|
1
|
Kumie G, Nigatie M, Alamrew A, Gedifie S, Kassahun W, Jemal A, Mulugeta C, Ayana S, Ayele M, Shitie E, Gtsadik B, Abebe W, Ashagre A, Misganaw T, Dejazmach Z, Sisay A, Asmare Z, Gashaw M, Getachew E, Gashaw Y, Tadesse S, Abate BB, Kidie AA, Reta MA. Prevalence of microvascular complications and associated factors among diabetes mellitus patients in Ethiopia: Systematic review and meta-analysis. Microvasc Res 2025; 158:104779. [PMID: 39732433 DOI: 10.1016/j.mvr.2024.104779] [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: 07/26/2024] [Revised: 12/14/2024] [Accepted: 12/17/2024] [Indexed: 12/30/2024]
Abstract
BACKGROUND Diabetes mellitus (DM) is a metabolic abnormality affecting 537 million people worldwide. Poor glycemic control, longer duration, and poor medication adherence increased the risk of DM complications. Comprehensive evidence on the pooled prevalence of microvascular complications in DM patients in Ethiopia is not available. Furthermore, individual study findings for the prevalence of microvascular complications in DM patients, and associated factors were not consistent. OBJECTIVE This systemic review and meta-analysis aimed to assess the pooled prevalence of microvascular complications in DM patients, and its associated risk factors in Ethiopia. METHODS Systematic search on Scopus, PubMed, Science Direct electronic database, Google Scholar search engine, and library registration was used to identify relevant studies following reviews and meta-analysis guidelines. Microsoft Excel spreadsheets were used to extract data, and Extracted data was analyzed using STATA software version 17.0. A Sensitivity analysis was conducted to assess the role of each study in the final result and the presence of publication bias was assessed by Egger's test. Heterogeneity across studies was checked by Cochran's Q statistic and I2 statistics and significant heterogeneity was assessed using subgroup analysis. RESULTS The pooled prevalence of microvascular complications in DM patients was 32.89 % (95 % CI: 28.17-37.60). In addition, the pooled prevalence of retinopathy, neuropathy, and nephropathy in DM patients was 17.16 % (95 % CI: 12-22 %), 10.49 % (95 % CI: 8-13 %) and 11.52 % (95 % CI: 9-15 %) respectively. Age >60 years old (AOR = 1.08 (95%CI = 1.02-1.15), longer duration of DM (AOR = 1.57 (95 % CI = 1.31-1.84), poor glycemic control (AOR = 2.21 (95 % CI = 1.52-2.91), poor adherence to diabetic medications (AOR = 3.61 (95 % CI = 1.83-5.38) and presence of hypertension (AOR = 2.26 (95 % CI = 1.73-2.80) ware associated risk factors for microvascular complications in DM patients. CONCUSSION Around one-third of DM patients had one or more microvascular complications. Patients with advanced age, longer duration of DM, poor glycemic control, poor medication adherence, and comorbidity like hypertension should be targeted to tackle the occurrence and severity of microvascular complications in DM patients. PROTOCOL REGISTRATION The review protocol was developed and was registered with PROSPERO registration number (CRD42023486459).
Collapse
Affiliation(s)
- Getinet Kumie
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia.
| | - Marye Nigatie
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Abebaw Alamrew
- School of Midwifery, College of Health Sciences, Woldia University, P.O. Box 400, Woldia, Ethiopia
| | - Solomon Gedifie
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Woldeteklehaymanot Kassahun
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Abdu Jemal
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Chalie Mulugeta
- School of Midwifery, College of Health Sciences, Woldia University, P.O. Box 400, Woldia, Ethiopia
| | - Sisay Ayana
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Mulat Ayele
- School of Midwifery, College of Health Sciences, Woldia University, P.O. Box 400, Woldia, Ethiopia
| | - Eyob Shitie
- School of Midwifery, College of Health Sciences, Woldia University, P.O. Box 400, Woldia, Ethiopia
| | - Belaynesh Gtsadik
- School of Medicine, College of Health Sciences, Woldia University, P.O. Box 400, Woldia, Ethiopia
| | - Wagaw Abebe
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Agenagnew Ashagre
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Tadesse Misganaw
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Zelalem Dejazmach
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Assefa Sisay
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Zelalem Asmare
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Muluken Gashaw
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Ermias Getachew
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Yalewayker Gashaw
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Selamyhun Tadesse
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia
| | - Biruk Beletew Abate
- School of Nursing, College of Health Sciences, Woldia University, P.O. Box 400, Woldia, Ethiopia
| | - Atitegeb Abera Kidie
- School of Public Health, College of Health Sciences, Woldia University, P.O. Box 400, Woldia, Ethiopia
| | - Melesse Abate Reta
- Department of Medical Laboratory Science, College of Health Sciences, Woldia University, P.O. box 400, Woldia, Ethiopia; Research Center for Tuberculosis and Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, Prinshof, 0084 Pretoria, South Africa
| |
Collapse
|
|
2
|
Morya AK, Ramesh PV, Nishant P, Kaur K, Gurnani B, Heda A, Salodia S. Diabetic retinopathy: A review on its pathophysiology and novel treatment modalities. World J Methodol 2024; 14:95881. [PMID: 39712561 PMCID: PMC11287547 DOI: 10.5662/wjm.v14.i4.95881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 05/28/2024] [Accepted: 07/10/2024] [Indexed: 07/26/2024] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic non-communicable disease with the ability to cause serious microvascular and macrovascular complications throughout the body, including in the eye. Diabetic retinopathy (DR), present in one-third of patients with diabetes, is a vision-threatening complication caused by uncontrolled diabetes, which greatly affects the retinal blood vessels and the light-sensitive inner retina, eventually leading to blindness. Several epidemiological studies elucidate that DR can vary by age of onset, duration, types of diabetes, and ethnicity. Recent studies show that the pathogenesis of diabetic retinopathy has spread its roots beyond merely being the result of hyperglycemia. The complexity of its etiopathology and diagnosis makes therapeutic intervention challenging. This review throws light on the pathological processes behind DR, the cascade of events that follow it, as well as the available and emerging treatment options.
Collapse
Affiliation(s)
- Arvind Kumar Morya
- Head of the Department, Department of Ophthalmology, All India Institute of Medical Sciences, Hyderabad 508126, Telangana, India
| | - Prasanna Venkatesh Ramesh
- Glaucoma Medical Officer, Department of Glaucoma and Research, Mahathma Eye Hospital Private Limited, Trichy 620017, Tamil Nadu, India
| | - Prateek Nishant
- Department of Ophthalmology, ESIC Medical College, Patna 801103, Bihar, India
| | - Kirandeep Kaur
- Department of Pediatric Ophthalmology and Strabismus, Gomabai Netralaya and Research Centre, Neemuch 458441, Madhya Pradesh, India
| | - Bharat Gurnani
- Cornea and Refractive Services, Gomabai Netralaya and Research Centre, Neemuch 458441, Madhya Pradesh, India
| | - Aarti Heda
- Department of Ophthalmology, National Institute of Ophthalmology, Pune 411000, Maharashtra, India
| | - Sarika Salodia
- Global Medical Safety, Lundbeck, Singapore 569933, Singapore, Singapore
| |
Collapse
|
|
3
|
Mizutani K, Minami I, Mikami R, Kido D, Takeda K, Nakagawa K, Takemura S, Saito N, Kominato H, Sakaniwa E, Konuma K, Izumi Y, Ogawa Y, Iwata T. Improvement of periodontal parameters following intensive diabetes care and supragingival dental prophylaxis in patients with type 2 diabetes: A prospective cohort study. J Clin Periodontol 2024; 51:733-741. [PMID: 38449337 DOI: 10.1111/jcpe.13958] [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: 11/25/2023] [Revised: 01/21/2024] [Accepted: 01/22/2024] [Indexed: 03/08/2024]
Abstract
AIM This study aimed to investigate the effects of diabetes care on periodontal inflammation. MATERIALS AND METHODS This prospective cohort study included 51 Japanese patients with type 2 diabetes who underwent intensive diabetes care including educational hospitalization and regular outpatient treatment for 6 months. Dental prophylaxis without subgingival scaling was provided three times during the observational period. Associations between changes in periodontal parameters and glycaemic control levels were evaluated using multiple regression analysis. RESULTS Overall, 33 participants (mean age: 58.7 ± 12.9) were followed up for 6 months. At baseline examination, 82% were diagnosed with Stage III or IV periodontitis. Haemoglobin A1c (HbA1c) level changed from 9.6 ± 1.8% at baseline to 7.4 ± 1.3% at 6 months. The ratio of probing pocket depth (PPD) ≥4 mm, bleeding on probing (BOP), full-mouth plaque control record (PCR), periodontal epithelial surface area (PESA) and periodontal inflamed surface area (PISA) also significantly improved. The reduction in PPD and PESA was significantly associated with changes in both HbA1c and fasting plasma glucose (FPG) levels, and the reduction in PISA was significantly associated with an improvement in FPG after adjusting for smoking, change in body mass index and full-mouth PCR. CONCLUSIONS This is the first study to report a significant improvement in PPD and BOP after intensive diabetes care and dental prophylaxis without subgingival scaling. CLINICAL TRIAL REGISTRATION NUMBER UMIN000040218.
Collapse
Affiliation(s)
- Koji Mizutani
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Isao Minami
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Endocrinology, Yokohama City Minato Red Cross Hospital, Yokohama, Japan
| | - Risako Mikami
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Daisuke Kido
- Department of General Dentistry, Tokyo Medical and Dental University Hospital, Tokyo, Japan
| | - Kohei Takeda
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Keita Nakagawa
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Shu Takemura
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Natsumi Saito
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hiromi Kominato
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Eri Sakaniwa
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kuniha Konuma
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yuichi Izumi
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Oral Care Periodontics Center, Southern Tohoku General Hospital, Fukushima, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takanori Iwata
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| |
Collapse
|
|
4
|
Fu J, Shinjo T, Li Q, St-Louis R, Park K, Yu MG, Yokomizo H, Simao F, Huang Q, Wu IH, King GL. Regenerating glomerular metabolism and function by podocyte pyruvate kinase M2 in diabetic nephropathy. JCI Insight 2022; 7:155260. [PMID: 35133981 PMCID: PMC8983139 DOI: 10.1172/jci.insight.155260] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 01/26/2022] [Indexed: 11/17/2022] Open
Abstract
Diabetic nephropathy (DN) arises from systemic and local changes in glucose metabolism and hemodynamics. We have reported that many glycolytic and mitochondrial enzymes, such as pyruvate kinase M2 (PKM2), were elevated in renal glomeruli of DN-protected type 1 and type 2 diabetic patients. Here, mice with PKM2-specific overexpression in podocytes (PPKM2Tg) were generated to uncover its renal protective function as potential therapeutic target, which prevented elevated albumin-creatinine ratio (ACR), mesangial expansion, basement membrane thickness and podocyte foot process effacement after 7-months of STZ-induced diabetes. Further, diabetes-induced impairment of glycolytic rate and mitochondrial function were normalized in diabetic PPKM2Tg glomeruli, in concordance with elevated Ppargc1a and Vegf expressions. Restored VEGF expression improved glomerular maximal mitochondrial function in diabetic PPKM2Tg and WT mice. Elevated VEGF levels were observed in the glomeruli of DN-protected patients with chronic type 1 diabetes, and clinically correlated with estimated GFR, but not glycemic control. Mechanistically, the preservations of mitochondrial function and VEGF expression were dependent on tetrameric structure and enzymatic activities of PKM2 in podocyte. These findings demonstrated that PKM2 structure and enzymatic activation in podocytes can preserve entire glomerular mitochondrial function against toxicity of hyperglycemia via paracrine factors such as VEGF and prevent DN progression.
Collapse
Affiliation(s)
- Jialin Fu
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, United States of America
| | - Takanori Shinjo
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, United States of America
| | - Qian Li
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, United States of America
| | - Ronald St-Louis
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, United States of America
| | - Kyoungmin Park
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, United States of America
| | - Marc G Yu
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, United States of America
| | - Hisashi Yokomizo
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, United States of America
| | - Fabricio Simao
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, United States of America
| | - Qian Huang
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, United States of America
| | - I-Hsien Wu
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, United States of America
| | - George L King
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, United States of America
| |
Collapse
|
|
5
|
Liu F, Guo J, Qiao Y, Pan S, Duan J, Liu D, Liu Z. MiR-138 plays an important role in diabetic nephropathy through SIRT1-p38-TTP regulatory axis. J Cell Physiol 2021; 236:6607-6618. [PMID: 33843045 DOI: 10.1002/jcp.30238] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 12/09/2020] [Accepted: 12/10/2020] [Indexed: 11/08/2022]
Abstract
Diabetic nephropathy (DN) is the main cause of chronic kidney disease (CKD) and is one of the most common and serious complications of diabetes mellitus (DM). Sirtuin 1 (SIRT1) and tristetraprolin (TTP) are two important protective factors in DN; however, the regulatory relationship between SIRT1 and TTP, and the underneath mechanism are interesting but still unclear. Identifying the key factors that regulate SIRT1 or TTP may be of great value to the understanding and treatment of the DN. In this study, through systematic experimental methods, we found that the expression of miR-138 was significantly upregulated in DN clinical patient samples, and our experimental results suggested that miR-138 could bind the 3'-UTR of SIRT1 and inhibit its expression in both cultured podocytes and db/db mice kidney tissues. Furthermore, our in vitro and in vivo experiments also indicated miR-138 could target SIRT1 and affect TTP through p38 pathway. And downregulation of miR-138 attenuated podocyte injury and showed some extent of therapeutic effects in DN mice models. Our findings revealed that the regulatory axis of miR-138-SIRT1-p38-TTP might play a key role in DN. We believe that these findings may be of some value for deepening the understanding of DN and may serve as a reference for future treatment of this disease.
Collapse
Affiliation(s)
- Fengxun Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jia Guo
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
| | - Yingjin Qiao
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Shaokang Pan
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, China
| | - Jiayu Duan
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, China
| | - Dongwei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, China
| |
Collapse
|
|
6
|
The cells involved in the pathological process of diabetic retinopathy. Biomed Pharmacother 2020; 132:110818. [PMID: 33053509 DOI: 10.1016/j.biopha.2020.110818] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 09/20/2020] [Accepted: 09/25/2020] [Indexed: 01/04/2023] Open
Abstract
Diabetic retinopathy(DR) is an expanding global health problem, the exact mechanism of which has not yet been clarified clearly, new insights into retinal physiology indicate that diabetes-induced retinal dysfunction may be viewed as an impairment of the retinal neurovascular unit, including retinal ganglion cells, glial cells, endothelial cells, pericytes, and retinal pigment epithelium. Different retinal cells have unique structure and functions, while the interactions among which are less known. Cells are the basic unit of organism structure and function, their impairment could lead to abnormal physiological functions and even organ disorder. Considering the body is multi-dimension and the complexity of DR, one point or a single type of cell can't be used to illustrate the mechanism of occurrence and development of DR. In this review, we provided a systematic and comprehensive elaboration of the cells that are involved in the process of DR. We underlined the importance of considering the neurovascular unit, not just retinal vascular and neural cells, in understanding the pathophysiology of DR. Our studies provided a better understanding of the pathological process in DR and provide a theoretical basis for further research.
Collapse
|
|
7
|
Kheiripour N, Alipoor B, Ranjbar A, Pourfarjam Y, Kazemi Najafabadi F, Dehkhodaei N, Farhadiannezhad M, Ghasemi H. The effects of synthetic orally administrated insulin nanoparticles in comparison to injectable insulin on the renal function markers of type 1- diabetic rats. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2020; 23:810-818. [PMID: 32695298 PMCID: PMC7351444 DOI: 10.22038/ijbms.2020.42292.9985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 01/31/2020] [Indexed: 11/23/2022]
Abstract
OBJECTIVES Injectable insulin is the most widely used therapy in patients with type 1 diabetes which has several disadvantages. The present study was aimed to evaluate the efficacy of injectable insulin on diabetes mellitus-related complications in comparison to orally encapsulated insulin nanoparticles. MATERIALS AND METHODS This study involved 42 Wistar rats separated into 5 groups, including control (C), diabetic control (D), diabetic receiving regular insulin (INS), diabetic receiving encapsulated insulin nanoparticle (INP), and diabetic receiving chitosan for two months. Biochemical parameters in serum and urine were measured using spectrophotometric or ELISA methods. mRNA levels of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated using quantitative PCR. RESULTS There were no significant differences between the two forms of insulin in controlling the glycemic condition (P-value>0.05), but oral INP was more effective in correcting diabetic dyslipidemia in comparison to injectable insulin (P-value<0.05). Urine volume and creatinine excretion were significantly modulated by insulin and oral INP in diabetic groups (P-value<0.05), although the effects of INP on the modulation of execration of urea, acid uric, and albumin was more dramatic. Oral INP caused a significant decrease in urine concentration of KIM-1 and NGAL as well as expression of KIM-1 in renal tissue (P-value<0.05). CONCLUSION Our results suggested that oral INP is more effective than injectable insulin in modulation of urine and serum diabetic-related parameters.
Collapse
Affiliation(s)
- Nejat Kheiripour
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Behnam Alipoor
- Department of Laboratory Sciences, Faculty of Paramedicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Akram Ranjbar
- Toxicology and Pharmacology Department, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Yasin Pourfarjam
- Department of Chemistry, University of Cincinnati, Cincinnati, OH, United States of America
| | - Farzaneh Kazemi Najafabadi
- Toxicology and Pharmacology Department, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Narges Dehkhodaei
- Toxicology and Pharmacology Department, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Hassan Ghasemi
- Department of Clinical Biochemistry, Abadan Faculty of Medical Sciences, Abadan, Iran
| |
Collapse
|
|
8
|
Arredondo-García VK, Cepeda-Nieto AC, Batallar-Gómez T, Salinas-Santander M, Zugasti-Cruz A, Ramírez-Calvillo L, Maldonado-Sánchez K, Morlett-Chávez J, Barajas-Martínez H. Association of the Vascular Endothelial Growth Factor Gene Polymorphism +936 C/T with Diabetic Neuropathy in Patients with Type 2 Diabetes Mellitus. Arch Med Res 2019; 50:181-186. [DOI: 10.1016/j.arcmed.2019.07.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 04/05/2019] [Accepted: 07/30/2019] [Indexed: 02/08/2023]
|
|
9
|
Wagnew F, Eshetie S, Kibret GD, Zegeye A, Dessie G, Mulugeta H, Alemu A. Diabetic nephropathy and hypertension in diabetes patients of sub-Saharan countries: a systematic review and meta-analysis. BMC Res Notes 2018; 11:565. [PMID: 30081966 PMCID: PMC6080368 DOI: 10.1186/s13104-018-3670-5] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 08/01/2018] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE This meta-analysis was undertaken to estimate the prevalence of diabetic nephropathy and its association with hypertension in diabetics of sub-Saharan African countries. RESULTS A total of 27 studies were included for the meta-analysis. The pooled overall prevalence of diabetic nephropathy was 35.3 (95% CI 27.46-43.14). In sub-group analyses by types of diabetes and regions, for instance, the prevalence was 41.4% (95% CI 32.2-50.58%) in type-2 diabetes mellitus and 29.7% (95% CI 14.3-45.1%) in Eastern Africa. Pooled point estimates from included studies revealed an increased risk of diabetic nephropathy with hypertension compared to without hypertension (OR = 1.67, 95% CI 1.31, 2.14). Diabetic nephropathy is a common complication in diabetic patients. Diabetic nephropathy complication is significantly higher in hypertensive patients. A preventive strategy should be adopted or planned to reduce diabetes mellitus and its complication of neuropathy, particularly in hypertensive.
Collapse
Affiliation(s)
- Fasil Wagnew
- College of Health Science, Debre Markos University, Debre Markos, Ethiopia.
| | - Setegn Eshetie
- College of Health Science, University of Gondar, Gondar, Ethiopia
| | | | - Abriham Zegeye
- College of Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Getenet Dessie
- College of Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Henok Mulugeta
- College of Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Amanuel Alemu
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
| |
Collapse
|
|
10
|
Yang CC, Lin CH, Wang NK, Lai CC, Lo FS. Risk Factors Associated With the Development of Nephropathy 10 Years After Diagnosis in Taiwanese Children With Juvenile-Onset Type 1 Diabetes-A Cohort Study From the CGJDES. Front Endocrinol (Lausanne) 2018; 9:429. [PMID: 30123184 PMCID: PMC6086139 DOI: 10.3389/fendo.2018.00429] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 07/10/2018] [Indexed: 12/29/2022] Open
Abstract
Objective: To examine the risk factors for diabetic nephropathy (DN) 10 years after the diagnosis of juvenile-onset type 1 diabetes mellitus (T1DM) in a Taiwanese population. Research Design and Methods: This retrospective, observational, longitudinal cohort study of 224 patients with T1DM for >10 years (mean duration 12.6 years) included participants from the Chang Gung Juvenile Diabetes Eye Study Group. The patients received a T1DM diagnosis before the age of 18 years and were treated at the pediatric endocrine department of Chang Gung Memorial Hospital in Taiwan. The epidemiological and laboratory data such as age, sex, duration of diabetes, self-reported smoking, blood pressure, lipid profiles, urinalysis, and glycated hemoglobin A1c (HbA1c) levels were collected from medical records retrospectively for investigating the relationship between the clinical parameters and the development of DN in T1DM. Results: During follow-up, 44 of the 224 patients (19.6%) developed DN, of whom 61.4% were female. Cox proportional hazards model analysis indicated that the female (HR 3.40, 95% CI 1.66-6.96, p = 0.001), smoking (HR 3.60, 95% CI 1.28-10.10, p = 0.015), HbA1c level (HR 1.27, 95% CI 1.07-1.49, p = 0.005), diastolic blood pressure (HR 1.06, 95% CI 1.03-1.09, p < 0.001) were significantly correlated with DN after adjustment for multiple variables. The tight glucose control with multiple daily injections produced 49 % risk reduction (HR 0.51, 95% CI 0.26-0.98, p = 0.043). Conclusions: The risk of DN in patients with juvenile-onset T1DM 10 years after the T1DM diagnosis was increased with female, smoking, high HbA1c, diastolic blood pressure levels and attenuated by intensive therapy.
Collapse
Affiliation(s)
- Ching-Chien Yang
- Division of Pediatric Endocrinology and Genetics, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Chia-Hung Lin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Taoyuan, Taiwan
| | - Nan-Kai Wang
- Department of Medicine, College of Medicine, Taoyuan, Taiwan
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Chi-Chun Lai
- Department of Medicine, College of Medicine, Taoyuan, Taiwan
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Fu-Sung Lo
- Division of Pediatric Endocrinology and Genetics, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Taoyuan, Taiwan
| |
Collapse
|
|
11
|
Duh EJ, Sun JK, Stitt AW. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight 2017; 2:93751. [PMID: 28724805 DOI: 10.1172/jci.insight.93751] [Citation(s) in RCA: 642] [Impact Index Per Article: 80.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Diabetic retinopathy (DR) causes significant visual loss on a global scale. Treatments for the vision-threatening complications of diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) have greatly improved over the past decade. However, additional therapeutic options are needed that take into account pathology associated with vascular, glial, and neuronal components of the diabetic retina. Recent work indicates that diabetes markedly impacts the retinal neurovascular unit and its interdependent vascular, neuronal, glial, and immune cells. This knowledge is leading to identification of new targets and therapeutic strategies for preventing or reversing retinal neuronal dysfunction, vascular leakage, ischemia, and pathologic angiogenesis. These advances, together with approaches embracing the potential of preventative or regenerative medicine, could provide the means to better manage DR, including treatment at earlier stages and more precise tailoring of treatments based on individual patient variations.
Collapse
Affiliation(s)
- Elia J Duh
- Wilmer Ophthalmologic Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jennifer K Sun
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Alan W Stitt
- Centre for Experimental Medicine, Queen's University Belfast, Northern Ireland, United Kingdom
| |
Collapse
|
|
12
|
Takir M, Unal AD, Kostek O, Bayraktar N, Demirag NG. Cystatin-C and TGF-β levels in patients with diabetic nephropathy. Nefrologia 2016; 36:653-659. [DOI: 10.1016/j.nefro.2016.06.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Revised: 06/15/2016] [Accepted: 06/25/2016] [Indexed: 12/22/2022] Open
|
|
13
|
Jiang F, Chen Q, Huang L, Wang Y, Zhang Z, Meng X, Liu Y, Mao C, Zheng F, Zhang J, Yan H. TNFSF15 Inhibits Blood Retinal Barrier Breakdown Induced by Diabetes. Int J Mol Sci 2016; 17:ijms17050615. [PMID: 27120595 PMCID: PMC4881442 DOI: 10.3390/ijms17050615] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Revised: 04/07/2016] [Accepted: 04/11/2016] [Indexed: 12/21/2022] Open
Abstract
Tumor necrosis factor superfamily 15 (TNFSF15) is an endogenous neovascularization inhibitor and an important negative regulator of vascular homeostasis. This study aimed to explore the potential role of TNFSF15 in diabetic retinopathy. Vitreous TNFSF15 and VEGF levels in proliferative diabetic retinopathy (PDR) patients were detected by ELISA. Retinal expression of TNFSF15 and the content of tight junction proteins (TJPs) in rats were detected by immunohistochemistry and Western blot, respectively. The blood retinal barrier (BRB) permeability was evaluated using Evans Blue (EB) dye. The TNFSF15/VEGF ratio was decreased in the vitreous fluid of patients with PDR relative to the controls, even though the expression levels of TNFSF15 were higher. TNFSF15 was dramatically decreased one month later after diabetes induction (p < 0.001), and then increased three months later and thereafter. TNFSF15 treatment significantly protected the BRB in the diabetic animals. Diabetes decreased TJPs levels in the retina, and these changes were inhibited by TNFSF15 treatment. Moreover, TNFSF15 decreased activation of VEGF both in mRNA and protein levels caused by diabetes. These results indicate that TNFSF15 is an important inhibitor in the progression of DR and suggest that the regulation of TNFSF15 shows promise for the development of diabetic retinopathy treatment strategies.
Collapse
Affiliation(s)
- Feng Jiang
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Qingzhong Chen
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Liming Huang
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Ying Wang
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Zhuhong Zhang
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Xiangda Meng
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Yuanyuan Liu
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Chunjie Mao
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Fang Zheng
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Jingkai Zhang
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Hua Yan
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China.
| |
Collapse
|
|
14
|
Khan FA, Al Jameil N, Arjumand S, Khan MF, Tabassum H, Alenzi N, Hijazy S, Alenzi S, Subaie S, Fatima S. Comparative Study of Serum Copper, Iron, Magnesium, and Zinc in Type 2 Diabetes-Associated Proteinuria. Biol Trace Elem Res 2015; 168:321-9. [PMID: 26024734 DOI: 10.1007/s12011-015-0379-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 05/20/2015] [Indexed: 01/03/2023]
Abstract
Trace element (TE) disturbances are well noted in type 2 diabetes mellitus (T2DM) and its associated complications. In present study, the effect of proteinuria on serum copper (Cu), iron (Fe), magnesium (Mg), and zinc (Zn) in T2DM patients with and without proteinuria was seen. Total subjects were aged between 30 and 90 years; 73 had proteinuria, 76 had T2DM with proteinuria, 76 had T2DM, and 75 were controls. Serum Cu(II), Fe(III), Mg(II), and Zn(II) were assayed by inductively coupled plasma optical emission spectrometer (ICP-OES). Urinary albumin estimation was performed by turbidimetric method. Other biochemical parameters were analyzed by ROCHE Module COBAS 6000 analyzer. Statistical analysis was performed using analysis of variance (ANOVA) at P<0.0001 followed by t test. Pearson correlation was applied to estimate the effect of proteinuria on TE. Serum Cu(II) level was increased in T2DM patients with proteinuria while Fe(III) was found elevated in T2DM (P<0.0001) compared to control groups. Zn(II) and Mg(II) were significantly low in proteinuria, T2DM with proteinuria, and T2DM (P<0.0001) compare to controls. Serum Cu(II) showed strong positive association with albumin creatinine ratio (ACR) in T2DM with proteinuria group and T2DM group (P<0.01). Fe(III) was positively and Zn(II) was negatively associated with ACR at P<0.10, in T2DM with proteinuria group. Mg(II) was negatively linked with ACR P<0.01 in proteinuria, T2DM with proteinuria, and T2DM group. TE were observed more disturbed in T2DM with proteinuria group, thus considered to be the part of T2DM routine checkup and restricts the disease towards its progression.
Collapse
Affiliation(s)
- Farah Aziz Khan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Noura Al Jameil
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia.
| | - Sadia Arjumand
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Mohammad Fareed Khan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Hajera Tabassum
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Naif Alenzi
- Department of Research and Seized, Saudi Food and Drug Authority, Element Analysis Unit, Riyadh, Kingdom of Saudi Arabia
| | - Sereen Hijazy
- Department of Research and Seized, Saudi Food and Drug Authority, Element Analysis Unit, Riyadh, Kingdom of Saudi Arabia
| | - Samyah Alenzi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Sahar Subaie
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Sabiha Fatima
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
| |
Collapse
|
|
15
|
Oltean S, Qiu Y, Ferguson JK, Stevens M, Neal C, Russell A, Kaura A, Arkill KP, Harris K, Symonds C, Lacey K, Wijeyaratne L, Gammons M, Wylie E, Hulse RP, Alsop C, Cope G, Damodaran G, Betteridge KB, Ramnath R, Satchell SC, Foster RR, Ballmer-Hofer K, Donaldson LF, Barratt J, Baelde HJ, Harper SJ, Bates DO, Salmon AHJ. Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy. J Am Soc Nephrol 2014; 26:1889-904. [PMID: 25542969 DOI: 10.1681/asn.2014040350] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 10/15/2014] [Indexed: 01/11/2023] Open
Abstract
Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A165b in diabetic nephropathy. Renal expression of VEGF-A165b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A165b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A165b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A165b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A165b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A165b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy.
Collapse
Affiliation(s)
| | - Yan Qiu
- School of Physiology and Pharmacology and
| | | | | | - Chris Neal
- School of Physiology and Pharmacology and
| | | | - Amit Kaura
- School of Physiology and Pharmacology and
| | | | | | | | | | | | | | - Emma Wylie
- School of Physiology and Pharmacology and Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom
| | | | | | - George Cope
- Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom
| | | | | | - Raina Ramnath
- Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom
| | - Simon C Satchell
- Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom
| | - Rebecca R Foster
- Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom
| | - Kurt Ballmer-Hofer
- Biomolecular Research, Molecular Cell Biology, Paul Scherrer Institut, Villigen, Switzerland
| | - Lucy F Donaldson
- School of Physiology and Pharmacology and School of Life Sciences and
| | - Jonathan Barratt
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom; and
| | - Hans J Baelde
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - David O Bates
- Cancer Biology, Division of Oncology, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Andrew H J Salmon
- School of Physiology and Pharmacology and Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, United Kingdom;
| |
Collapse
|
|
16
|
Abstract
Diabetic complications are the major causes of morbidity and mortality in patients with diabetes. Microvascular complications include retinopathy, nephropathy and neuropathy, which are leading causes of blindness, end‐stage renal disease and various painful neuropathies; whereas macrovascular complications involve atherosclerosis related diseases, such as coronary artery disease, peripheral vascular disease and stroke. Diabetic complications are the result of interactions among systemic metabolic changes, such as hyperglycemia, local tissue responses to toxic metabolites from glucose metabolism, and genetic and epigenetic modulators. Chronic hyperglycemia is recognized as a major initiator of diabetic complications. Multiple molecular mechanisms have been proposed to mediate hyperglycemia’s adverse effects on vascular tissues. These include increased polyol pathway, activation of the diacylglycerol/protein kinase C pathway, increased oxidative stress, overproduction and action of advanced glycation end products, and increased hexosamine pathway. In addition, the alterations of signal transduction pathways induced by hyperglycemia or toxic metabolites can also lead to cellular dysfunctions and damage vascular tissues by altering gene expression and protein function. Less studied than the toxic mechanisms, hyperglycemia might also inhibit the endogenous vascular protective factors such as insulin, vascular endothelial growth factor, platelet‐derived growth factor and activated protein C, which play important roles in maintaining vascular homeostasis. Thus, effective therapies for diabetic complications need to inhibit mechanisms induced by hyperglycemia’s toxic effects and also enhance the endogenous protective factors. The present review summarizes these multiple biochemical pathways activated by hyperglycemia and the potential therapeutic interventions that might prevent diabetic complications. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00018.x, 2010)
Collapse
Affiliation(s)
- Munehiro Kitada
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Boston, MA, USA
| | - Zhaoyun Zhang
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Boston, MA, USA
| | - Akira Mima
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Boston, MA, USA
| | - George L King
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Boston, MA, USA
| |
Collapse
|
|
17
|
Xu Z, Wei Y, Gong J, Cho H, Park JK, Sung ER, Huang H, Wu L, Eberhart C, Handa JT, Du Y, Kern TS, Thimmulappa R, Barber AJ, Biswal S, Duh EJ. NRF2 plays a protective role in diabetic retinopathy in mice. Diabetologia 2014; 57:204-13. [PMID: 24186494 PMCID: PMC4039644 DOI: 10.1007/s00125-013-3093-8] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Accepted: 10/07/2013] [Indexed: 12/29/2022]
Abstract
AIMS/HYPOTHESIS Although much is known about the pathophysiological processes contributing to diabetic retinopathy (DR), the role of protective pathways has received less attention. The transcription factor nuclear factor erythroid-2-related factor 2 (also known as NFE2L2 or NRF2) is an important regulator of oxidative stress and also has anti-inflammatory effects. The objective of this study was to explore the potential role of NRF2 as a protective mechanism in DR. METHODS Retinal expression of NRF2 was investigated in human donor and mouse eyes by immunohistochemistry. The effect of NRF2 modulation on oxidative stress was studied in the human Müller cell line MIO-M1. Non-diabetic and streptozotocin-induced diabetic wild-type and Nrf2 knockout mice were evaluated for multiple DR endpoints. RESULTS NRF2 was expressed prominently in Müller glial cells and astrocytes in both human and mouse retinas. In cultured MIO-M1 cells, NRF2 inhibition significantly decreased antioxidant gene expression and exacerbated tert-butyl hydroperoxide- and hydrogen peroxide-induced oxidative stress. NRF2 activation strongly increased NRF2 target gene expression and suppressed oxidant-induced reactive oxygen species. Diabetic mice exhibited retinal NRF2 activation, indicated by nuclear translocation. Superoxide levels were significantly increased by diabetes in Nrf2 knockout mice as compared with wild-type mice. Diabetic Nrf2 knockout mice exhibited a reduction in retinal glutathione and an increase in TNF-α protein compared with wild-type mice. Nrf2 knockout mice exhibited early onset of blood-retina barrier dysfunction and exacerbation of neuronal dysfunction in diabetes. CONCLUSIONS/INTERPRETATION These results indicate that NRF2 is an important protective factor regulating the progression of DR and suggest enhancement of the NRF2 pathway as a potential therapeutic strategy.
Collapse
Affiliation(s)
- Zhenhua Xu
- Department of Ophthalmology, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Abstract
Oxidative stress has been linked to the pathogenesis of the major complications of diabetes in the kidney, the heart, the eye or the vasculature. NADPH oxidases of the Nox family are a major source of ROS (reactive oxygen species) and are critical mediators of redox signalling in cells from different organs afflicted by the diabetic milieu. In the present review, we provide an overview of the current knowledge related to the understanding of the role of Nox in the processes that control cell injury induced by hyperglycaemia and other predominant factors enhanced in diabetes, including the renin–angiotensin system, TGF-β (transforming growth factor-β) and AGEs (advanced glycation end-products). These observations support a critical role for Nox homologues in diabetic complications and indicate that NADPH oxidases are an important therapeutic target. Therefore the design and development of small-molecule inhibitors that selectively block Nox oxidases appears to be a reasonable approach to prevent or retard the complications of diabetes in target organs. The bioefficacy of these agents in experimental animal models is also discussed in the present review.
Collapse
|
|
19
|
Mima A, Qi W, King GL. Implications of treatment that target protective mechanisms against diabetic nephropathy. Semin Nephrol 2013; 32:471-8. [PMID: 23062988 DOI: 10.1016/j.semnephrol.2012.07.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Diabetes results in vascular changes and dysfunction, and vascular complications are the leading cause of morbidity and mortality in diabetic patients. There has been a continual increase in the number of diabetic nephropathy patients and epidemic increases in the number of patients progressing to end-stage renal diseases. To identify targets for therapeutic intervention, most studies have focused on understanding how abnormal levels of glucose metabolites cause diabetic nephropathy, which is of paramount importance in devising strategies to combat the development and progression of diabetic nephropathy. However, less studied than the systemic toxic mechanisms, hyperglycemia and dyslipidemia might inhibit the endogenous vascular protective factors such as insulin, vascular endothelial growth factor, and platelet-derived growth factor. In this review, we highlight the importance of enhancing endogenous protective factors to prevent or delay diabetic nephropathy.
Collapse
Affiliation(s)
- Akira Mima
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | | | | |
Collapse
|
|
20
|
Fiorentino L, Cavalera M, Menini S, Marchetti V, Mavilio M, Fabrizi M, Conserva F, Casagrande V, Menghini R, Pontrelli P, Arisi I, D'Onofrio M, Lauro D, Khokha R, Accili D, Pugliese G, Gesualdo L, Lauro R, Federici M. Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. EMBO Mol Med 2013; 5:441-55. [PMID: 23401241 PMCID: PMC3598083 DOI: 10.1002/emmm.201201475] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Revised: 12/10/2012] [Accepted: 12/11/2012] [Indexed: 01/15/2023] Open
Abstract
ADAM17 and its inhibitor TIMP3 are involved in nephropathy, but their role in diabetic kidney disease (DKD) is unclear. Diabetic Timp3−/− mice showed increased albuminuria, increased membrane thickness and mesangial expansion. Microarray profiling uncovered a significant reduction of Foxo1 expression in diabetic Timp3−/− mice compared to WT, along with FoxO1 target genes involved in autophagy, while STAT1, a repressor of FoxO1 transcription, was increased. Re-expression of Timp3 in Timp3−/− mesangial cells rescued the expression of Foxo1 and its targets, and decreased STAT1 expression to control levels; abolishing STAT1 expression led to a rescue of FoxO1, evoking a role of STAT1 in linking Timp3 deficiency to FoxO1. Studies on kidney biopsies from patients with diabetic nephropathy confirmed a significant reduction in TIMP3, FoxO1 and FoxO1 target genes involved in autophagy compared to controls, while STAT1 expression was strongly increased. Our study suggests that loss of TIMP3 is a hallmark of DKD in human and mouse models and designates TIMP3 as a new possible therapeutic target for diabetic nephropathy.
Collapse
|
|
21
|
Liu Y, Leo LF, McGregor C, Grivitishvili A, Barnstable CJ, Tombran-Tink J. Pigment epithelium-derived factor (PEDF) peptide eye drops reduce inflammation, cell death and vascular leakage in diabetic retinopathy in Ins2(Akita) mice. Mol Med 2012; 18:1387-401. [PMID: 23019073 DOI: 10.2119/molmed.2012.00008] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Accepted: 09/20/2012] [Indexed: 12/19/2022] Open
Abstract
Inflammation, neurodegeneration and microvascular irregularities are included in the spectrum of defects associated with diabetic retinopathy. Here, we evaluated intraocular deliverability features of two pigment epithelium-derived factor (PEDF) derivatives given as eye drops and their efficacy in modulating diabetes-induced retinal complications. The antiangiogenic PEDF60-77 (P60) and neuroprotective PEDF78-121 (P78) derivatives were applied to Ins2(Akita) mouse eyes once a week for 15 wks at the onset of hyperglycemia. Peptides, labeled with Alexa Fluor 488, were observed penetrating the cornea by 1-4 h and gained access to the ciliary body, retinal pigment epithelium (RPE)-choroid complex, retina microvasculature and vitreous. Peak vitreous levels were 0.2 μg/mL for P60 and 0.9 μg/mL for P78 after 0.5 and 4 h, respectively. Both peptides reduced vascular leakage by ~60% and increased zona occludens 1 (ZO1) and occludin expression in the microvasculature to nondiabetic levels. P60 induced pERK1/2 and P78 promoted pAKT in Muller glia, two signals that were dampened in diabetic conditions. Pharmacologically inhibiting AKT signaling in the retina blocked effects of the peptides on ZO1 and occludin expression. P78 reduced levels of 9/20 cytokines in diabetic vitreous including interferon (IFN)-γ, interleukin (IL)-6, IL-3 and tumor necrosis factor (TNF)-α. P60 lowered levels of 6/20 cytokines but was less effective than P78. Neuroprotective P78 prevented diabetes-induced microglia activation by ~60%, retinal ganglion cell (RGC) death by ~22% and inner plexiform layer thinning by ~13%. In summary, we provide evidence that PEDF bioactive derivatives gained access to the retina by topical delivery and validated their efficacy in reducing diabetic retinopathy complications. Our findings argue for glia regulation of microvascular leakage and an early root cause for RGC degeneration embedded in microglia activation.
Collapse
Affiliation(s)
- Yanling Liu
- Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, United States of America
| | | | | | | | | | | |
Collapse
|
|
22
|
Matsui F, Meldrum KK. The role of the Janus kinase family/signal transducer and activator of transcription signaling pathway in fibrotic renal disease. J Surg Res 2012; 178:339-45. [PMID: 22883438 DOI: 10.1016/j.jss.2012.06.050] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Revised: 06/01/2012] [Accepted: 06/21/2012] [Indexed: 12/15/2022]
Abstract
Over the past several years, a number of cytokines and growth factors including transforming growth factor β1, tumor necrosis factor α, and angiotensin II have been shown to play a crucial role in renal fibrosis. The Janus kinase family (JAK) and signal transducers and activators of transcription (STATs) constitute one of the primary signaling pathways that regulate cytokine expression, and the JAK/STAT signaling pathway has increasingly been implicated in the pathophysiology of renal disease. This review examines the role of the JAK/STAT signaling pathway in fibrotic renal disease. The JAK/STAT signaling pathway is activated in a variety of renal diseases and has been implicated in the pathophysiology of renal fibrosis. Experimental evidence suggests that inhibition of the JAK/STAT signaling pathway, in particular JAK2 and STAT3, may suppress renal fibrosis and protect renal function. However, it is incompletely understood which cells activate the JAK/STAT signaling pathway and which JAK/STAT signaling pathway is activated in each renal disease. Research regarding JAK/STAT signaling and its contribution to renal disease is still ongoing in humans. Future studies are required to elucidate the potential role of JAK/STAT signaling inhibition as a therapeutic strategy in the attenuation of renal fibrosis.
Collapse
Affiliation(s)
- Futoshi Matsui
- Department of Urology, University of Florida School of Medicine, Gainesville, Florida 32610, USA
| | | |
Collapse
|
|
23
|
Le Guelte A, Gavard J. Role of endothelial cell-cell junctions in endothelial permeability. Methods Mol Biol 2011; 763:265-79. [PMID: 21874458 DOI: 10.1007/978-1-61779-191-8_18] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
The endothelial barrier separates the inner blood compartment from the surrounding tissues. At the molecular level, adhesion molecules accumulate at the endothelial cell-cell junction and contribute to maintain vascular integrity. An increase in the endothelial permeability is frequently associated with the deregulation of junctional adhesion. Here, we review how to evaluate the in vitro functions of endothelial cell-cell contacts. We focus this chapter on cell imagery and biochemical analysis of VE-cadherin, the main constituent of adherens junction, and we also provide description of endothelial cell models and methods for studying tight junctions.
Collapse
Affiliation(s)
- Armelle Le Guelte
- Institut Cochin, Université Paris Descartes, UMR-CNRS 8104, Paris, France
| | | |
Collapse
|
|
24
|
Abstract
The results of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) and Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) clinical trials raise important questions about the prevention and treatment of coronary heart disease among type 2 diabetics and nondiabetics. The BARI 2D and COURAGE trials showed that pharmacological therapy is as effective as surgery or angioplasty, because of the incidence of total mortality and cardiovascular disease events. The results are consistent with the clinical trials of lipid-lowering, antihypertensive therapy. The efficacy of lowering glycohemoglobin below 7% or benefits of specific glucose-lowering drugs is still unresolved. The BARI 2D trial focused on more advanced atherosclerotic disease. An important question is whether newly incident diabetics should be screened for subclinical atherosclerosis and treated aggressively with pharmacological therapy as in the BARI 2D trial. We are still uncertain whether raising high-density lipoprotein cholesterol will provide further benefit in reducing coronary heart disease. Better measurement of plaque morphology, determinants of hypercoagulable status, and drugs to reduce thrombosis and plaque are of high priority. Longer follow-up of the BARI 2D and COURAGE trials will provide important information about the risks of cardiovascular disease events and disability. It will be important but difficult to translate the results of the trials to community practice under the current health care system.
Collapse
|
|
25
|
|