Hou
- Department of Biochemistry and Molecular Biology, Medical College, Qingdao University, Qingdao, China
| | - Yongchao Liu
- Department of Biochemistry and Molecular Biology, Medical College, Qingdao University, Qingdao, China
| | - Lingling Sun
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Quan Li
- Department of Biochemistry and Molecular Biology, Medical College, Qingdao University, Qingdao, China
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Al-Shabrawey M, Ahmad S, Megyerdi S, Othman A, Baban B, Palenski TL, Shin ES, Gurel Z, Hsu S, Sheibani N. Caspase-14: a novel caspase in the retina with a potential role in diabetic retinopathy. Mol Vis 2012; 18:1895-906. [PMID: 22876114 PMCID: PMC3413417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2011] [Accepted: 07/11/2012] [Indexed: 10/27/2022] Open
Abstract
PURPOSE The purpose of this study was to evaluate caspase-14 expression in the retina under normal and diabetic conditions, and to determine whether caspase-14 contributes to retinal microvascular cell death under high glucose conditions. METHODS Quantitative real-time polymerase chain reaction and western blot analysis were used to evaluate caspase-14 expression in retinal cells, including pericytes (PCs), endothelial cells (ECs), astrocytes (ACs), choroidal ECs, and retinal pigment epithelium (RPE) cells. We also determined caspase-14 expression in the retinas of human subjects with or without diabetic retinopathy (DR) and in experimental diabetic mice. Retinal ECs and PCs were infected with adenoviruses expressing human caspase-14 or green fluorescent protein. Caspase-14 expression was also assessed in retinal vascular cells cultured under high glucose conditions. The number of apoptotic cells was determined with terminal deoxynucleotidyl transferase dUTP nick end labeling staining and confirmed by determining the levels of cleaved poly (ADP-ribose) polymerase-1 and caspase-3. RESULTS Our experiments demonstrated that retinal ECs, PCs, ACs, choroidal ECs, and RPE cells expressed caspase-14, and DR was associated with upregulation and/or activation of caspase-14 particularly in retinal vasculature. High glucose induced marked elevation of the caspase-14 level in retinal vascular cells. There was a significant increase in the apoptosis rate and the levels of cleaved poly (ADP-ribose) polymerase-1 and caspase-3 in retinal ECs and PCs overexpressing caspase-14. CONCLUSIONS Our findings indicate that caspase-14 might play a significant role in the pathogenesis of DR by accelerating retinal PC and EC death. Further investigations are required to elaborate the underlying mechanisms.
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Affiliation(s)
- Mohamed Al-Shabrawey
- Department of Oral Biology and Anatomy, Georgia Health Sciences University (GHSU), College of Dental Medicine, Augusta, GA,Ophthalmology and Vision Discovery Institute, GHSU, Medical College of Georgia, Augusta, GA,Department of Anatomy, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - Saif Ahmad
- Ophthalmology and Vision Discovery Institute, GHSU, Medical College of Georgia, Augusta, GA
| | - Sylvia Megyerdi
- Department of Oral Biology and Anatomy, Georgia Health Sciences University (GHSU), College of Dental Medicine, Augusta, GA
| | - Amira Othman
- Department of Oral Biology and Anatomy, Georgia Health Sciences University (GHSU), College of Dental Medicine, Augusta, GA,Department of Anatomy, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - Babak Baban
- Department of Oral Biology and Anatomy, Georgia Health Sciences University (GHSU), College of Dental Medicine, Augusta, GA
| | - Tammy L. Palenski
- Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Eui Seok Shin
- Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Zafer Gurel
- Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Stephen Hsu
- Department of Oral Biology and Anatomy, Georgia Health Sciences University (GHSU), College of Dental Medicine, Augusta, GA
| | - Nader Sheibani
- Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI
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Supplementation with antioxidants attenuates transient worsening of retinopathy in diabetes caused by acute intensive insulin therapy. Graefes Arch Clin Exp Ophthalmol 2012; 250:1453-8. [PMID: 22695936 DOI: 10.1007/s00417-012-2079-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Revised: 04/25/2012] [Accepted: 05/28/2012] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND To investigate whether insulin can increase the production of reactive oxygen species (ROS) in bovine retinal microvascular endothelial cells (BRECs), the role of antioxidants in the insulin-induced exacerbation of diabetic retinopathy and the related mechanisms. METHODS BRECs were cultured in either 5 or 30 mM glucose for 3 days before stimulation with 100 nM insulin for 24 h or incubated with 1 mM apocynin, 100 μM LY294002, 50 μM U0126, 2 μM GF109203X, 250 U/ml catalase, 100 μg/ml ascorbic acid, 100 μM α-lipoic acid and 50 μM α-tocopherol before stimulation with 100 nM insulin. H(2)O(2) (200 μM) was added to cells to measure the VEGF protein expression. Intracellular ROS was measured by immunofluorescence and flow cytometry, superoxide anion measurement was done by cytochrome c reduction, and VEGF protein was measured by ELISA analysis. RESULTS Insulin or (and) high glucose significantly increased intracellular ROS production in BRECs, and pretreatment of the cells with apocynin and LY294002 decreased insulin-induced superoxide anion production. Neither pretreatment with GF109203X nor U0126 showed an effect on the superoxide anion production. Ascorbic acid, α-lipoic acid, and α-tocopherol also decreased superoxide anion production. Furthermore, H(2)O(2) increased VEGF protein expression in BRECs and catalase suppressed insulin-induced VEGF protein expression. CONCLUSIONS Insulin can increase ROS production through an NAD(P)H, phosphatidylinositol 3´-kinase-dependent mechanism in bovine retinal microvascular endothelial cells ex vivo. ROS can regulate insulin-induced VEGF expression. Supplementation with antioxidants may help to attenuate the transient worsening of retinopathy in diabetes caused by acute intensive insulin therapy.
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