The morbidity and mortality associated with diabetic complications impose a huge socioeconomic burden worldwide. Therefore, the ultimate goal of managing diabetes mellitus (DM) is to lower the risk of macrovascular complications and highly morbid microvascular complications such as diabetic nephropathy (DN) and diabetic retinopathy (DR). Potential benefits of incretin-based therapies such as glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors on the diabetic macrovascular complications have been recently suggested, owing to their pleiotropic effects on multiple organ systems. However, studies primarily investigating the role of these therapies in diabetic microvascular complications are rare. Nevertheless, preclinical and limited clinical data suggest the potential protective effect of incretin-based agents against DN and DR via their anti-inflammatory, antioxidative, and antiapoptotic properties. Evidence also suggests that these incretin-dependent and independent beneficial effects are not necessarily associated with the glucose-lowering properties of GLP-1 RAs and DPP-4 inhibitors. Hence, in this review, we revisit the preclinical and clinical evidence of incretin-based therapy for DR and DN, the two most common, morbid complications in individuals with DM. In addition, the review discusses a few recent studies raising concerns of aggravating DR with the use of incretin-based therapies.

Citations

Citations to this article as recorded by  

• Efficacy and Safety of the Utilization of Dipeptidyl Peptidase IV Inhibitors in Diabetic Patients with Chronic Kidney Disease: A Meta-Analysis of Randomized Clinical Trials
  Moeber Mahzari, Muhannad Alqirnas, Moustafa Alhamadh, Faisal Alrasheed, Abdulrahman Alhabeeb, Wedad Al Madani, Hussain Aldera
  Diabetes, Metabolic Syndrome and Obesity.2024; Volume 17: 1425.     CrossRef
• Anti-Inflammatory Effects of GLP-1R Activation in the Retina
  Alessandra Puddu, Davide Maggi
  International Journal of Molecular Sciences.2022; 23(20): 12428.     CrossRef
• Diabetes and Its Complications: Therapies Available, Anticipated and Aspired
  Anu Grover, Komal Sharma, Suresh Gautam, Srishti Gautam, Monica Gulati, Sachin Kumar Singh
  Current Diabetes Reviews.2021; 17(4): 397.     CrossRef
• SGLT2 Inhibitors, GLP-1 Agonists, and DPP-4 Inhibitors in Diabetes and Microvascular Complications: A Review
  Christopher El Mouhayyar, Ruba Riachy, Abir Bou Khalil, Asaad Eid, Sami Azar
  International Journal of Endocrinology.2020; 2020: 1.     CrossRef
• Novel therapeutic agents for the treatment of diabetic kidney disease
  Rachel E. Hartman, P.S.S. Rao, Mariann D. Churchwell, Susan J. Lewis
  Expert Opinion on Investigational Drugs.2020; 29(11): 1277.     CrossRef
• Nationwide Trends in Pancreatitis and Pancreatic Cancer Risk Among Patients With Newly Diagnosed Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors
  Minyoung Lee, Jiyu Sun, Minkyung Han, Yongin Cho, Ji-Yeon Lee, Chung Mo Nam, Eun Seok Kang
  Diabetes Care.2019; 42(11): 2057.     CrossRef
• Effects of Dipeptidyl Peptidase-4 Inhibitors on Renal Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis
  Jae Hyun Bae, Sunhee Kim, Eun-Gee Park, Sin Gon Kim, Seokyung Hahn, Nam Hoon Kim
  Endocrinology and Metabolism.2019; 34(1): 80.     CrossRef
• Serum adipocytokines are associated with microalbuminuria in patients with type 1 diabetes and incipient chronic complications
  Tomislav Bulum, Marijana Vučić Lovrenčić, Martina Tomić, Sandra Vučković-Rebrina, Vinko Roso, Branko Kolarić, Vladimir Vuksan, Lea Duvnjak
  Diabetes & Metabolic Syndrome: Clinical Research & Reviews.2019; 13(1): 496.     CrossRef
• Protective Effects of Incretin Against Age-Related Diseases
  Di Zhang, Mingzhu Ma, Yueze Liu
  Current Drug Delivery.2019; 16(9): 793.     CrossRef
• The role of dipeptidylpeptidase-4 inhibitors in management of cardiovascular disease in diabetes; focus on linagliptin
  Annayya R. Aroor, Camila Manrique-Acevedo, Vincent G. DeMarco
  Cardiovascular Diabetology.2018;[Epub]     CrossRef

Management of diabetic complications has been a worldwide major global health issue for decades. Recent studies from many parts of the world indicate improvement in this area. However, it is unknown if such an improvement is being realized in Koreans. Although there is limited information regarding diabetic retinopathy management among Koreans, recent epidemiologic studies have indicated improved screening rates and less frequent visual impairment among type 2 diabetics. Moreover, results achieved with new diagnostic and treatment modalities aimed to improve diabetic retinopathy management are encouraging for both physicians and patients.

Citations

Citations to this article as recorded by  

• Plasma amino acids and oxylipins as potential multi-biomarkers for predicting diabetic macular edema
  Sang Youl Rhee, Eun Sung Jung, Dong Ho Suh, Su Jin Jeong, Kiyoung Kim, Suk Chon, Seung-Young Yu, Jeong-Taek Woo, Choong Hwan Lee
  Scientific Reports.2021;[Epub]     CrossRef
• Urine protein: Urine creatinine ratio correlation with diabetic retinopathy
  Samya Mujeeb, GladysR Rodrigues, RajeshR Nayak, AjayR Kamath, SumanaJ Kamath, Gurudutt Kamath
  Indian Journal of Ophthalmology.2021; 69(11): 3359.     CrossRef
• Diabetic Retinopathy in the Asia-Pacific
  
  Asia-Pacific Journal of Ophthalmology.2019;[Epub]     CrossRef
• Plasma glutamine and glutamic acid are potential biomarkers for predicting diabetic retinopathy
  Sang Youl Rhee, Eun Sung Jung, Hye Min Park, Su Jin Jeong, Kiyoung Kim, Suk Chon, Seung-Young Yu, Jeong-Taek Woo, Choong Hwan Lee
  Metabolomics.2018;[Epub]     CrossRef
• Articles inEndocrinology and Metabolismin 2016
  Won-Young Lee
  Endocrinology and Metabolism.2017; 32(1): 62.     CrossRef
• Normal-to-mildly increased albuminuria predicts the risk for diabetic retinopathy in patients with type 2 diabetes
  Min-Kyung Lee, Kyung-Do Han, Jae-Hyuk Lee, Seo-Young Sohn, Oak-Kee Hong, Jee-Sun Jeong, Mee-Kyoung Kim, Ki-Hyun Baek, Ki-Ho Song, Hyuk-Sang Kwon
  Scientific Reports.2017;[Epub]     CrossRef

Citations

Citations to this article as recorded by  

• The Vitamin D Receptor Bsm1 Variant is not Associated With Temporomandibular Disorder With or Without Bruxism
  Serkan YILDIZ, Serbülent YİĞİT, Ayşe Feyda NURSAL, Nevin KARAKUŞ, Mehmet Kemal TÜMER
  ADO Klinik Bilimler Dergisi.2024; 13(1): 100.     CrossRef
• Association analysis between the VDR gene variants and type 2 diabetes
  Shabnam Salehizadeh, Sara Ramezani, Mojgan Asadi, Mahdi Afshari, Seyed Hamid Jamaldini, Farhad Adhami Moghadam, Mandana Hasanzad
  Journal of Diabetes & Metabolic Disorders.2023;[Epub]     CrossRef
• Metabolic impact of the VDR rs1544410 in diabetic retinopathy
  Caroline Severo de Assis, Tainá Gomes Diniz, João Otávio Scarano Alcântara, Vanessa Polyana Alves de Sousa Brito, Rayner Anderson Ferreira do Nascimento, Mayara Karla dos Santos Nunes, Alexandre Sérgio Silva, Isabella Wanderley de Queiroga Evangelista, Ma
  PLOS ONE.2022; 17(2): e0263346.     CrossRef
• Vitamin D, the Vitamin D Receptor, Calcitriol Analogues and Their Link with Ocular Diseases
  Miłosz Caban, Urszula Lewandowska
  Nutrients.2022; 14(11): 2353.     CrossRef
• Vitamin D-Related Single Nucleotide Polymorphisms as Risk Biomarker of Cardiovascular Disease
  Paula González Rojo, Cristina Pérez Ramírez, José María Gálvez Navas, Laura Elena Pineda Lancheros, Susana Rojo Tolosa, María del Carmen Ramírez Tortosa, Alberto Jiménez Morales
  International Journal of Molecular Sciences.2022; 23(15): 8686.     CrossRef
• Effects of Vitamin D Receptor Genotype on Lipid Profiles and Retinopathy Risk in Type 2 Diabetes Patients: A Pilot Study
  Hussam Alhawari, Yazun Jarrar, Dina Abulebdah, Sara J. Abaalkhail, Marah Alkhalili, Sura Alkhalili, Hussein Alhawari, Munther Momani, Mohammed N. Obeidat, Rand K. Fram, Mohammad A. Salahat, Su-Jun Lee
  Journal of Personalized Medicine.2022; 12(9): 1488.     CrossRef
• Relation of vitamin D and BsmI variant with temporomandibular diseases in the Turkish population
  S. Yildiz, M.K. Tumer, S. Yigit, A.F. Nursal, A. Rustemoglu, Y. Balel
  British Journal of Oral and Maxillofacial Surgery.2021; 59(5): 555.     CrossRef
• The relationship between vitamin D receptor (VDR) rs2228570 and rs7975232 genetic variants and the risk of recurrent pregnancy loss
  Zohreh Salari, Nasrollah Saleh-Gohari, Monire Rezapour, Ahamad Khosravi, Hadi Tavakkoli, Ehsan Salarkia, Fatemeh Karami-Robati
  Meta Gene.2021; 27: 100833.     CrossRef
• Association of Bone Metabolism Indices and Bone Mineral Density with Diabetic Retinopathy in Elderly Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Inpatient Study in China
  Xin Zhao, Lili Huo, Xiaofeng Yu, Xiaomei Zhang, Fabio Vescini
  Journal of Diabetes Research.2021; 2021: 1.     CrossRef
• The Associations Between Vitamin D Receptor BsmI and ApaI Polymorphisms and Obesity in Korean Patients with Type 2 Diabetes Mellitus
  Sang Won Nam, Jinwoo Choi, Hyun Jeong Jeon, Tae Keun Oh, Dong-Hwa Lee
  Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy.2021; Volume 14: 557.     CrossRef
• Vitamin D Deficiency at Mid-Pregnancy Is Associated with a Higher Risk of Postpartum Glucose Intolerance in Women with Gestational Diabetes Mellitus
  Kyung-Soo Kim, Seok Won Park, Yong-Wook Cho, Soo-Kyung Kim
  Endocrinology and Metabolism.2020; 35(1): 97.     CrossRef
• The role of vitamin D in the pathogenesis and treatment of diabetes mellitus: a narrative review
  Maria Grammatiki, Spiros Karras, Kalliopi Kotsa
  Hormones.2019; 18(1): 37.     CrossRef
• Vitamin D-binding protein and vitamin D receptor genotypes and 25-hydroxyvitamin D levels are associated with development of aortic and mitral valve calcification and coronary artery diseases
  Amir Kiani, Ehsan Mohamadi-Nori, Asad Vaisi-Raygani, Maryam Tanhapour, Said Elahi-Rad, Fariborz Bahrehmand, Zohreh Rahimi, Tayebeh Pourmotabbed
  Molecular Biology Reports.2019; 46(5): 5225.     CrossRef
• Is Hypovitaminosis D Related to Incidence of Type 2 Diabetes and High Fasting Glucose Level in Healthy Subjects: A Systematic Review and Meta-Analysis of Observational Studies
  Shamaila Rafiq, Per Jeppesen
  Nutrients.2018; 10(1): 59.     CrossRef
• Association between the vitamin D receptor gene polymorphisms and diabetic nephropathy risk: A meta‐analysis
  Fang Yin, Jing Liu, Ming‐Xiu Fan, Xiao‐Li Zhou, Xiao‐Ling Zhang
  Nephrology.2018; 23(2): 107.     CrossRef
• BSMI single nucleotide polymorphism in vitamin D receptor gene is associated with decreased circulatory levels of serum 25-hydroxyvitamin D among micro and macrovascular complications of type 2 diabetes mellitus
  Krishnamoorthy Ezhilarasi, Umapathy Dhamodharan, Viswanathan Vijay
  International Journal of Biological Macromolecules.2018; 116: 346.     CrossRef
• Diabetic macular oedema: under‐represented in the genetic analysis of diabetic retinopathy
  Suzanne Broadgate, Christine Kiire, Stephanie Halford, Victor Chong
  Acta Ophthalmologica.2018; 96(A111): 1.     CrossRef
• Expression of JAZF1, ABCC8, KCNJ11and Notch2 genes and vitamin D receptor polymorphisms in type 2 diabetes, and their association with microvascular complications
  Maha A. Rasheed, Nagwa Kantoush, Nagwa Abd El-Ghaffar, Hebatallah Farouk, Solaf Kamel, Alshaymaa Ahmed Ibrahim, Aliaa Shalaby, Eman Mahmoud, Hala M. Raslan, Omneya M. Saleh
  Therapeutic Advances in Endocrinology and Metabolism.2017; 8(6): 97.     CrossRef
• Vitamin D and diabetes mellitus: Causal or casual association?
  M. Grammatiki, E. Rapti, S. Karras, R. A. Ajjan, Kalliopi Kotsa
  Reviews in Endocrine and Metabolic Disorders.2017; 18(2): 227.     CrossRef
• The Association between Vitamin D Deficiency and Diabetic Retinopathy in Type 2 Diabetes: A Meta-Analysis of Observational Studies
  Bang-An Luo, Fan Gao, Lu-Lu Qin
  Nutrients.2017; 9(3): 307.     CrossRef
• The Association between VDR Gene Polymorphisms and Diabetic Retinopathy Susceptibility: A Systematic Review and Meta-Analysis
  Yun Zhang, Wei Xia, Ping Lu, Huijuan Yuan
  BioMed Research International.2016; 2016: 1.     CrossRef
• Candidate gene studies of diabetic retinopathy in human
  Petra Priščáková, Gabriel Minárik, Vanda Repiská
  Molecular Biology Reports.2016; 43(12): 1327.     CrossRef

Diabetes is a common metabolic disorder with a worldwide prevalence of 8.3% and is the leading cause of visual loss, end-stage renal disease and amputation. Recently, genome-wide association studies (GWASs) have identified genetic risk factors for diabetic microvascular complications of retinopathy, nephropathy, and neuropathy. We summarized the recent findings of GWASs on diabetic microvascular complications and highlighted the challenges and our opinion on future directives. Five GWASs were conducted on diabetic retinopathy, nine on nephropathy, and one on neuropathic pain. The majority of recent GWASs were underpowered and heterogeneous in terms of study design, inclusion criteria and phenotype definition. Therefore, few reached the genome-wide significance threshold and the findings were inconsistent across the studies. Recent GWASs provided novel information on genetic risk factors and the possible pathophysiology of diabetic microvascular complications. However, further collaborative efforts to standardize phenotype definition and increase sample size are necessary for successful genetic studies on diabetic microvascular complications.

Citations

Citations to this article as recorded by  

• Genetics of diabetes
  Shiwali Goyal, Jyoti Rani, Mohd Akbar Bhat, Vanita Vanita
  World Journal of Diabetes.2023; 14(6): 656.     CrossRef
• Plasma thrombin-activatable fibrinolysis inhibitor and the 1040C/T polymorphism are risk factors for diabetic kidney disease in Chinese patients with type 2 diabetes
  Qinghua Huang, Dujin Feng, Lianlian Pan, Huan Wang, Yan Wu, Bin Zhong, Jianguang Gong, Huijun Lin, Xianming Fei
  PeerJ.2023; 11: e16352.     CrossRef
• The G Allele of the rs12050217 Polymorphism in the BDKRB1 Gene Is Associated with Protection for Diabetic Retinopathy
  Leticia A. Brondani, Daisy Crispim, Julia Pisco, Jorge A. Guimarães, Markus Berger
  Current Eye Research.2019; 44(9): 994.     CrossRef
• Genome‐wide association study identifies new susceptibility loci for diabetic nephropathy in Korean patients with type 2 diabetes mellitus
  Kyung H. Jeong, Jin S. Kim, Jeong‐Taek Woo, Sang Y. Rhee, Yu H. Lee, Yang G. Kim, Ju‐Young Moon, Su K. Kim, Sun W. Kang, Sang H. Lee, Yeong H. Kim
  Clinical Genetics.2019; 96(1): 35.     CrossRef
• Diabetic polyneuropathy, deep white matter lesions, and carotid atherosclerosis: is there any association?
  Sevgi Ferik, Hayat Güven, Mehlika Panpallı Ateş, Işık Conkbayır, Selçuk Çomoğlu, Bülent Güven
  Neurological Sciences.2018; 39(1): 103.     CrossRef
• Altered expression of WFS1 and NOTCH2 genes associated with diabetic nephropathy in T2DM patients
  Sahar A. Sharaf, Nagwa A. Kantoush, Dina F. Ayoub, Alshaymaa A. Ibrahim, Amaal A. Abdelaal, Rokaya Abdel Aziz, Mahmoud M. ElHefnawi, Amira N. Ahmed
  Diabetes Research and Clinical Practice.2018; 140: 304.     CrossRef
• Precision medicine in diabetes prevention, classification and management
  Fangying Xie, Juliana CN Chan, Ronald CW Ma
  Journal of Diabetes Investigation.2018; 9(5): 998.     CrossRef
• Clinical worthlessness of genetic prediction of common forms of diabetes mellitus and related chronic complications
  R. Buzzetti, S. Prudente, M. Copetti, M. Dauriz, S. Zampetti, M. Garofolo, G. Penno, V. Trischitta
  Nutrition, Metabolism and Cardiovascular Diseases.2017; 27(2): 99.     CrossRef
• Diabetic macular oedema: clinical risk factors and emerging genetic influences
  Ebony Liu, Jamie E Craig, Kathryn Burdon
  Clinical and Experimental Optometry.2017; 100(6): 569.     CrossRef
• Normoalbuminuric diabetic kidney disease
  Chao Chen, Chang Wang, Chun Hu, Yachun Han, Li Zhao, Xuejing Zhu, Li Xiao, Lin Sun
  Frontiers of Medicine.2017; 11(3): 310.     CrossRef
• Biomarkers of Diabetic Retinopathy
  Daniel Shu Wei Ting, Kara-Anne Tan, Val Phua, Gavin Siew Wei Tan, Chee Wai Wong, Tien Yin Wong
  Current Diabetes Reports.2016;[Epub]     CrossRef
• Association Between Heme Oxygenase-1 Promoter Polymorphisms and the Development of Albuminuria in Type 2 Diabetes
  Eun Young Lee, Yong-ho Lee, Soo Hyun Kim, Kyu Sik Jung, Obin Kwon, Beom Seok Kim, Chung Mo Nam, Chun Sik Park, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Hyun Chul Lee
  Medicine.2015; 94(43): e1825.     CrossRef