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Atikah A, Suzana M, Wan Haslina WAH, Norshamsiah MD, Mushawiahti M, Birinder KSS, Tang SF, Bastion MLC. Randomised controlled trial on effects of topical insulin compared to artificial tears and normal saline on tear inflammatory mediator levels and clinical parameters in diabetics with dry eye disease. Cont Lens Anterior Eye 2025; 48:102346. [PMID: 39676005 DOI: 10.1016/j.clae.2024.102346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 11/25/2024] [Accepted: 11/28/2024] [Indexed: 12/17/2024]
Abstract
PURPOSE To assess the short-term effects of topical insulin (TI) as compared to topical Systane UltraTM (Alcon, USA) as artificial tears (AT) and topical normal saline (NS) on tear inflammatory mediators; interleukin 1-alpha (IL-1a), interleukin 6 (IL-6) and matrix metalloproteinase 9 (MMP-9) and clinical dry eye parameters in diabetics with dry eye disease (DDED). METHODS In this randomized, multi-arm parallel single-centre trial, 73 diabetics with dry eye disease (30 female and 43 male) aged 18 to 50 years were recruited. They were randomly assigned to four weeks of treatment of either TI 0.5 unit/drop, AT or NS four times per day. Tear sample analysis and clinical parameters of dry eye (Ocular Surface Disease Index (OSDI), tear break-up time (TBUT), corneal Oxford score and Schirmers test) were evaluated at baseline and four weeks later. Objective clinical parameters for corneal Oxford score and tear break-up time were assessed by two masked investigators. RESULTS Significant reduction was seen in all inflammatory biomarkers (IL-1a, IL-6 and MMP-9) in all treatment groups at 4 weeks. In addition, inflammatory biomarkers demonstrated a significant reduction with TI (p < 0.001). Meanwhile, in AT and NS groups, reduction was also significant but less than TI group. Similarly, significant improvements were seen in all clinical parameters evaluated with all 3 treatments at 4 weeks; with TI group showing largest improvement as compared to AT and NS groups (p < 0.001). This is supported with the results as follows: mean difference -20.90 for OSDI as compared to -11.38 and -6.78 for AT and NS groups, respectively, 5.55 s for TBUT as compared to 3.00 s and 1.00 s for AT and NS group respectively, -2.40 for Oxford score as compared to -0.38 and -1.39 for AT and NS group respectively, and 5.20 mm for Schirmers test as compared to 3.00 mm and 1.00 mm for AT and NS group respectively. CONCLUSION Treatment with TI resulted in the greatest reduction in inflammatory biomarkers and ocular eye parameters, as compared to AT and NS. TI was most effective in improving clinical parameters of DDED, although all topical therapies showed significant improvements, suggesting that use of TI may be beneficial in treating DDED.
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Affiliation(s)
- A Atikah
- Department of Ophthalmology, UKM Medical Centre, 56000 Kuala Lumpur, Malaysia.
| | - M Suzana
- Department of Biochemistry, UKM Medical Centre, 56000 Kuala Lumpur, Malaysia.
| | - W A H Wan Haslina
- Department of Ophthalmology, UKM Medical Centre, 56000 Kuala Lumpur, Malaysia.
| | - M D Norshamsiah
- Department of Ophthalmology, UKM Medical Centre, 56000 Kuala Lumpur, Malaysia.
| | - M Mushawiahti
- Department of Ophthalmology, UKM Medical Centre, 56000 Kuala Lumpur, Malaysia.
| | - K S S Birinder
- Department of Pharmacy, UKM Medical Centre, 56000 Kuala Lumpur, Malaysia.
| | - S F Tang
- Department of Ophthalmology, UKM Medical Centre, 56000 Kuala Lumpur, Malaysia.
| | - M L C Bastion
- Department of Ophthalmology, UKM Medical Centre, 56000 Kuala Lumpur, Malaysia.
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Karabay Kılıçarslan S, Tortumlu G, Asena L, İncekaş C, Helvacıoğlu F, Altınörs DD. Topical Insulin Treatment Efficacy in Rat Corneal Epithelial Wound Healing Model and Comparison of Efficacy with Topical Hyaluronate Treatment. Exp Eye Res 2025:110359. [PMID: 40147684 DOI: 10.1016/j.exer.2025.110359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 01/07/2025] [Accepted: 03/23/2025] [Indexed: 03/29/2025]
Abstract
This study aimed to examine the effect of topical insulin on healing of the corneal epithelium in a rat corneal epithelial defect model, comparing it to artificial tears and non-treated controls. 28 adult male Sprague Dawley rats were divided into 4 groups in this study. A 2 mm diameter epithelial defect was created at the central cornea of one eye under sedation. Group A had untreated epithelial defects, Group B received 0.15% sodium hyaluronate qid, and Group C received topical 1IU/ml insulin qid. The last group was healthy controls. Biomicroscopic examinations were performed at the 4th hour, 12th hour, 1st day, 2nd day, and 3rd day0. The defect size of epithelium was photographed during each examination using fluorescein staining. The area of the defect was calculated using the ImageJ software to determine the percentage of defect closure. On the 10th day, corneal tissues were excised for histopathological examination, after sacrification. Topical insulin and sodium hyaluronate treatment groups showed faster healing rate of corneal epithelial defect closure biomicroscopically compared to the untreated group. However, there was no statistically significant difference in the rate of epithelial defect closure between topical insulin and sodium hyaluronate groups. Histopathologically, topical insulin group showed superior epithelial remodeling at the fine structural level. Although no biomicroscopic difference was observed in corneal epithelial healing with topical insulin treatment compared to sodium hyaluronate, it has been demonstrated to be more effective histopathologically.
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Affiliation(s)
| | - Gökhan Tortumlu
- Baskent University Faculty of Medicine, Department of Ophthalmology, Ankara, Turkey
| | - Leyla Asena
- Baskent University Faculty of Medicine, Department of Ophthalmology, Ankara, Turkey
| | - Caner İncekaş
- Baskent University Faculty of Medicine, Department of Biostatistics, Ankara, Turkey
| | - Fatma Helvacıoğlu
- Baskent University Faculty of Medicine, Department of Histology and Embryology, Ankara, Turkey
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Bastion MLC, Wan Abdul Halim WH, Mohd Said M, Sadu Singh BK, Abdul Ghani A. Topical Insulin in Artificial Tears Stability Study: Short-term Physical, Chemical and Microbiological Stability Study of 0.5 Units (25 IU/mL) of Topical Insulin in Artificial Tears. Eye Contact Lens 2025:00140068-990000000-00274. [PMID: 40036826 DOI: 10.1097/icl.0000000000001175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/24/2024] [Indexed: 03/06/2025]
Abstract
OBJECTIVES Topical insulin (TI) at 25 IU/mL effectively normalizes healing of corneal epithelium and dry eye in diabetic patients. We aim to determine physicochemical stability and sterility of TI in sodium hyaluronate 0.18% (TI-artificial tears [AT]) in an eye drop formulation. METHODS The physicochemical stability of TI-AT at 5°C±3°C and 30°C±2°C in sterile low-density polyethylene bottles was studied. Samples were put in conditions of simulated use and analyzed weekly for stability parameters (visual inspection, turbidity, ultraviolet spectral absorption, osmolality, and pH) and culture growth. Insulin was quantified using the stability-indicating high-performance liquid chromatographic method with diode-array detection with RP-C18 column, o-nitrophenol as an internal standard, and ultraviolet detection at 214 nm. Stability was set according to British Pharmacopoeia with 90% to 110% of initial concentration (with 95% confidence interval) considered acceptable. RESULTS All tested physicochemical and sterility parameters remained stable for 1 month in both temperature conditions with stable TI concentrations. CONCLUSION Topical insulin-artificial tears is stable in both room temperature and refrigeration. Topical insulin-artificial tears can be prescribed with a 1-month shelf life.
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Affiliation(s)
- Mae-Lynn Catherine Bastion
- Department of Ophthalmology (M.-L.C.B., W.H.W.A.H.), Faculty of Medicine, Universiti Kebangsaan Malaysia; Hospital Canselor Tuanku Muhriz (M.-L.C.B., W.H.W.A.H.), Universiti Kebangsaan Malaysia Medical Centre (UKMMC); Faculty of Pharmacy (M.M.S., A.A.G.), Universiti Kebangsaan Malaysia Kuala Lumpur Campus (UKMKL), Kuala Lumpur, Malaysia; Department of Pharmacy (B.K.S.S.), Hospital Canselor Tuanku Muhriz, Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Kuala Lumpur, Malaysia; and School of Optometry (W.H.W.A.H.), Faculty of Medicine and Health Sciences, UCSI University, Kuala Lumpur, Malaysia
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Ziafati M, Mirshahi R, Cicinelli MV, Nazari R. Persistent Corneal Epithelial Defect Following Pars Plana Vitrectomy: A Narrative Review. Semin Ophthalmol 2025:1-13. [PMID: 39989218 DOI: 10.1080/08820538.2025.2470253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 02/12/2025] [Accepted: 02/17/2025] [Indexed: 02/25/2025]
Abstract
PURPOSE Persistent corneal epithelial defects (PCEDs) following pars plana vitrectomy (PPV) represent a significant clinical challenge, potentially leading to corneal scarring, vision loss, and other severe complications. This review aims to summarize the prevalence, associated risk factors, and management strategies for PCEDs in the context of PPV, providing evidence-based guidance for clinicians. METHODS A comprehensive systematic review was conducted using PubMed and Embase databases, identifying English-language studies addressing PCEDs after PPV. RESULTS The prevalence of PCEDs post-PPV varied widely, from 0% to 78.37%, influenced by intrinsic factors such as diabetes mellitus, which impairs corneal nerve function and healing, and extrinsic factors like intraoperative tamponade with C3F8. Management strategies ranged from conservative options like bandage contact lenses to advanced treatments like topical insulin. CONCLUSION PCEDs after PPV are multifactorial and demand individualized management. Advanced therapies, particularly serum-based treatments, and topical insulin, show promising outcomes. Further prospective research is warranted to refine these treatments.
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Affiliation(s)
- Makan Ziafati
- The Five Senses Institute, Rassoul Akram Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Mirshahi
- The Five Senses Institute, Rassoul Akram Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maria Vittoria Cicinelli
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
- Department of Ophthalmology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Rezvaneh Nazari
- The Five Senses Institute, Rassoul Akram Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Kurt B, Özaydin İ, Balyen L, Vural SA, Aydin U, Özöner Ö. Effects of topical neutral protamine Hagedorn insulin on corneal wound healing: an experimental study in rabbits. Biotech Histochem 2025; 100:63-71. [PMID: 39840941 DOI: 10.1080/10520295.2025.2454399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2025] Open
Abstract
Corneal injuries are common in human and veterinary ophthalmology. There are many studies which have investigated the treatment of corneal epithelial defects. This study aimed to investigate the effects of Neutral Protamine Hagedorn (NPH) insulin as an ointment for wound healing in experimental corneal defects. First, a superficial keratectomy was performed on 12 rabbits using a corneal trephine. The animals were divided into two groups, Group I (treated, n = 6) and Group II (vehicle control, n = 6). Insulin ointment was applied topically once daily in the treated group, and saline ointment was applied in the same manner in the vehicle control group. Corneal defects were observed and photographed, and changes in wound surface were recorded on days 7, 14, 21, 30, and 60. In both groups, a significant reduction in the wound surface area was noticeable on the 30th day after defect creation. Between the 30th and 60th days, while the changes in the wound surface area in Group II remained limited, the decrease continued rapidly in Group I. At the end of the study, the corneal opacity score observed was lower in Group I than in Group II. In conclusion, we determined that topical NPH insulin may accelerate corneal wound healing after superficial lamellar keratectomy. A new alternative treatment may be developed for treating corneal wounds through continuing studies on this subject.
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Affiliation(s)
- Başak Kurt
- Faculty of Veterinary Medicine, Department of Surgery, Kafkas University, Kars, Turkiye
| | - İsa Özaydin
- Faculty of Veterinary Medicine, Department of Surgery, Kafkas University, Kars, Turkiye
| | - Lokman Balyen
- Faculty of Medicine, Department of Ophthalmology, Harran University, Sanliurfa, Turkiye
| | - Sevil Atalay Vural
- Faculty of Veterinary Medicine, Department of Pathology, Ankara University, Ankara, Turkiye
| | - Uğur Aydin
- Faculty of Veterinary Medicine, Department of Surgery, Kafkas University, Kars, Turkiye
| | - Özgür Özöner
- Faculty of Veterinary Medicine, Department of Pathology, Siirt University, Siirt, Turkiye
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Mester A, Gabriel M, Boldin I, Aminfar H, Woltsche N, Heidinger A, Guttmann A, Wintersteller P, Horwath-Winter J. The Performance of Topical Insulin in Persistent Corneal Epithelial Defects and Persistent Corneal Ulcers - A Case Series. Curr Eye Res 2025:1-4. [PMID: 39862213 DOI: 10.1080/02713683.2025.2456784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 01/14/2025] [Indexed: 01/27/2025]
Abstract
PURPOSE To retrospectively describe the performance of topical insulin in persistent corneal epithelial defects (CED) and persistent corneal ulcers. METHODS We reviewed cases of patients treated for persistent CED and persistent corneal ulcers using topical insulin in a concentration of 25 IU per milliliter three times per day. The closure rate of CED and corneal ulcers was the main outcome measure. RESULTS Thirty-seven episodes of 29 patients treated with topical insulin were reviewed. There was a wide range of additionally used medication, underlying pathologies as well as ocular and systemic comorbidities in our cohort. On average, insulin drops were started after 36 days of conventional therapy (SD 59, range 0-193) and were used for 42 days (SD 38, range 3-130). Therapy success was achieved in 15 of 28 (53.5%) cases with CED and in 4 of 9 (44%) cases with corneal ulcers. While insulin generally showed a good safety profile, one patient reported intolerable discomfort related to the use of topical insulin. CONCLUSION Topical insulin may be considered as a treatment option in complicated cases refractory to conventional treatment, but outcomes may be less favorable than previously reported.
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Affiliation(s)
- Amalia Mester
- Department of Ophthalmology, LKH Hochsteiermark, Bruck an der Mur, Austria
| | | | - Ingrid Boldin
- Department of Ophthalmology, Medical University of Graz, Graz, Austria
| | - Haleh Aminfar
- Department of Ophthalmology, Medical University of Graz, Graz, Austria
| | - Nora Woltsche
- Department of Ophthalmology, Medical University of Graz, Graz, Austria
| | - Astrid Heidinger
- Department of Ophthalmology, Medical University of Graz, Graz, Austria
| | - Andreas Guttmann
- Department of Ophthalmology, Medical University of Graz, Graz, Austria
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Scarinci F, De Simone G, Ciancimino C, Caggiano C, Pocobelli G, Di Masi A. Enhancing Corneal Sensitivity in Diabetic Patients Through an Innovative Ophthalmic Solution: In Vivo and Vitro Results. J Clin Med 2025; 14:245. [PMID: 39797325 PMCID: PMC11721187 DOI: 10.3390/jcm14010245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 12/25/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
Background/Objectives: Diabetes is a well-recognised factor inducing a plethora of corneal alterations ranging from dry eye to reduced corneal sensibility, epithelial defects, and reduced cicatrisation. This cohort study aimed to assess the efficacy of a novel ophthalmic solution combining cross-linked hyaluronic acid (CHA), chondroitin sulfate (CS), and inositol (INS) in managing diabetes-induced corneal alterations. Specifically, it evaluated the solution's impact on the tear breakup time (TBUT), the ocular surface disease index (OSDI), and corneal sensitivity after three months of treatment. Additionally, the solution's potential to promote wound healing was examined. Methods: Two different populations were retrieved from the database; the first one was composed of 20 diabetic subjects treated for three months with the ophthalmic CAH-CS (OPHTAGON srl, Rome, Italy), while the second group was composed of 20 diabetic subjects who did not want to use any eye lubricant or other treatment. The outcome measures were the TBUT, the OSDI score, and the corneal sensitivity measured using a Cochet-Bonnet aesthesiometer. To investigate the wound-healing properties, in vitro tests were conducted using two cell lines, comparing the results of scratch tests with and without the solution. Results: The results indicate that CHA-CS significantly improved the tear film stability, as evidenced by an increased TBUT and a reduction in dry eye symptoms reflected by lower OSDI scores. Moreover, the solution was associated with an enhanced corneal sensitivity in treated patients. In wound-healing assays, CHA-CS promoted cell motility, suggesting a supportive role in tissue repair compared to untreated cells. Conclusions: Collectively, the results suggest that CHA-CS could serve as an innovative tool for the treatment of diabetic patients with corneal alterations and delayed corneal sensitivity. Clinical trial registration number: Clinical Trial.gov NCT06573606.
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Affiliation(s)
- Fabio Scarinci
- Ophthalmology, San Giovanni-Addolorata Hospital, Via Santo Stefano Rotondo, 6, 00184 Rome, Italy
| | - Giovanna De Simone
- Department of Sciences, Section of Biomedical Sciences and Technologies, Roma Tre University, Viale Marconi 446, 00146 Rome, Italy
| | - Chiara Ciancimino
- Ophthalmology Unit, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), St. Andrea Hospital, “Sapienza” University of Rome, Via di Grottarossa 1035/1039, 00189 Rome, Italy
| | | | - Giulio Pocobelli
- Department of Microbiology, Immunology, Infectious Diseases, and Transplants (MIMIT), University of Rome Tor Vergata, 00133 Rome, Italy
| | - Alessandra Di Masi
- Department of Sciences, Section of Biomedical Sciences and Technologies, Roma Tre University, Viale Marconi 446, 00146 Rome, Italy
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Issac L, Dolev D, Irit B, Assaf D, Levy I. Assessment of insulin-degrading enzyme inhibitor for the treatment of corneal erosion in a rat model. Graefes Arch Clin Exp Ophthalmol 2024:10.1007/s00417-024-06717-1. [PMID: 39714747 DOI: 10.1007/s00417-024-06717-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 12/07/2024] [Accepted: 12/12/2024] [Indexed: 12/24/2024] Open
Abstract
BACKGROUND Diabetes poses a risk to diabetic keratopathy in up to two-thirds of patients. Insulin-degrading enzyme (IDE) is a protease that can break down insulin and several growth factors and may impair wound healing. Increased IDE levels have been found in fluid from diabetic skin ulcers. This study sought to determine the effect of IDE inhibitor on corneal wound healing in a rat model. METHODS Thirty-four male Wistar rats were divided into two groups: no diabetes and streptozocin-induced diabetes. Six weeks later, a 4-mm central corneal erosion was created under anesthesia in the right eye of all rats. In each group, half the rats were treated with ADT21 drops (IDE inhibitor) and half with NaCl 0.9% (sham) drops, four times daily. Image J analysis was performed to evaluate the area of erosion and healing rate. RESULTS There was a trend for more rapid healing in rats treated with IDEI than NaCl drops, regardless of the diabetic condition. Comparison of erosion closure over time revealed that the wounds closed significantly more quickly in the non-diabetic rats treated with IDEI than in the non-diabetic rats treated with NaCl (p = 0.045), overall mean closure time 56.00 h, 95% CI [50.54, 61.46]. No such difference was seen in the diabetic group. CONCLUSIONS To our knowledge, this is the first study to test ADT21 drops as a novel treatment for corneal wound repair. Our results suggest a potential benefit of IDE inhibitor for treating corneal injury.
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Affiliation(s)
- Levy Issac
- Department of Ophthalmology and Laboratory of Eye Research, Rabin Medical Center - Beilinson Hospital, Felsenstein Medical Research Center , 39 Jabotinski St., Petach Tikva, 49100, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dollberg Dolev
- Department of Ophthalmology and Laboratory of Eye Research, Rabin Medical Center - Beilinson Hospital, Felsenstein Medical Research Center , 39 Jabotinski St., Petach Tikva, 49100, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Bahar Irit
- Department of Ophthalmology and Laboratory of Eye Research, Rabin Medical Center - Beilinson Hospital, Felsenstein Medical Research Center , 39 Jabotinski St., Petach Tikva, 49100, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dotan Assaf
- Department of Ophthalmology and Laboratory of Eye Research, Rabin Medical Center - Beilinson Hospital, Felsenstein Medical Research Center , 39 Jabotinski St., Petach Tikva, 49100, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Issac Levy
- Department of Ophthalmology and Laboratory of Eye Research, Rabin Medical Center - Beilinson Hospital, Felsenstein Medical Research Center , 39 Jabotinski St., Petach Tikva, 49100, Israel.
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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Mancini A, Mancini M, Taloni A, Bifezzi L, Romeo MA, Rijillo L, Verdiglione M, Scorcia V, Aragona P, Giannaccare G. Topical insulin used alone or in combination with drug-depository contact lens for refractory cases of neurotrophic keratopathy. Am J Ophthalmol Case Rep 2024; 36:102227. [PMID: 39697672 PMCID: PMC11652743 DOI: 10.1016/j.ajoc.2024.102227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 10/07/2024] [Accepted: 11/20/2024] [Indexed: 12/20/2024] Open
Abstract
Purpose To report the clinical outcomes achieved in refractory cases of neurotrophic keratopathy (NK) through the utilization of insulin eye drops alone or in conjunction with a drug-depository contact lens (DDCL). Observations This multicentric prospective open-label uncontrolled case series included consecutive patients with NK refractory to conventional treatment. Insulin eye drops (1 unit/mL) were prescribed 4 times/day in all cases, and a Therapeutic Hyper-CL™ soft contact lens (EyeYon Medical, Ness Ziona, Israel), designed to act as a drug reservoir, was applied in selected patients. Data about stage and duration of NK, corneal sensitivity, previous treatments, rate and speed of healing, changes of NK area over time were collected. Nine eyes of 8 patients (mean age 52.50 ± 12.03 years [95 % CI, 44.13-60.87]) affected by NK refractory to conventional medical therapy were included. All patients received topical insulin, while DDCL was also applied in 3 cases. At T0, the mean area of the corneal epithelial defect was 21.84 ± 18.35 mm2 [95 % CI, 9.86-33.84]. Complete corneal re-epithelialization occurred in all cases, after a mean time interval of 25.78 ± 8.39 days [95 % CI, 20.30-31.26]. Mean reduction rate of epithelial defect areas was -0.81 ± 0.44 mm2/day [95 % CI, -1.16 to -0.46] for patients treated with insulin eye drops, and -0.63 ± 0.30 mm2/day [95 % CI, -0.96 to -0.29] for those treated with insulin eye drops plus DDCL (p = 0.71). Neither adverse events nor episodes of NK recurrence were reported. Conclusions and importance Topical insulin, used alone or in combination with DDCL, is an accessible, inexpensive, and effective treatment for refractory NK.
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Affiliation(s)
- Alessandra Mancini
- Department of Ophthalmology, University Magna Graecia of Catanzaro, Catanzaro, 88100, Italy
| | - Maura Mancini
- Department of Biomedical Sciences, Ophthalmology Clinic, University of Messina, Messina, 98122, Italy
| | - Andrea Taloni
- Department of Ophthalmology, University Magna Graecia of Catanzaro, Catanzaro, 88100, Italy
| | - Luca Bifezzi
- Department of Ophthalmology, University Magna Graecia of Catanzaro, Catanzaro, 88100, Italy
| | - Maria Angela Romeo
- Department of Ophthalmology, University Magna Graecia of Catanzaro, Catanzaro, 88100, Italy
| | - Lorenzo Rijillo
- Department of Ophthalmology, University Magna Graecia of Catanzaro, Catanzaro, 88100, Italy
| | | | - Vincenzo Scorcia
- Department of Ophthalmology, University Magna Graecia of Catanzaro, Catanzaro, 88100, Italy
| | - Pasquale Aragona
- Department of Biomedical Sciences, Ophthalmology Clinic, University of Messina, Messina, 98122, Italy
| | - Giuseppe Giannaccare
- Eye Clinic, Department of Surgical Sciences, University of Cagliari, Cagliari, 09124, Italy
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Krolo I, Behaegel J, Termote K, de Bruyn B, De Schepper M, Oellerich S, Ní Dhubhghaill S. The role of topical insulin in ocular surface restoration: A review. Surv Ophthalmol 2024; 69:805-817. [PMID: 38609022 DOI: 10.1016/j.survophthal.2024.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 04/02/2024] [Accepted: 04/08/2024] [Indexed: 04/14/2024]
Abstract
Corneal epithelial defects are one of the most common ocular disorders. Restoring corneal integrity is crucial to reduce pain and regain function, but in cases of neurotrophic or desensitized corneas, healing can be significantly delayed. Treating neurotrophic corneas is challenging for ophthalmologists, and surgical intervention is often indicated to manage refractory cases that are unresponsive to medical therapy. Over the last decade, as more expensive therapeutics reach the market, topical insulin has returned to the forefront as an affordable option to improve corneal wound healing. There is still a paucity of data on the use and the efficacy of topical insulin, with no consensus regarding its indications, preparation, or posology. Here we review the literature on topical insulin for corneal and ocular surface pathologies, with a focus on the current evidence, its mechanisms of action, and its safety profile. Additionally, we share our experience in the field and provide a potential framework for future research.
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Affiliation(s)
- Iva Krolo
- Department of Ophthalmology, Universitair Ziekenhuis Brussel, Jette, Belgium; Department of Medicine and Pharmacology, Vrije Universiteit Brussel (VUB), Brussels, Belgium; Oftalmología Médica y Quirúrgica (OMIQ) Research, Barcelona, Spain.
| | - Joséphine Behaegel
- Department of Ophthalmology, Universitair Ziekenhuis Brussel, Jette, Belgium; Department of Medicine and Pharmacology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Karolien Termote
- Department of Ophthalmology, Universitair Ziekenhuis Brussel, Jette, Belgium; Department of Medicine and Pharmacology, Vrije Universiteit Brussel (VUB), Brussels, Belgium; Department of Ophthalmology, Imelda Hospital, Bonheiden, Belgium
| | - Barbara de Bruyn
- Department of Ophthalmology, Antwerp University Hospital, Edegem, Belgium; Department of Medicine, Antwerp University Hospital, Antwerp, Belgium
| | - Manon De Schepper
- Department of Medicine, Antwerp University Hospital, Antwerp, Belgium
| | - Silke Oellerich
- Department of Ophthalmology, Universitair Ziekenhuis Brussel, Jette, Belgium; Department of Medicine and Pharmacology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Sorcha Ní Dhubhghaill
- Department of Ophthalmology, Universitair Ziekenhuis Brussel, Jette, Belgium; Department of Medicine and Pharmacology, Vrije Universiteit Brussel (VUB), Brussels, Belgium; Department of Ophthalmology, Antwerp University Hospital, Edegem, Belgium; Department of Medicine, Antwerp University Hospital, Antwerp, Belgium
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Vera-Duarte GR, Jimenez-Collado D, Kahuam-López N, Ramirez-Miranda A, Graue-Hernandez EO, Navas A, Rosenblatt MI. Neurotrophic keratopathy: General features and new therapies. Surv Ophthalmol 2024; 69:789-804. [PMID: 38679146 DOI: 10.1016/j.survophthal.2024.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 04/12/2024] [Accepted: 04/22/2024] [Indexed: 05/01/2024]
Abstract
Neurotrophic keratopathy is an uncommon degenerative corneal disorder characterized by compromised corneal sensory innervation resulting in the formation of epithelial defects and nonhealing corneal ulcers. Various treatment modalities are available to stabilize disease progression, improve patient well-being, and prevent vision loss. For eligible patients, medical and surgical reinnervation have emerged as pioneering therapies, holding promise for better management. We present a comprehensive review of the disorder, providing an update relevant to ophthalmologists on pathogenesis, diagnosis, treatment options, and novel therapies targeting pathophysiological pathways.
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Affiliation(s)
- Guillermo Raul Vera-Duarte
- Department of Cornea and Refractive Surgery, Instituto de Oftalmología "Conde de Valenciana, Mexico City, Mexico
| | - David Jimenez-Collado
- Department of Cornea and Refractive Surgery, Instituto de Oftalmología "Conde de Valenciana, Mexico City, Mexico
| | - Nicolás Kahuam-López
- Department of Cornea and Refractive Surgery, Instituto de Oftalmología "Conde de Valenciana, Mexico City, Mexico
| | - Arturo Ramirez-Miranda
- Department of Cornea and Refractive Surgery, Instituto de Oftalmología "Conde de Valenciana, Mexico City, Mexico
| | - Enrique O Graue-Hernandez
- Department of Cornea and Refractive Surgery, Instituto de Oftalmología "Conde de Valenciana, Mexico City, Mexico
| | - Alejandro Navas
- Department of Cornea and Refractive Surgery, Instituto de Oftalmología "Conde de Valenciana, Mexico City, Mexico
| | - Mark I Rosenblatt
- Department of Ophthalmology and Visual Sciences, University of Illinois-Chicago (UIC), Chicago, IL 60612, USA.
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12
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Zhang X, Jie Y. Importance of Circadian Rhythms in the Ocular Surface. Biomolecules 2024; 14:796. [PMID: 39062510 PMCID: PMC11274730 DOI: 10.3390/biom14070796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 06/22/2024] [Accepted: 07/02/2024] [Indexed: 07/28/2024] Open
Abstract
Circadian rhythms are a ubiquitous feature throughout the organism. Accumulating evidence suggests that the dysfunction of circadian rhythms due to genetic mutations or environmental factors contributes to the genesis and progress of multiple diseases. The physiological homeostasis of the ocular surface, like any other tissue or organ, is also orchestrated by circadian rhythms. In this review, we summarize the molecular clocks and the expression of clock-controlled genes in the mammalian ocular surface. Based on the circadian expression of these genes, we conclude the diurnal oscillations of cellular biological activities in the mammalian ocular surface. Moreover, we evaluate the factors entraining circadian oscillators in the ocular surface. Finally, we further discuss the latest development of the close correlation between circadian rhythms and ocular health. Briefly, this review aimed to synthesize the previous studies to aid in understanding the importance of circadian rhythms in the ocular surface and the possible opportunities for circadian rhythm-based interventional strategies to restore the homeostasis of the ocular surface.
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Affiliation(s)
| | - Ying Jie
- Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, No. 1 Dong Jiao Min Xiang, Dong Cheng District, Beijing 100730, China;
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13
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Moin KA, Pandiri S, Manion GN, Brown AH, Moshirfar M, Hoopes PC. The Utilization of Topical Insulin for Ocular Surface Diseases: A Narrative Review. Cureus 2024; 16:e62065. [PMID: 38989397 PMCID: PMC11235153 DOI: 10.7759/cureus.62065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2024] [Indexed: 07/12/2024] Open
Abstract
Various etiologies, including diabetic keratopathy (DK), dry eye disease (DED), and neurotrophic keratopathy (NK), can disrupt corneal homeostasis, exacerbating corneal epithelial defects. Topical insulin has emerged as a promising therapy for promoting corneal wound healing and addressing underlying pathologies. This review systematically evaluates the efficacy of topical insulin across different corneal disorders. A literature review was conducted across the PubMed, Google Scholar, and Scopus research databases. The search resulted in a total of 19 articles, consisting of clinical trials, retrospective studies, and case reports. In DK, topical insulin accelerates corneal wound healing post-vitreoretinal surgery with lower concentrations showing higher outcomes when compared to conventional therapy, possibly due to improved epithelial stem cell migration. In comparison, the dry-eye disease results are inconclusive regarding patient-reported outcomes and corneal staining. For NK, topical insulin accelerates corneal wound healing and restores corneal nerve sensation. Other persistent epithelial defect (PED) etiologies that have been treated with topical insulin are infection, immune-mediated, mechanical and chemical trauma, and chronic ocular surface alterations. Although individual mechanisms for the benefits of topical insulin for each of these etiologies have not been studied, the literature demonstrates that topical insulin is efficacious for PEDs regardless of etiology. Future clinical trials need to be conducted to further evaluate optimal dosing, duration, and use of topical insulin for the restoration of the corneal surface.
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Affiliation(s)
- Kayvon A Moin
- Hoopes Vision Research Center, Hoopes Vision, Draper, USA
| | - Srujay Pandiri
- Ophthalmology, University of Missouri Kansas City School of Medicine, Kansas City, USA
| | - Garrett N Manion
- Ophthalmology, Creighton University School of Medicine, Omaha, USA
| | - Alex H Brown
- Ophthalmology, University of Arizona College of Medicine - Phoenix, Phoenix, USA
| | - Majid Moshirfar
- Eye Banking and Corneal Transplantation, Utah Lions Eye Bank, Murray, USA
- Corneal and Refractive Surgery, Hoopes Vision Research Center, Draper, USA
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14
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Abdi P, Ghaffari R, Azad N, Alshaheeb A, Latifi G, Soltani Shahgoli S, Fakhredin H. Topical insulin for refractory persistent corneal epithelial defects. Sci Rep 2024; 14:12459. [PMID: 38816428 PMCID: PMC11139959 DOI: 10.1038/s41598-024-63091-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 05/24/2024] [Indexed: 06/01/2024] Open
Abstract
The aim was clinical evaluation of the efficacy of topical insulin eye drops in patients with refractory persistent epithelial defects (PEDs). This prospective non-randomized investigation was conducted to examine the efficacy of insulin eye drops in treating patients with PEDs that did not respond to conventional therapy. A total of twenty-three patients were included in the study, and they were administered insulin eye drops formulated as 1 U/mL, four times a day. The rate of epithelial defect resolution and time to complete corneal re-epithelialization were considered primary outcome measures. The relative prognostic impact of initial wound size and other parameters, including age, sex, smoking, diabetes, and hypertension were also analyzed. The results showed that during follow-up (maximum 50 days), a total of 16 patients (69.6%) achieved improvement. Insulin eye drops significantly reduced the corneal wounding area in 75% of patients with small epithelial defects (5.5 mm2 or less) during 20 days. Only 61% of patients with moderate epithelial defects (5.51-16 mm2) showed a significant recovery in 20-30 days. Also, 71% of patients with a defect size greater than 16 mm2, demonstrated a significant improvement in the rate of corneal epithelial wound healing in about 50 days. In conclusion topical insulin reduces the PED area and accelerates the ocular surface epithelium wound healing.
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Affiliation(s)
- Parisa Abdi
- Translational ophthalmology Research center, Farabi Eye Hospital, School of medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Ophthalmology Department, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.
| | - Reza Ghaffari
- Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA
| | - Nikoo Azad
- Department of Plant Sciences, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Ahmed Alshaheeb
- Translational ophthalmology Research center, Farabi Eye Hospital, School of medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Golshan Latifi
- Translational ophthalmology Research center, Farabi Eye Hospital, School of medicine, Tehran University of Medical Sciences, Tehran, Iran
- Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA
| | - Sahel Soltani Shahgoli
- Translational ophthalmology Research center, Farabi Eye Hospital, School of medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hanieh Fakhredin
- Translational ophthalmology Research center, Farabi Eye Hospital, School of medicine, Tehran University of Medical Sciences, Tehran, Iran
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15
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Eleiwa TK, Khater AA, Elhusseiny AM. Topical insulin in neurotrophic keratopathy after diabetic vitrectomy. Sci Rep 2024; 14:10986. [PMID: 38744994 PMCID: PMC11094097 DOI: 10.1038/s41598-024-60699-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 04/26/2024] [Indexed: 05/16/2024] Open
Abstract
To assess the efficacy and safety of topical insulin (TI) for treating neurotrophic keratopathy (NK) within one-month post-diabetic vitrectomy (DV) compared to conventional non-invasive measures, we conducted this retrospective case-control study including all eyes that developed acute NK (stages 2 and 3) following DV between October 2020 and June 2023. The control group included NK cases managed with preservative-free lubricant eye drops and prophylactic topical antibiotics. In contrast, the study group included NK cases treated with TI [1 unit per drop] four times daily, in addition to the previously mentioned treatment. The primary outcome measure was time to epithelial healing. Secondary outcome measures included any adverse effect of TI or the need for amniotic membrane transplantation (AMT). During the study period, 19 patients with a mean age of 49.3 ± 8.6 years received TI versus 18 controls with a mean age of 52.5 ± 10.7 years. Corneal epithelial healing was significantly faster in the TI-treated group compared to controls, with a mean difference of 12.16 days (95% CI 6.1-18.3, P = 0.001). Survival analysis indicated that the insulin-treated group had 0% and 20% of NK stages 2 and 3, respectively, that failed to achieve corneal epithelial healing, compared to 20% and 66.7% for the control group (P < 0.001). In the control group, two eyes required AMT due to progressive thinning. Additionally, three patients in the control group, progressing to stage 3 NK, were switched to TI, achieving healing after a mean of 14 days. No adverse effects were reported in the TI-treated group. Our study suggests that TI can effectively and safely promote the healing of NK after DV.
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Affiliation(s)
- Taher K Eleiwa
- Department of Ophthalmology, Benha University, Benha, Egypt.
| | - Ahmed A Khater
- Department of Ophthalmology, Benha University, Benha, Egypt
| | - Abdelrahman M Elhusseiny
- Department of Ophthalmology, Kasr. Al-Ainy Hospitals, Cairo University, Cairo, Egypt
- Department of Ophthalmology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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16
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Burgos-Blasco B, Diaz-Valle D, Rego-Lorca D, Perez-Garcia P, Puebla-Garcia V, Fernandez-Vigo JI, Benitez-Del-Castillo JM, Gegundez-Fernandez JA. Topical insulin, a novel corneal epithelial regeneration agent in dry eye disease. Eur J Ophthalmol 2024; 34:719-725. [PMID: 37814519 DOI: 10.1177/11206721231206790] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/11/2023]
Abstract
OBJECTIVE To evaluate the efficacy of insulin eye drops for dry eye disease in reducing corneal staining and improving symptoms. METHODS In this retrospective case series, patients with dry eye disease treated with off-label use of insulin eye drops were collected. The main inclusion criterion was diagnosis of dry eye disease with epithelial damage and acceptance of the off-label use of topical insulin. Age, sex, type of dry eye disease, time since diagnosis, previous ocular surgeries, concomitant treatment, best corrected visual acuity, symptoms, conjunctival hyperemia and corneal staining were recorded. Data from the 1 and 3-month visit were included. RESULTS 16 patients (32 eyes) were treated with insulin (14 females and 2 males; mean age 61.3 ± 16.8 years). 12 patients (71%) were also on autologous serum and 10 patients (63%) on cyclosporine. Symptoms were 3.4 ± 1.3 (range 2-5) when scaled from 0 to 5. Mean hyperemia was 1.0 ± 0.9 (range 0-3) and corneal staining was 2.5 ± 1.3 (range 0-5). After 3 months, 5 patients (31%) referred to be much better, 6 (38%) better, 3 (19%) slightly better and 2 patients (13%) were subjectively similar, mean symptoms being 2.3 ± 1.0 (range 1-4; p = 0.001). Hyperemia was 0.3 ± 0.4 (range 0-1) and corneal staining was 1.1 ± 1.0 (range 0-3; both p < 0.001). Topical insulin was well tolerated with no adverse events. CONCLUSIONS The excellent results presented in these case series illustrate topical insulin as a promising treatment in dry eye disease with refractory epithelial damage.
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Affiliation(s)
- Barbara Burgos-Blasco
- Servicio de Oftalmología, Instituto de Investigación Sanitaria, Hospital Clínico San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | - David Diaz-Valle
- Servicio de Oftalmología, Instituto de Investigación Sanitaria, Hospital Clínico San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Daniela Rego-Lorca
- Servicio de Oftalmología, Instituto de Investigación Sanitaria, Hospital Clínico San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | - Pilar Perez-Garcia
- Servicio de Oftalmología, Instituto de Investigación Sanitaria, Hospital Clínico San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | | | - Jose Ignacio Fernandez-Vigo
- Servicio de Oftalmología, Instituto de Investigación Sanitaria, Hospital Clínico San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | - Jose Manuel Benitez-Del-Castillo
- Servicio de Oftalmología, Instituto de Investigación Sanitaria, Hospital Clínico San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Jose Antonio Gegundez-Fernandez
- Servicio de Oftalmología, Instituto de Investigación Sanitaria, Hospital Clínico San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
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17
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Vicario-de-la-Torre M, Puebla-García V, Ybañez-García L, López-Cano JJ, González-Cela-Casamayor MA, Brugnera M, Burgos-Blasco B, Díaz-Valle D, Gegúndez-Fernández JA, Benítez-del-Castillo JM, Herrero-Vanrell R. Topical Insulin Eye Drops: Stability and Safety of Two Compounded Formulations for Treating Persistent Corneal Epithelial Defects. Pharmaceutics 2024; 16:580. [PMID: 38794241 PMCID: PMC11124528 DOI: 10.3390/pharmaceutics16050580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/12/2024] [Accepted: 04/19/2024] [Indexed: 05/26/2024] Open
Abstract
Compounded insulin eye drops were prepared at 1 IU/mL from commercially available subcutaneous insulin by dilution in saline solution or artificial tears. Physicochemical characterization and in vitro tolerance testing in human and conjunctival cells were followed by a 28-day short-term stability study under various conditions. The formulations were isotonic (280-300 mOsm/L), had a pH close to neutral (7-8), medium surface-tension values (<56 MN/m-1), and low (≈1 mPa·s) and medium (≈5 mPa·s) viscosities (compounded normal saline solution and artificial tear-based preparation, respectively). These values remained stable for 28 days under refrigeration. Microbiological stability was also excellent. Insulin potency remained in the 90-110% range in the compounded formulations containing normal saline solution when stored at 2-8 °C for 28 days, while it decreased in those based on artificial tears. Although both formulations were well tolerated in vitro, the compounded insulin diluted in a normal saline solution exhibited better cell tolerance. Preliminary data in humans showed that insulin in saline solution was an effective and safe treatment for persistent corneal epithelial defects. Compounded insulin eye drops diluted in normal saline solution could, therefore, constitute an emergent therapy for the treatment of persistent corneal epithelial defects.
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Affiliation(s)
- Marta Vicario-de-la-Torre
- Innovation, Therapy and Pharmaceutical Development in Ophthalmology (InnOftal) Research Group (UCM 920415), Department of Pharmaceutics and Food Technology, Faculty of Pharmacy (UCM), Plaza Ramón y Cajal s/n, 28040 Madrid, Spain (R.H.-V.)
- National Ocular Pathology Network (OFTARED), Carlos III Institute of Health, San Carlos Clinical Hospital Institute of Health Research (IdISSC), 28040 Madrid, Spain (D.D.-V.)
| | | | | | - José Javier López-Cano
- Innovation, Therapy and Pharmaceutical Development in Ophthalmology (InnOftal) Research Group (UCM 920415), Department of Pharmaceutics and Food Technology, Faculty of Pharmacy (UCM), Plaza Ramón y Cajal s/n, 28040 Madrid, Spain (R.H.-V.)
- National Ocular Pathology Network (OFTARED), Carlos III Institute of Health, San Carlos Clinical Hospital Institute of Health Research (IdISSC), 28040 Madrid, Spain (D.D.-V.)
| | - Miriam Ana González-Cela-Casamayor
- Innovation, Therapy and Pharmaceutical Development in Ophthalmology (InnOftal) Research Group (UCM 920415), Department of Pharmaceutics and Food Technology, Faculty of Pharmacy (UCM), Plaza Ramón y Cajal s/n, 28040 Madrid, Spain (R.H.-V.)
- National Ocular Pathology Network (OFTARED), Carlos III Institute of Health, San Carlos Clinical Hospital Institute of Health Research (IdISSC), 28040 Madrid, Spain (D.D.-V.)
| | - Marco Brugnera
- Innovation, Therapy and Pharmaceutical Development in Ophthalmology (InnOftal) Research Group (UCM 920415), Department of Pharmaceutics and Food Technology, Faculty of Pharmacy (UCM), Plaza Ramón y Cajal s/n, 28040 Madrid, Spain (R.H.-V.)
- National Ocular Pathology Network (OFTARED), Carlos III Institute of Health, San Carlos Clinical Hospital Institute of Health Research (IdISSC), 28040 Madrid, Spain (D.D.-V.)
| | - Bárbara Burgos-Blasco
- National Ocular Pathology Network (OFTARED), Carlos III Institute of Health, San Carlos Clinical Hospital Institute of Health Research (IdISSC), 28040 Madrid, Spain (D.D.-V.)
- Ocular Surface and Inflammation Unit, Department of Ophthalmology, San Carlos Clinical Hospital Institute of Health Research (IdISSC), 28040 Madrid, Spain
| | - David Díaz-Valle
- National Ocular Pathology Network (OFTARED), Carlos III Institute of Health, San Carlos Clinical Hospital Institute of Health Research (IdISSC), 28040 Madrid, Spain (D.D.-V.)
- Ocular Surface and Inflammation Unit, Department of Ophthalmology, San Carlos Clinical Hospital Institute of Health Research (IdISSC), 28040 Madrid, Spain
| | - José Antonio Gegúndez-Fernández
- National Ocular Pathology Network (OFTARED), Carlos III Institute of Health, San Carlos Clinical Hospital Institute of Health Research (IdISSC), 28040 Madrid, Spain (D.D.-V.)
- Ocular Surface and Inflammation Unit, Department of Ophthalmology, San Carlos Clinical Hospital Institute of Health Research (IdISSC), 28040 Madrid, Spain
| | - José Manuel Benítez-del-Castillo
- National Ocular Pathology Network (OFTARED), Carlos III Institute of Health, San Carlos Clinical Hospital Institute of Health Research (IdISSC), 28040 Madrid, Spain (D.D.-V.)
- Ocular Surface and Inflammation Unit, Department of Ophthalmology, San Carlos Clinical Hospital Institute of Health Research (IdISSC), 28040 Madrid, Spain
| | - Rocío Herrero-Vanrell
- Innovation, Therapy and Pharmaceutical Development in Ophthalmology (InnOftal) Research Group (UCM 920415), Department of Pharmaceutics and Food Technology, Faculty of Pharmacy (UCM), Plaza Ramón y Cajal s/n, 28040 Madrid, Spain (R.H.-V.)
- National Ocular Pathology Network (OFTARED), Carlos III Institute of Health, San Carlos Clinical Hospital Institute of Health Research (IdISSC), 28040 Madrid, Spain (D.D.-V.)
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18
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Chen S, Li Y, Song W, Cheng Y, Gao Y, Xie L, Huang M, Yan X. Insulin eye drops improve corneal wound healing in STZ-induced diabetic mice by regulating corneal inflammation and neuropeptide release. BMC Ophthalmol 2024; 24:155. [PMID: 38594682 PMCID: PMC11003036 DOI: 10.1186/s12886-024-03436-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 04/05/2024] [Indexed: 04/11/2024] Open
Abstract
INTRODUCTION In recent years, insulin eye drops have attracted increasing attention from researchers and ophthalmologists. The aim of this study was to investigate the efficacy and possible mechanism of action of insulin eye drops in diabetic mice with corneal wounds. METHODS A type 1 diabetes model was induced, and a corneal epithelial injury model of 2.5 mm was established. We used corneal fluorescein staining, hematoxylin-eosin (H-E) staining and the Cochet-Bonnet esthesiometer to examine the process of wound healing. Subsequently, the expression levels of Ki-67, IL-1β, β3-tubulin and neuropeptides, including substance P (SP) and calcitonin gene-related peptide (CGRP), were examined at 72 h after corneal injury. RESULTS Fluorescein staining demonstrated an acceleration of the recovery of corneal epithelial injury in diabetic mice compared with the saline treatment, which was further evidenced by the overexpression of Ki-67. Moreover, 72 h of insulin application attenuated the expression of inflammatory cytokines and neutrophil infiltration. Remarkably, the results demonstrated that topical insulin treatment enhanced the density of corneal epithelial nerves, as well as neuropeptide SP and CGRP release, in the healing cornea via immunofluorescence staining. CONCLUSIONS Our results indicated that insulin eye drops may accelerate corneal wound healing and decrease inflammatory responses in diabetic mice by promoting nerve regeneration and increasing levels of neuropeptides SP and CGRP.
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Affiliation(s)
- Shudi Chen
- Department of Ophthalmology, Peking University First Hospital, No.8 Xishiku Avenue, 100034, Beijing, China
| | - Yingsi Li
- Department of Ophthalmology, Peking University First Hospital, No.8 Xishiku Avenue, 100034, Beijing, China
| | - Wenjing Song
- Department of Ophthalmology, Peking University First Hospital, No.8 Xishiku Avenue, 100034, Beijing, China
| | - Yu Cheng
- Department of Ophthalmology, Peking University First Hospital, No.8 Xishiku Avenue, 100034, Beijing, China
| | - Yuan Gao
- Department of Ophthalmology, Peking University First Hospital, No.8 Xishiku Avenue, 100034, Beijing, China
| | - Luoying Xie
- Department of Ophthalmology, Peking University First Hospital, No.8 Xishiku Avenue, 100034, Beijing, China
| | - Meiting Huang
- Department of Ophthalmology, Peking University First Hospital, No.8 Xishiku Avenue, 100034, Beijing, China
| | - Xiaoming Yan
- Department of Ophthalmology, Peking University First Hospital, No.8 Xishiku Avenue, 100034, Beijing, China.
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19
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Chen Y, Zhang Y, Jiang M, Ma H, Cai Y. HMOX1 as a therapeutic target associated with diabetic foot ulcers based on single-cell analysis and machine learning. Int Wound J 2024; 21:e14815. [PMID: 38468410 PMCID: PMC10928352 DOI: 10.1111/iwj.14815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 01/15/2024] [Accepted: 02/12/2024] [Indexed: 03/13/2024] Open
Abstract
Diabetic foot ulcers (DFUs) are a serious chronic complication of diabetes mellitus and a leading cause of disability and death in diabetic patients. However, current treatments remain unsatisfactory. Although macrophages are associated with DFU, their exact role in this disease remains uncertain. This study sought to detect macrophage-related genes in DFU and identify possible therapeutic targets. Single-cell datasets (GSE223964) and RNA-seq datasets (GSM68183, GSE80178, GSE134431 and GSE147890) associated with DFU were retrieved from the gene expression omnibus (GEO) database for this study. Analysis of the provided single-cell data revealed the distribution of macrophage subpopulations in the DFU. Four independent RNA-seq datasets were merged into a single DFU cohort and further analysed using bioinformatics. This included differential expression (DEG) analysis, multiple machine learning algorithms to identify biomarkers and enrichment analysis. Finally, key results were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western bolt. Finally, the findings were validated using RT-qPCR and western blot. We obtained 802 macrophage-related genes in single-cell analysis. Differential expression analysis yielded 743 DEGs. Thirty-seven macrophage-associated DEGs were identified by cross-analysis of marker genes with macrophage-associated DEGs. Thirty-seven intersections were screened and cross-analysed using four machine learning algorithms. Finally, HMOX1 was identified as a potentially valuable biomarker. HMOX1 was significantly associated with biological pathways such as the insulin signalling pathway. The results showed that HMOX1 was significantly overexpressed in DFU samples. In conclusion, the analytical results of this study identified HMOX1 as a potentially valuable biomarker associated with macrophages in DFU. The results of our analysis improve our understanding of the mechanism of macrophage action in this disease and may be useful in developing targeted therapies for DFU.
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Affiliation(s)
- Yiqi Chen
- Department of Burn and Plastic SurgeryAffiliated Hospital of Nantong UniversityNantongChina
| | - Yixin Zhang
- Department of Burn and Plastic SurgeryAffiliated Hospital of Nantong UniversityNantongChina
- Department of Breast SurgeryYantai City Yantai Hill hospitalYantaiChina
| | - Ming Jiang
- Department of Burn and Plastic SurgeryAffiliated Hospital of Nantong UniversityNantongChina
| | - Hong Ma
- Department of Burn and Plastic SurgeryAffiliated Hospital of Nantong UniversityNantongChina
- Department of BurnHanzhong Central HospitalHanZhongChina
| | - Yuhui Cai
- Department of Burn and Plastic SurgeryAffiliated Hospital of Nantong UniversityNantongChina
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20
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Wouters C, Saelens I, Delbeke H. Topical Insulin for Neurotrophic-Related Epithelial Defects: Where do We Stand? A Systematic Review. J Curr Ophthalmol 2024; 36:9-22. [PMID: 39553318 PMCID: PMC11567610 DOI: 10.4103/joco.joco_32_24] [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: 01/25/2024] [Revised: 03/18/2024] [Accepted: 08/23/2024] [Indexed: 11/19/2024] Open
Abstract
Purpose To review the existing literature to evaluate the utility of insulin eye drops as a treatment for neurotrophic-related epithelial defects. Methods A comprehensive literature search of Medline, Embase, and Web of Science and additional manual searches were conducted using relevant keywords. All articles published from January 2005 to January 2024 were examined. Studies on the use of topical insulin drops in neurotrophic epithelial defects were included. Results A total of 16 articles were found relevant to be discussed in the review. All included patients had neurotrophic-related epithelial defects ranging from 3.8 mm2 to 144 mm2. After treatment with topical insulin, most of the epithelial defects showed a complete epithelialization. Various concentrations and types of insulin were used. The studies also varied in the type of vehicle used in the preparation of insulin drops. Two randomized controlled trials demonstrated that topical insulin drops were more effective than conventional treatment with artificial tears or autologous serum. All included studies, except for two, reported the absence of local or systemic side effects. Conclusions Topical insulin is a promising and effective (adjuvant) treatment for neurotrophic keratopathy. It facilitates the healing of neurotrophic epithelial defects and offers many advantages over the current treatment options; insulin is widely available and it is relatively inexpensive. Topical insulin drops do not affect systemic blood glucose levels and are well tolerated. However, further investigation is needed.
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Affiliation(s)
- Colette Wouters
- Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium
| | - Isabelle Saelens
- Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium
| | - Heleen Delbeke
- Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium
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Jaworski M, Lorenc A, Leszczyński R, Mrukwa-Kominek E. Topical Insulin in Neurotrophic Keratopathy: A Review of Current Understanding of the Mechanism of Action and Therapeutic Approach. Pharmaceutics 2023; 16:15. [PMID: 38276493 PMCID: PMC10818503 DOI: 10.3390/pharmaceutics16010015] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 12/17/2023] [Accepted: 12/18/2023] [Indexed: 01/27/2024] Open
Abstract
Neurotrophic keratopathy is a corneal disease characterized by impaired corneal innervation. It can lead to corneal epithelial defects, ulcerations, and perforations. Topical insulin has been shown to be effective in treating this disorder. Insulin is a growth factor that can promote corneal epithelial cell proliferation and migration. In addition, it can also inhibit corneal epithelial cell apoptosis. Topical insulin has previously been found to enhance corneal wound healing. This article reviews the current understanding of the mechanism of action of topical insulin in the treatment of neurotrophic keratopathy.
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Affiliation(s)
- Marcin Jaworski
- Department of Ophthalmology, Kornel Gibiński University Clinical Center, Medical University of Silesia, 40-752 Katowice, Poland
- OPTOMED Ophthalmological Center for Children and Adults, 41-500 Chorzów, Poland
| | - Anna Lorenc
- Department of Ophthalmology, Kornel Gibiński University Clinical Center, Medical University of Silesia, 40-752 Katowice, Poland
- Department of Ophthalmology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland
| | - Rafał Leszczyński
- Department of Ophthalmology, Kornel Gibiński University Clinical Center, Medical University of Silesia, 40-752 Katowice, Poland
| | - Ewa Mrukwa-Kominek
- Department of Ophthalmology, Kornel Gibiński University Clinical Center, Medical University of Silesia, 40-752 Katowice, Poland
- Department of Ophthalmology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland
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Esmail A, Ibrahim M, Nage S. Efficacy of topical insulin for recurrent epithelial corneal erosions. Ir J Med Sci 2023; 192:3117-3123. [PMID: 37140764 DOI: 10.1007/s11845-023-03373-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 04/11/2023] [Indexed: 05/05/2023]
Abstract
BACKGROUND Topical insulin can promote and accelerate corneal regeneration, even in eyes with serious comorbidities, and offers several benefits over other treatment options. AIMS The aim of this study is to evaluate the effect of topical insulin in treatment of recurrent epithelial corneal erosion. METHODS Patients with recurrent epithelial erosions were included in a prospective non-randomized hospital-based study, divided into two groups, one of them received persistent epithelial defects (PEDs) conventional treatment and the other received the same treatment with insulin eye drops 4 times/day. All patients were examined carefully by slit lamp. Patients during the 1st, 2nd, 3rd, and 4th weeks as well as after 2 months. Demographics, etiology, therapy, comorbidities, and the healing time of PED were performed. RESULTS Area shows significant improvement after 2 weeks (p = 0.006), 2 months (p = 0.046), and 3 months (p = 0.002) in group II (cornetears gel and topical insulin) as compared to group I (cornetears gel). The recurrence was statistically significant decreased with cornetears gel and topical insulin (group II) by 0.0%, as compared to cornetears gel (group I) by 3 patients (21.4%). CONCLUSION Topical insulin can promote corneal reepithelization in recurrent epithelial erosion and decreases recurrence in these cases. Other advantages include excellent tolerance, availability, and cost-effectiveness.
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Affiliation(s)
- Ahmed Esmail
- Ophthalmology Department, Faculty of Medicine, Menoufia University, Menoufia, Shebin El Kom, Egypt.
| | - Mohamed Ibrahim
- Ophthalmology Department, Faculty of Medicine, Kafrelshiekh University Hospital, Kafrelshiekh, Egypt
| | - Sara Nage
- Ophthalmology Department, Faculty of Medicine, Menoufia University, Menoufia, Shebin El Kom, Egypt
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Cheung AY, Holland EJ, Lee WB, Beckman KA, Tu E, Farid M, Pepose J, Gupta PK, Fram N, Mah F, Mannis MJ. Neurotrophic keratopathy: An updated understanding. Ocul Surf 2023; 30:129-138. [PMID: 37666470 DOI: 10.1016/j.jtos.2023.09.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 08/10/2023] [Accepted: 09/01/2023] [Indexed: 09/06/2023]
Abstract
PURPOSE To propose an updated definition and staging system for neurotrophic keratopathy (NK) and provide consensus on diagnosis and treatment. METHODS A study group was convened to review the data pertinent to NK using a modified nominal group process. They proposed an updated definition for NK and a new 6-step staging system (Neurotrophic Keratopathy Study Group [NKSG] Classification) that can be used in conjunction with the different treatment options available currently or in the future. RESULTS NK is defined as the dysfunction of corneal innervation that results in dysregulation of corneal and/or cellular function. It is characterized by loss of corneal sensation and neuronal homeostasis, leading to eventual corneal epithelial breakdown and ultimately keratolysis if untreated. The NKSG classification emphasizes verifying corneal sensation early and distinguishes different epithelial and stromal aspects of NK with the following stages: stage 1 (altered sensation without keratopathy), stage 2 (epitheliopathy/punctate epithelial keratopathy [PEK] without stromal haze), stage 3 (persistent/recurrent epithelial defects without stromal haze), stage 4 (epitheliopathy/PEK or persistent/recurrent epithelial defects with stromal haze), stage 5 (persistent/recurrent epithelial defect with corneal ulceration), and stage 6 (corneal perforation). Treatment consists of a variety of modalities (both indirect and direct). CONCLUSIONS This updated definition and staging system will provide clinicians with the necessary information to diagnose and treat NK at an early stage before it becomes a sight-threatening disorder. It also provides a framework for evaluating current and future treatment options at distinct stages of the disease.
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Leong CY, Naffi AA, Wan Abdul Halim WH, Bastion MLC. Usage of topical insulin for the treatment of diabetic keratopathy, including corneal epithelial defects. World J Diabetes 2023; 14:930-938. [PMID: 37383598 PMCID: PMC10294054 DOI: 10.4239/wjd.v14.i6.930] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/14/2023] [Accepted: 04/24/2023] [Indexed: 06/14/2023] Open
Abstract
BACKGROUND Diabetic keratopathy (DK) occurs in 46%-64% of patients with diabetes and requires serious attention. In patients with diabetes, the healing of corneal epithelial defects or ulcers takes longer than in patients without diabetes. Insulin is an effective factor in wound healing. The ability of systemic insulin to rapidly heal burn wounds has been reported for nearly a century, but only a few studies have been performed on the effects of topical insulin (TI) on the eye. Treatment with TI is effective in treating DK.
AIM To review clinical and experimental animal studies providing evidence for the efficacy of TI to heal corneal wounds.
METHODS National and international databases, including PubMed and Scopus, were searched using relevant keywords, and additional manual searches were conducted to assess the effectiveness of TI application on corneal wound healing. Journal articles published from January 1, 2000 to December 1, 2022 were examined. The relevancy of the identified citations was checked against predetermined eligibility standards, and relevant articles were extracted and reviewed.
RESULTS A total of eight articles were found relevant to be discussed in this review, including four animal studies and four clinical studies. According to the studies conducted, TI is effective for corneal re-epithelialization in patients with diabetes based on corneal wound size and healing rate.
CONCLUSION Available animal and clinical studies have shown that TI promotes corneal wound healing by several mechanisms. The use of TI was not associated with adverse effects in any of the published cases. Further studies are needed to enhance our knowledge and understanding of TI in the healing of DK.
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Affiliation(s)
- Ching Yee Leong
- Department of Ophthalmology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur 56000, Wilayah Persekutuan, Malaysia
| | - Ainal Adlin Naffi
- Department of Ophthalmology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur 56000, Wilayah Persekutuan, Malaysia
| | - Wan Haslina Wan Abdul Halim
- Department of Ophthalmology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur 56000, Wilayah Persekutuan, Malaysia
| | - Mae-Lynn Catherine Bastion
- Department of Ophthalmology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur 56000, Wilayah Persekutuan, Malaysia
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Le Nguyen M, Naoum M, Andre C, Lethier L, Limat S, Fagnoni-Legat C, Guillaume Y, Gauthier A. Physicochemical and microbiological stability of insulin eye drops in an artificial tear vehicle used in the treatment of refractory neurotrophic keratopathy. J Fr Ophtalmol 2022; 45:860-871. [DOI: 10.1016/j.jfo.2022.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/14/2022] [Accepted: 04/21/2022] [Indexed: 11/29/2022]
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Diaz‐Valle D, Burgos‐Blasco B, Rego‐Lorca D, Puebla‐Garcia V, Perez‐Garcia P, Benitez‐del‐Castillo JM, Herrero‐Vanrell R, Vicario‐de‐la‐Torre M, Gegundez‐Fernandez JA. Comparison of the efficacy of topical insulin with autologous serum eye drops in persistent epithelial defects of the cornea. Acta Ophthalmol 2022; 100:e912-e919. [PMID: 34407296 DOI: 10.1111/aos.14997] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/21/2021] [Accepted: 08/04/2021] [Indexed: 01/01/2023]
Abstract
PURPOSE To investigate the effect of topical insulin on epithelization in persistent epithelial defects (PED) refractory to usual treatment compared to autologous serum. DESIGN Retrospective, consecutive case-control series. METHODS The charts of 61 consecutive patients with PED treated with topical insulin (case group) and 23 treated with autologous serum (control group) were reviewed. Primary efficacy end points were the percentage of patients in which epithelization was achieved, as well as the rate and time until epithelization. Secondary efficacy point was need for amniotic membrane transplantation (AMT) or other surgeries. RESULTS Mean time between PED diagnosis and start of topical insulin was 22.7 ± 18.5 days (range 13-115) and the mean area was 14.8 ± 16.2 mm2 (range 1.1-70.6). In the control group, mean time was 27.9 ± 16.8 days, mean epithelial defect area being 18.6 ± 15.0 mm2 (range 1.7-52.9). No differences in baseline characteristics were found between groups (p > 0.05). Epithelization was achieved in 51 patients (84%) on insulin and 11 patients (48%) on autologous serum (p = 0.002). In those patients, mean time until reepithelization was 32.6 ± 28.3 days (range 4-124) in the insulin group and 82.6 ± 82.4 days (range 13-231) in the autologous serum group (p = 0.011). The need for AMT was significantly lower in the insulin group (p = 0.005). PED recurrence was higher in patients treated on autologous serum (43%) compared with insulin (11%) (p = 0.002). CONCLUSIONS Topical insulin is an effective treatment and safely promotes healing of PED. In our series, topical insulin presented better epithelization outcomes than autologous serum and could thus be considered as a first-line treatment.
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Affiliation(s)
- David Diaz‐Valle
- Servicio de Oftalmología Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC) Hospital Clinico San Carlos Madrid Spain
| | - Barbara Burgos‐Blasco
- Servicio de Oftalmología Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC) Hospital Clinico San Carlos Madrid Spain
| | - Daniela Rego‐Lorca
- Servicio de Oftalmología Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC) Hospital Clinico San Carlos Madrid Spain
| | | | - Pilar Perez‐Garcia
- Servicio de Oftalmología Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC) Hospital Clinico San Carlos Madrid Spain
| | - Jose M. Benitez‐del‐Castillo
- Servicio de Oftalmología Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC) Hospital Clinico San Carlos Madrid Spain
| | - Rocio Herrero‐Vanrell
- Departamento de Farmacia y Tecnología Farmacéutica Facultad de Farmacia Universidad Complutense de Madrid Madrid España
| | - Marta Vicario‐de‐la‐Torre
- Departamento de Farmacia y Tecnología Farmacéutica Facultad de Farmacia Universidad Complutense de Madrid Madrid España
| | - Jose A. Gegundez‐Fernandez
- Servicio de Oftalmología Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC) Hospital Clinico San Carlos Madrid Spain
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Peterson C, Chandler HL. Insulin facilitates corneal wound healing in the diabetic environment through the RTK-PI3K/Akt/mTOR axis in vitro. Mol Cell Endocrinol 2022; 548:111611. [PMID: 35231580 PMCID: PMC9053186 DOI: 10.1016/j.mce.2022.111611] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 02/24/2022] [Accepted: 02/24/2022] [Indexed: 12/13/2022]
Abstract
Diabetic patients can develop degenerative corneal changes, termed diabetic keratopathy, during the course of their disease. Topical insulin has been shown to reduce corneal wound area and restore sensitivity in diabetic rats, and both the insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) stimulate cell signaling of the PI3K-Akt pathway. The purpose of this study was to assess a mechanism by which improved wound healing occurs by characterizing expression within the PI3K-Akt pathway in corneal epithelial and stromal cells. In vitro scratch tests were used to evaluate wound healing outcomes under variable glucose conditions in the presence or absence of insulin. Protein expression of intracellular kinases in the PI3K pathway, stromal cell markers, and GLUT-1 was evaluated by immunoblotting.TGF-β1 expression was evaluated by ELISA. Insulin promoted in vitro wound healing in all cell types. In human corneal epithelial cells, insulin did not induce PI3K-Akt signaling; however, in all other cell types evaluated, insulin increased expression of PI3K-Akt signaling proteins compared to vehicle control. Fibroblasts variably expressed α-SMA under all treatment conditions, with significant increases in α-SMA and TGF-β1 occurring in a dose-dependent manner with glucose concentration. These results indicate that insulin can promote corneal cellular migration and proliferation by inducing Akt signaling. Exogenous insulin therapy may serve as a novel target of therapeutic intervention for diabetic keratopathy.
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Affiliation(s)
- C Peterson
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Vision Science, The Ohio State University College of Optometry, Columbus, OH, 43210, USA.
| | - H L Chandler
- Department of Vision Science, The Ohio State University College of Optometry, Columbus, OH, 43210, USA
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Koay SY, Larkin DFP. New Pharmacological Approaches for the Treatment of Neurotrophic Keratitis. Front Pharmacol 2022; 13:796854. [PMID: 35392574 PMCID: PMC8981034 DOI: 10.3389/fphar.2022.796854] [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: 10/17/2021] [Accepted: 03/07/2022] [Indexed: 11/24/2022] Open
Abstract
Neurotrophic keratitis (NK) is a rare degenerative condition that is caused by damage to the trigeminal nerve, with partial or complete loss of corneal sensory innervation. The loss of innervation leads to impaired healing of corneal epithelium, which subsequently results in punctate epithelial erosions, persistent epithelial defects, corneal ulcers and corneal perforation. Management of NK is often supportive and aims to promote epithelial healing and prevent progression of disease. Multiple novel pharmacological approaches have been proposed to address the underlying pathophysiology of NK, which are discussed in this paper.
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Affiliation(s)
- Su Yin Koay
- Cornea and External Diseases Service, Moorfields Eye Hospital, London, United Kingdom
| | - Daniel F P Larkin
- Cornea and External Diseases Service, Moorfields Eye Hospital, London, United Kingdom
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29
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Zhou T, Lee A, Lo ACY, Kwok JSWJ. Diabetic Corneal Neuropathy: Pathogenic Mechanisms and Therapeutic Strategies. Front Pharmacol 2022; 13:816062. [PMID: 35281903 PMCID: PMC8905431 DOI: 10.3389/fphar.2022.816062] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/27/2022] [Indexed: 12/27/2022] Open
Abstract
Diabetes mellitus (DM) is a major global public health problem that can cause complications such as diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. Besides the reporting of reduction in corneal nerve density and decrease in corneal sensitivity in diabetic patients, there may be a subsequent result in delayed corneal wound healing and increased corneal infections. Despite being a potential cause of blindness, these corneal nerve changes have not gained enough attention. It has been proposed that corneal nerve changes may be an indicator for diabetic neuropathy, which can provide a window for early diagnosis and treatment. In this review, the authors aimed to give an overview of the relationship between corneal nerves and diabetic neuropathy as well as the underlying pathophysiological mechanisms of corneal nerve fiber changes caused by DM for improved prediction and prevention of diabetic neuropathy. In addition, the authors summarized current and novel therapeutic methods for delayed corneal wound healing, nerve protection and regeneration in the diabetic cornea.
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Affiliation(s)
- Ting Zhou
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Allie Lee
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Amy Cheuk Yin Lo
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Jeremy Sze Wai John Kwok
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
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Topical Insulin-Utility and Results in Refractory Neurotrophic Keratopathy in Stages 2 and 3. Cornea 2021; 41:990-994. [PMID: 34483270 DOI: 10.1097/ico.0000000000002858] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 07/08/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE The purpose of this study was to evaluate the clinical outcome of patients with refractory neurotrophic keratopathy (NK) in stages 2 and 3 treated with topical insulin. METHODS Retrospective analysis of eyes with NK in stages 2 and 3 refractory to standard medical and/or surgical treatment which were treated with topical insulin (1 unit per mL). This treatment was applied 4 times per day and was continued until the persistent epithelial defect (PED) or ulcer resolved. The primary outcome of the study was the complete reepithelialization of the PED or persistent ulcer. "Best-corrected visual acuity" pretreatment and posttreatment, "days until complete reepithelialization" data, and anterior segment photographs were obtained. Outcome measures were compared before and after treatment in both groups using paired and independent samples t tests. RESULTS Twenty-one eyes were included in this study, and 90% achieved complete reepithelialization of the PED and/or persistent ulcer within 7 to 45 days of follow-up. The mean number of days until complete reepithelialization was significantly lower in NK stage 2 (18 ± 9 days) when compared with NK stage 3 (29 ± 11 days) (P = 0.025). The best-corrected visual acuity improved significantly in both NK stage 2 (P < 0.001) and NK stage 3 (P = 0.004). No side effects were reported during the follow-up. CONCLUSIONS Our results suggest that topical insulin drops may be an effective therapeutic in refractory NK. This therapy may prove extremely useful because of its low cost and high accessibility.
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McLaughlin PJ, Sassani JW, Purushothaman I, Zagon IS. Naltrexone blockade of OGFr enhances cutaneous wound closure in diabetic rats. MEDICINE IN DRUG DISCOVERY 2021. [DOI: 10.1016/j.medidd.2021.100098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Ruiz-Lozano RE, Hernandez-Camarena JC, Loya-Garcia D, Merayo-Lloves J, Rodriguez-Garcia A. The molecular basis of neurotrophic keratopathy: Diagnostic and therapeutic implications. A review. Ocul Surf 2021; 19:224-240. [DOI: 10.1016/j.jtos.2020.09.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 09/13/2020] [Accepted: 09/22/2020] [Indexed: 12/11/2022]
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Tong CM, Iovieno A, Yeung SN. Topical insulin for neurotrophic corneal ulcers. CANADIAN JOURNAL OF OPHTHALMOLOGY 2020; 55:e170-e172. [DOI: 10.1016/j.jcjo.2020.04.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 04/03/2020] [Indexed: 10/24/2022]
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Diaz-Valle D, Burgos-Blasco B, Gegundez-Fernandez JA, Garcia-Caride S, Puebla-Garcia V, Peña-Urbina P, Benitez-Del-Castillo JM. Topical insulin for refractory persistent corneal epithelial defects. Eur J Ophthalmol 2020; 31:2280-2286. [PMID: 32951459 DOI: 10.1177/1120672120958307] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE To evaluate insulin eye drops for persistent epithelial defects (PEDs) that are refractory to usual treatment in clinical practice and to analyze how it may improve epithelization. METHODS A prospective non-randomized hospital-based study was performed. Patients with PEDs that were refractory to conventional treatment were treated with insulin eye drops four times a day. Patients' demographics, PED etiology, concomitant treatments, and comorbidities were reviewed. The rate of PED closure and epithelial healing time were considered the primary outcome measures. RESULTS 21 patients were treated with insulin drops (12 females and 9 males; mean age 72.2 years). Mean PED area before treatment was 17.6 ± 16.5 mm2 (median 13.2; range 3.9-70.6). PED comorbidities included seven eyes with infectious keratitis (33%), five eyes with calcium keratopathy (24%), ocular surgery on three eyes (14%), three eyes with lagophthalmos (14%), two eyes with bullous keratopathy (10%), and one patient with herpetic eye disease (5%). The eyes of 17 patients (81%) with refractory PEDs had reepithelized and four patients (19%) had still presented an epithelial defect by the end of the study follow-up period, although it had decreased in size. In patients where PED closure was achieved, mean time until reepithelization was 34.8 ± 29.9 days (median 23; range 7-114). In the remaining patients, a mean area reduction of 91.5% was achieved for the PEDs. CONCLUSION Topical insulin can promote and accelerate corneal reepithelization of refractory PEDs. It also offers many other advantages, including excellent tolerance, availability, and cost-effectiveness.
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Affiliation(s)
- David Diaz-Valle
- Opthalmology Department and Health Research Institute (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | - Barbara Burgos-Blasco
- Opthalmology Department and Health Research Institute (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | - Jose A Gegundez-Fernandez
- Opthalmology Department and Health Research Institute (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | - Sara Garcia-Caride
- Opthalmology Department and Health Research Institute (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | | | - Pilar Peña-Urbina
- Opthalmology Department and Health Research Institute (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
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Yang S, Zhang Y, Zhang Z, Dan J, Zhou Q, Wang X, Li W, Zhou L, Yang L, Xie L. Insulin Promotes Corneal Nerve Repair and Wound Healing in Type 1 Diabetic Mice by Enhancing Wnt/β-Catenin Signaling. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:2237-2250. [PMID: 32858016 DOI: 10.1016/j.ajpath.2020.08.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 07/31/2020] [Accepted: 08/12/2020] [Indexed: 12/20/2022]
Abstract
The insulin and Wnt signaling pathways are involved in cell proliferation, tissue homeostasis, and tumorigenesis. However, their interrelationship in the pathophysiological process of diabetic corneal injury remains unclear. In this study, the role of insulin in the diabetic cornea was investigated in vitro, using cultured TKE2 cells and trigeminal ganglion neurons, and in vivo, by assessing corneal wound-healing responses in diabetic mice. A selective Wnt antagonist (XAV-939) and activator (BML-284) were used to regulate the interactions between insulin and the Wnt pathway. The results demonstrated that insulin promoted corneal epithelial wound healing and sensation recovery, whereas the expression of molecules involved in the Wnt/β-catenin pathway was also up-regulated in the injured corneal epithelium. However, XAV-939 limited the insulin-induced epithelial and corneal nerve repair. By contrast, BML-284 treatment promoted the healing of the corneal epithelium and corneal nerve repair in diabetic mice. These results indicate that insulin, via Wnt signaling, contributes to diabetic corneal epithelial wound healing and nerve injury recovery and is, therefore, a potential protective factor for diabetic corneal epithelial wounds and nerve injury.
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Affiliation(s)
- Shuo Yang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Qingdao, China; Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan, China
| | - Yangyang Zhang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Qingdao, China
| | - Zhaohua Zhang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Qingdao, China
| | - Jing Dan
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Qingdao, China
| | - Qingjun Zhou
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Qingdao, China
| | - Xiaochuan Wang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Qingdao, China
| | - Weina Li
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Qingdao, China
| | - Li Zhou
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Qingdao, China
| | - Lingling Yang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Qingdao, China.
| | - Lixin Xie
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Qingdao, China.
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Tear Levels of IGFBP-3: A Potential Biomarker for Diabetic Nerve Changes in the Cornea. Eye Contact Lens 2020; 46:319-325. [DOI: 10.1097/icl.0000000000000700] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Stuard WL, Titone R, Robertson DM. The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease. Front Endocrinol (Lausanne) 2020; 11:24. [PMID: 32194500 PMCID: PMC7062709 DOI: 10.3389/fendo.2020.00024] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 01/14/2020] [Indexed: 12/11/2022] Open
Abstract
The insulin-like growth factor (IGF) family plays key roles in growth and development. In the cornea, IGF family members have been implicated in proliferation, differentiation, and migration, critical events that maintain a smooth refracting surface that is essential for vision. The IGF family is composed of multiple ligands, receptors, and ligand binding proteins. Expression of IGF type 1 receptor (IGF-1R), IGF type 2 receptor (IGF-2R), and insulin receptor (INSR) in the cornea has been well characterized, including the presence of the IGF-1R and INSR hybrid (Hybrid-R) in the corneal epithelium. Recent data also indicates that each of these receptors display unique intracellular localization. Thus, in addition to canonical ligand binding at the plasma membrane and the initiation of downstream signaling cascades, IGF-1R, INSR, and Hybrid-R also function to regulate mitochondrial stability and nuclear gene expression. IGF-1 and IGF-2, two of three principal ligands, are polypeptide growth factors that function in all cellular layers of the cornea. Unlike IGF-1 and IGF-2, the hormone insulin plays a unique role in the cornea, different from many other tissues in the body. In the corneal epithelium, insulin is not required for glucose uptake, due to constitutive activation of the glucose transporter, GLUT1. However, insulin is needed for the regulation of metabolism, circadian rhythm, autophagy, proliferation, and migration after wounding. There is conflicting evidence regarding expression of the six IGF-binding proteins (IGFBPs), which function primarily to sequester IGF ligands. Within the cornea, IGFBP-2 and IGFBP-3 have identified roles in tissue homeostasis. While IGFBP-3 regulates growth control and intracellular receptor localization in the corneal epithelium, both IGFBP-2 and IGFBP-3 function in corneal fibroblast differentiation and myofibroblast proliferation, key events in stromal wound healing. IGFBP-2 has also been linked to cellular overgrowth in pterygium. There is a clear role for IGF family members in regulating tissue homeostasis in the cornea. This review summarizes what is known regarding the function of IGF and related proteins in corneal development, during wound healing, and in the pathophysiology of disease. Finally, we highlight key areas of research that are in need of future study.
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Wang J, Xu J. Effects of Topical Insulin on Wound Healing: A Review of Animal and Human Evidences. Diabetes Metab Syndr Obes 2020; 13:719-727. [PMID: 32214835 PMCID: PMC7078652 DOI: 10.2147/dmso.s237294] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 02/25/2020] [Indexed: 12/12/2022] Open
Abstract
Wound healing is a complex biological process that repairs damaged tissues and restores skin integrity. Insulin, a potent factor of wound healing, has been reported for nearly a century to induce rapid recovery of various wounds, as shown by numerous human and animal studies. Although many studies have addressed the healing effect of systemic insulin on burn wound, only few have investigated the efficacy of topical insulin. Thus, this study aimed to review evidence of the effects of topical insulin on wound healing, including on diabetic and non-diabetic wounds. The presented animal and clinical studies support that topical insulin improves wound healing through several mechanisms without causing side effects. Additionally, various wound dressings accelerate the wound healing with controlled and sustained delivery of bioactive insulin. Therefore, topical insulin has been appreciated in field of wound healing, and further studies are needed to improve our understanding of the role of insulin in the healing of various wounds.
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Affiliation(s)
- Jiao Wang
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
| | - Jixiong Xu
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
- Correspondence: Jixiong Xu Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng St., Nanchang, Jiangxi Province330006, People’s Republic of ChinaTel +86 13307086069 Email
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Titone R, Robertson DM. Insulin receptor preserves mitochondrial function by binding VDAC1 in insulin insensitive mucosal epithelial cells. FASEB J 2019; 34:754-775. [PMID: 31914671 DOI: 10.1096/fj.201901316rr] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 10/08/2019] [Accepted: 10/21/2019] [Indexed: 01/07/2023]
Abstract
Unlike many epithelial tissues, the corneal epithelium is insulin insensitive, meaning it does not require insulin for glucose uptake. In this study, we show that insulin differentially regulates mitochondrial respiration in two human mucosal epithelial cell types: insulin-insensitive corneal epithelial cells and insulin-sensitive bronchial epithelial cells. In both cell types, insulin blocks glycogen synthase kinase beta (GSK3β) activity. In the corneal epithelium however, insulin selectively regulates PTEN-induced kinase 1 (PINK-1)-mediated mitophagy and mitochondrial accumulation of insulin receptor (INSR). While insulin blocked basal levels of PINK-1-mediated mitophagy in bronchial epithelial cells, mitochondrial trafficking of INSR was not detectable. We further show that in corneal epithelia, INSR interacts with the voltage-dependent anion channel-1 (VDAC1) in mitochondria and that INSR knockdown triggers robust mitochondrial fragmentation, alterations in mitochondrial polarization, and blocks the induction of PINK-1-mediated mitophagy. Collectively, these data demonstrate that INSR interacts with VDAC1 to mediate mitochondrial stability. We also demonstrate unique interactions between VDAC1 and other receptor tyrosine kinases, indicating a novel role for this family of receptors in mitochondria.
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Affiliation(s)
- Rossella Titone
- Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Danielle M Robertson
- Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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El-Wakeel NM, Dawoud MHS. Topical insulin-liposomal formulation in management of recurrent aphthous ulcers: A randomized placebo-controlled trial. JOURNAL OF INVESTIGATIVE AND CLINICAL DENTISTRY 2019; 10:e12437. [PMID: 31350870 DOI: 10.1111/jicd.12437] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 06/05/2019] [Accepted: 06/15/2019] [Indexed: 11/29/2022]
Abstract
AIM To evaluate the effectiveness of topical insulin-liposomal gel in aphthous ulcer treatment. METHODS 80 participants with minor aphthous ulcers were randomly divided to receive either topical insulin-liposomal gel or placebo gel (once daily) for 6 days. Assessment of outcomes included visual analog scale (VAS) for pain (primary outcome), and secondary outcomes included ulcer duration and impact of treatment on quality of life using the Oral Health Impact Profile 14 (OHIP-14). Testing of the outcomes was carried out at 1, 2, 3, 4 and 6 days after treatment for VAS and at 6 days for OHIP-14. RESULTS For pain scores, the test group showed a significant decrease by time, this was evident from day 1 (P < .001); at day 3, median and interquartile range (IQR) values were 0 (0-1). For the placebo group, a non-significant change by time was reported between baseline and day 1; at day 3, the median value was 7 (IQR, 7-9). The test group showed significantly lower mean duration than the placebo group (P < .001). OHIP-14 scores after 6 days showed that the test group had a significantly lower score than placebo (P < .001). CONCLUSIONS Topical insulin-liposomal formulation showed marked effectiveness in management of aphthous ulcers.
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Affiliation(s)
- Naglaa M El-Wakeel
- Department of Oral Medicine and Periodontology, Faculty of Dentistry, October University for Modern Sciences and Arts (MSA), Cairo, Egypt.,Faculty of Dentistry,Al-Azhar University (Girls Branch), Cairo, Egypt
| | - Marwa H S Dawoud
- Department of Pharmaceutics, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA ), Cairo, Egypt
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McKay TB, Priyadarsini S, Karamichos D. Mechanisms of Collagen Crosslinking in Diabetes and Keratoconus. Cells 2019; 8:cells8101239. [PMID: 31614631 PMCID: PMC6830090 DOI: 10.3390/cells8101239] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/09/2019] [Accepted: 10/10/2019] [Indexed: 12/14/2022] Open
Abstract
Collagen crosslinking provides the mechanical strength required for physiological maintenance of the extracellular matrix in most tissues in the human body, including the cornea. Aging and diabetes mellitus (DM) are processes that are both associated with increased collagen crosslinking that leads to increased corneal rigidity. By contrast, keratoconus (KC) is a corneal thinning disease associated with decreased mechanical stiffness leading to ectasia of the central cornea. Studies have suggested that crosslinking mediated by reactive advanced glycation end products during DM may protect the cornea from KC development. Parallel to this hypothesis, riboflavin-mediated photoreactive corneal crosslinking has been proposed as a therapeutic option to halt the progression of corneal thinning by inducing intra- and intermolecular crosslink formation within the collagen fibrils of the stroma, leading to stabilization of the disease. Here, we review the pathobiology of DM and KC in the context of corneal structure, the epidemiology behind the inverse correlation of DM and KC development, and the chemical mechanisms of lysyl oxidase-mediated crosslinking, advanced glycation end product-mediated crosslinking, and photoreactive riboflavin-mediated corneal crosslinking. The goal of this review is to define the biological and chemical pathways important in physiological and pathological processes related to collagen crosslinking in DM and KC.
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Affiliation(s)
- Tina B McKay
- Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
| | - Shrestha Priyadarsini
- Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA.
| | - Dimitrios Karamichos
- Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA.
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Jiang QW, Kaili D, Freeman J, Lei CY, Geng BC, Tan T, He JF, Shi Z, Ma JJ, Luo YH, Chandler H, Zhu H. Diabetes inhibits corneal epithelial cell migration and tight junction formation in mice and human via increasing ROS and impairing Akt signaling. Acta Pharmacol Sin 2019; 40:1205-1211. [PMID: 30867543 DOI: 10.1038/s41401-019-0223-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 02/21/2019] [Indexed: 12/15/2022]
Abstract
Corneal wounds usually heal quickly; but diabetic patients have more fragile corneas and experience delayed and painful healing. In the present study, we compared the healing capacity of corneal epithelial cells (CECs) between normal and diabetic conditions and the potential mechanisms. Primary murine CEC derived from wild-type and diabetic (db/db) mice, as well as primary human CEC were prepared. Human CEC were exposed to high glucose (30 mM) to mimic diabetic conditions. Cell migration and proliferation were assessed using Scratch test and MTT assays, respectively. Reactive oxygen species (ROS) production in the cells was measured using dichlorofluorescein reagent. Western blot was used to evaluate the expression levels of Akt. Transepithelial electrical resistance (TEER) and zonula occludens-1 (ZO-1) expression were used to determine tight junction integrity. We found that the diabetic CEC displayed significantly slower cell proliferation and migration compared with the normal CEC from both mice and humans. Furthermore, ROS production was markedly increased in CEC grown under diabetic conditions. Treatment with an antioxidant N-acetyl cysteine (NAC, 100 μM) significantly decreased ROS production and increased wound healing in diabetic CEC. Barrier function was significantly reduced in both diabetic mouse and human CEC, while NAC treatment mitigated these effects. We further showed that Akt signaling was impaired in diabetic CEC, which was partially improved by NAC treatment. These results show that diabetic conditions lead to delayed wound-healing capacity of CEC and impaired tight junction formation in both mice and human. Increased ROS production and inhibited Akt signaling may contribute to this outcome, implicating these as potential targets for treating corneal wounds in diabetic patients.
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Cubayachi C, Lemos CN, Pereira F, Dias K, Herculano RD, de Freitas O, Lopez RF. Silk fibroin films stabilizes and releases bioactive insulin for the treatment of corneal wounds. Eur Polym J 2019. [DOI: 10.1016/j.eurpolymj.2019.06.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Cruz-Cazarim ELC, Cazarim MS, Ogunjimi AT, Petrilli R, Rocha EM, Lopez RFV. Prospective insulin-based ophthalmic delivery systems for the treatment of dry eye syndrome and corneal injuries. Eur J Pharm Biopharm 2019; 140:1-10. [PMID: 31015020 DOI: 10.1016/j.ejpb.2019.04.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 04/10/2019] [Accepted: 04/19/2019] [Indexed: 12/18/2022]
Abstract
The presence of insulin (INS) receptors on the ocular surface (OS) and lacrimal gland (LG), and the high prevalence of dry eye syndrome (DES) and corneal lesions in diabetic patients suggest that INS is relevant for OS homeostasis and wound healing. The study aims at developing delivery systems for the topical administration of INS to the OS in order to improve INS local bioavailability and evaluate the influence of the delivery systems on DES in diabetic rats (DM) (n = 05/group). Chitosan microparticles (MP), chitosan/poloxamer gel (GEL) and MP-loaded GEL (GELMP), with or without INS were developed. Formulations were instilled into the eyes of diabetic rats (DM) for 15 days and the tear fluid volume, corneal cells morphology and cornea thickness were assessed and compared with an aqueous dispersion of INS (DISP-INS). All delivery systems had pH of about 6, osmolality suitable for topical application and positive zeta potential. The MPs with or without INS had sizes close to 4 μm, spherical morphology and INS encapsulation efficiency of 77 ± 6%. DISP-INS and GELMP-INS formulations produced tear secretion amounts significantly higher than those receiving formulations containing no INS and similar to healthy animals. Cornea surface impression cytology showed that treatment with INS-delivery systems and not DISP-INS almost normalized cells morphology. Treatment with GELMP-INS increased INS by 2.5 in the LG and eyeball as compared to the groups treated with GEL-INS and MP-INS, while treatment with DISP-INS left no traces of drug in the eye after treatment termination. GEL and GELMP containing INS were also able to normalize the thickness of the corneal epithelia. In conclusion, GELMP-INS normalized tear fluid volume, corneal thickness, protected corneal cells morphology and increased ocular bioavailability of INS, making it a promising treatment strategy for DES and corneal lesions.
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Affiliation(s)
- Estael L C Cruz-Cazarim
- School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Av. Cafe s/n, 14040-903 Ribeirao Preto, SP, Brazil
| | - Maurílio S Cazarim
- School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Av. Cafe s/n, 14040-903 Ribeirao Preto, SP, Brazil
| | - Abayomi T Ogunjimi
- School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Av. Cafe s/n, 14040-903 Ribeirao Preto, SP, Brazil
| | - Raquel Petrilli
- School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Av. Cafe s/n, 14040-903 Ribeirao Preto, SP, Brazil
| | - Eduardo M Rocha
- School of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil
| | - Renata F V Lopez
- School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Av. Cafe s/n, 14040-903 Ribeirao Preto, SP, Brazil.
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Abstract
Diabetes mellitus (DM) has been emerging as one of the most serious health problems worldwide. Ocular complications of DM are currently one of the major causes of blindness in developed countries, among which diabetic retinopathy is relatively well studied and understood. However, although ocular surface complications of DM are common, diabetic complications of anterior segment of the eye, such as, cornea, conjunctiva, and lacrimal glands, are often overlooked. DM is associated with progressive damage to corneal nerves and epithelial cells, which increases the risk of anterior segment disorders including dry eye disease, corneal erosion, persistent epithelial defects, and even sight-threatening corneal ulcer. In this review, the authors will discuss the association of DM with disorders of anterior segment of the eye. Studies indicating the value of corneal nerve assessment as a sensitive, noninvasive, and repeatable biomarker for diabetic neuropathy will also be introduced. In addition, treatment modalities of anterior segment disorders associated with DM is discussed. The studies introduced in this review suggest that early and periodic screening of the anterior segment of the eye, as well as the retina, is important for the optimal treatment of DM.
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Affiliation(s)
- Sang Beom Han
- Department of Ophthalmology, School of Medicine, Kangwon National University, Kangwon National University Hospital, Chuncheon, Korea,
| | - Hee Kyung Yang
- Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Joon Young Hyon
- Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
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Therapeutic potential of curcumin in diabetic complications. Pharmacol Res 2018; 136:181-193. [DOI: 10.1016/j.phrs.2018.09.012] [Citation(s) in RCA: 150] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 08/19/2018] [Indexed: 12/22/2022]
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Liu G, Jin N, Bi H, Du B, Gu T, Zhang B, Wei R. Long-Term Changes in Straylight Induced by Overnight Orthokeratology: An Objective Measure Using the Double-Pass System. Curr Eye Res 2018; 44:11-18. [PMID: 30198800 DOI: 10.1080/02713683.2018.1514056] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Purpose: To map the time course of changes in intraocular straylight of the human eye 1 year after initial lens wearing for orthokeratology treatment using the objective double-pass technique. Materials and Methods: A total of 35 subjects (19 males and 16 females) completed the study. The mean age was 11.46 ± 2.33 years (range, 8-16 years). All subjects were fitted with spherical four-zone orthokeratology lenses following the procedures recommended by the lens manufacturer. The subjects were required to wear the lens for at least eight consecutive hours at night. After lens removal during the daytime, objective scattering index (OSI) was evaluated using the double-pass technique (OQAS-II, Visiometrics, Terrassa, Spain) prior to lens dispatch (baseline), followed by evaluations at 1 week, 1 month, 6 months, and 12 months after the initial lens wearing. Longitudinal changes were fitted to a model containing both an impairing and recovery component, and the results were based on an extrapolation between the visits. Results: OSI rose quickly following lens wearing, reaching its highest level (double that of baseline values) by approximately 1.47 months. However, the recovery phase was slow and modest. One year after the initial lens wearing, OSI exhibited a 20% recovery from the peak level, but remained 63% higher than the baseline level. Conclusions: Intraocular straylight immediately increased flowing lens wearing, and this change reaches maximal level around 1 month after lens wearing. Slow but significant recoveries of optical quality subsequently followed.
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Affiliation(s)
- Guihua Liu
- a School of Optometry and Ophthalmology , Tianjin Medical University Eye Hospital , Tianjin , China
| | - Nan Jin
- a School of Optometry and Ophthalmology , Tianjin Medical University Eye Hospital , Tianjin , China
| | - Hua Bi
- b College of Optometry , Nova Southeastern University , Davie , FL , USA
| | - Bei Du
- a School of Optometry and Ophthalmology , Tianjin Medical University Eye Hospital , Tianjin , China
| | - Tianpu Gu
- a School of Optometry and Ophthalmology , Tianjin Medical University Eye Hospital , Tianjin , China
| | - Bin Zhang
- b College of Optometry , Nova Southeastern University , Davie , FL , USA
| | - Ruihua Wei
- a School of Optometry and Ophthalmology , Tianjin Medical University Eye Hospital , Tianjin , China
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Galvis V, Niño CA, Tello A, Grice JM, Gómez MA. Topical insulin in neurotrophic keratopathy after resection of acoustic neuroma. ACTA ACUST UNITED AC 2018; 94:100-104. [PMID: 30025986 DOI: 10.1016/j.oftal.2018.06.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 05/30/2018] [Accepted: 06/04/2018] [Indexed: 11/18/2022]
Abstract
CASE REPORT A patient with a history of surgical resection of an acoustic neuroma presented with involvement of both the left facial nerve and the left trigeminal nerve. She initially consulted for exposure keratitis, but two weeks later presented with an infectious keratitis. After taking the corneal sample, she presented with persistent epithelial defect, which did not respond to medical management. Topical insulin was indicated, and a decrease in the area of the lesion was seen in the following 5 days. A therapeutic contact lens was also placed at that time and finally, two weeks after the initiation of insulin, the epithelial defect completely closed. DISCUSSION This was a complex case due to the confluence of facial paralysis, neurotrophic keratitis, and infectious keratitis, which finally had a successful outcome. Topical insulin can be an effective adjuvant therapy in cases of neurotrophic ulcers that do not respond to standard therapy.
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Affiliation(s)
- V Galvis
- Centro Oftalmológico Virgilio Galvis, Floridablanca, Santander, Colombia; Departamento de Oftalmología, Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia
| | - C A Niño
- Centro Oftalmológico Virgilio Galvis, Floridablanca, Santander, Colombia; Departamento de Oftalmología, Fundación Oftalmológica de Santander FOSCAL, Floridablanca, Santander, Colombia
| | - A Tello
- Centro Oftalmológico Virgilio Galvis, Floridablanca, Santander, Colombia; Departamento de Oftalmología, Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga, Bucaramanga, Santander, Colombia.
| | - J M Grice
- Centro Oftalmológico Virgilio Galvis, Floridablanca, Santander, Colombia
| | - M A Gómez
- Centro Oftalmológico Virgilio Galvis, Floridablanca, Santander, Colombia
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Ohta M, Morita Y, Yamada N, Nishida T, Morishige N. Remodeling of the Corneal Epithelial Scaffold for Treatment of Persistent Epithelial Defects in Diabetic Keratopathy. Case Rep Ophthalmol 2018. [DOI: 10.1159/000490479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
<b><i>Background:</i></b> To develop a strategy based on surgical removal of a degenerated corneal epithelial scaffold for treatment of persistent epithelial defects (PEDs) in diabetic keratopathy. <b><i>Case Presentation:</i></b> Three diabetic patients with PEDs were initially treated with eyedrops containing the fibronectin-based peptide PHSRN (Pro-His-Ser-Arg-Asn) or both the substance P-derived peptide FGLM-NH<sub>2</sub> and the insulin-like growth factor-1-derived peptide SSSR. A degenerated Bowman’s layer or calcified lesion thought to be responsible for incomplete healing was surgically removed after confirmation of reactivity to the peptide eyedrops. All three patients achieved complete epithelial wound closure after surgery. Two cases treated by phototherapeutic keratectomy or lamellar keratoplasty did not show PED recurrence during 6 or 36 months of follow-up, respectively. One case treated by mechanical removal of a degenerated Bowman’s layer manifested recurrence after 1 month, but resurfacing of the defect was again achieved after repeat surgery. <b><i>Conclusion:</i></b> We propose a new strategy for treatment of diabetic PEDs based on surgical remodeling of the corneal epithelial scaffold for patients who respond to peptide eyedrops but fail to achieve wound closure.
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Promotion of Corneal Epithelial Wound Healing in Diabetic Rats by the Fibronectin-Derived Peptide PHSRN. Cornea 2018; 36:1544-1548. [PMID: 28834817 DOI: 10.1097/ico.0000000000001344] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Topical application of the fibronectin-derived peptide PHSRN facilitates corneal epithelial wound healing in healthy animals and in patients with nonhealing epithelial defects. We have now examined the effect of PHSRN eye drops on the healing of corneal epithelial wounds in diabetic rats. METHODS Wistar rats were injected intraperitoneally with streptozotocin to induce diabetes or with a vehicle as a control. Four weeks after confirmation of the corresponding presence or absence of glycosuria, a 3-mm-diameter portion of the corneal epithelium of the right eye was excised and eye drops containing PHSRN (200 μM) or phosphate-buffered saline (PBS) vehicle were administered to the injured eye every 6 hours. RESULTS The area of the epithelial defect did not differ significantly among the 4 experimental groups (diabetic or nondiabetic rats treated with PHSRN or vehicle) at 12 hours after wounding. At 18 hours, however, the area of the defect in diabetic rats treated with PHSRN (0.50 ± 0.34 mm) was significantly (P < 0.05) smaller than that in diabetic rats treated with PBS (1.06 ± 0.42 mm) and was similar to that in nondiabetic rats treated with PBS (0.60 ± 0.23 mm). The decrease in the size of the epithelial defect in diabetic rats treated with PHSRN was also found to be dependent on the dose of the peptide. CONCLUSIONS Administration of PHSRN significantly facilitated healing of corneal epithelial wounds in diabetic rats, which suggests that PHSRN eye drops warrant further investigation as a treatment option for patients with diabetic keratopathy.
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