The effect of GLP-1 receptor agonist lixisenatide on experimental diabetic retinopathy.

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 9200299 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-5233 (Electronic) Linking ISSN: 09405429 NLM ISO Abbreviation: Acta Diabetol Subsets: MEDLINE

Publication: Berlin : Springer Verlag
Original Publication: Berlin : Springer International, c1991-

Diabetic Retinopathy*/drug therapy ; Diabetic Retinopathy*/etiology ; Diabetic Retinopathy*/metabolism ; Diabetes Mellitus, Type 2*/metabolism ; Diabetes Mellitus, Experimental*/drug therapy ; Diabetes Mellitus, Experimental*/metabolism; Rats ; Animals ; Hypoglycemic Agents/pharmacology ; Hypoglycemic Agents/therapeutic use ; Glucagon-Like Peptide-1 Receptor/agonists ; Caenorhabditis elegans ; Chromatography, Liquid ; Rats, Wistar ; Tandem Mass Spectrometry ; Antioxidants/pharmacology ; Glucose

Aims: Glucagon-like peptide-1 receptor agonists are effective treatments for type 2 diabetes, effectively lowering glucose without weight gain and with low risk for hypoglycemia. However, their influence on the retinal neurovascular unit remains unclear. In this study, we analyzed the effects of the GLP-1 RA lixisenatide on diabetic retinopathy.
Methods: Vasculo- and neuroprotective effects were assessed in experimental diabetic retinopathy and high glucose-cultivated C. elegans, respectively. In STZ-diabetic Wistar rats, acellular capillaries and pericytes (quantitative retinal morphometry), neuroretinal function (mfERG), macroglia (GFAP western blot) and microglia (immunohistochemistry) quantification, methylglyoxal (LC-MS/MS) and retinal gene expressions (RNA-sequencing) were determined. The antioxidant properties of lixisenatide were tested in C. elegans.
Results: Lixisenatide had no effect on glucose metabolism. Lixisenatide preserved the retinal vasculature and neuroretinal function. The macro- and microglial activation was mitigated. Lixisenatide normalized some gene expression changes in diabetic animals to control levels. Ets2 was identified as a regulator of inflammatory genes. In C. elegans, lixisenatide showed the antioxidative property.
Conclusions: Our data suggest that lixisenatide has a protective effect on the diabetic retina, most likely due to a combination of neuroprotective, anti-inflammatory and antioxidative effects of lixisenatide on the neurovascular unit.
(© 2023. The Author(s).)

Yuan T et al (2019) New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis. Redox Biol 20:247–260. (PMID: 3038425910.1016/j.redox.2018.09.025)
Hammes HP et al (2015) Risk factors for retinopathy and DME in Type 2 diabetes-results from the German/Austrian DPV database. PLoS ONE 10(7):e0132492. (PMID: 26177037450330110.1371/journal.pone.0132492)
Hammes HP (2018) Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond. Diabetologia 61(1):29–38. (PMID: 2894245810.1007/s00125-017-4435-8)
Kilhovd BK et al (2003) Increased serum levels of the specific AGE-compound methylglyoxal-derived hydroimidazolone in patients with type 2 diabetes. Metabolism 52(2):163–167. (PMID: 1260162610.1053/meta.2003.50035)
Fosmark DS et al (2009) Increased retinopathy occurrence in type 1 diabetes patients with increased serum levels of the advanced glycation endproduct hydroimidazolone. Acta Ophthalmol 87(5):498–500. (PMID: 1863132810.1111/j.1755-3768.2008.01300.x)
Fosmark DS et al (2006) Increased serum levels of the specific advanced glycation end product methylglyoxal-derived hydroimidazolone are associated with retinopathy in patients with type 2 diabetes mellitus. Metabolism 55(2):232–236. (PMID: 1642363110.1016/j.metabol.2005.08.017)
Hammes HP et al (1991) Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy. Proc Natl Acad Sci USA 88(24):11555–11558. (PMID: 17630695317410.1073/pnas.88.24.11555)
McVicar CM et al (2015) Role of the receptor for advanced glycation endproducts (RAGE) in retinal vasodegenerative pathology during diabetes in mice. Diabetologia 58(5):1129–1137. (PMID: 25687235439217010.1007/s00125-015-3523-x)
Chen M, Curtis TM, Stitt AW (2013) Advanced glycation end products and diabetic retinopathy. Curr Med Chem 20(26):3234–3240. (PMID: 2374554710.2174/09298673113209990025)
Kolibabka M et al (2016) Dicarbonyl stress mimics diabetic neurovascular damage in the retina. Exp Clin Endocrinol Diabetes 124(7):437–439. (PMID: 2721989010.1055/s-0042-106081)
Barlovic DP, Soro-Paavonen A, Jandeleit-Dahm KA (2011) RAGE biology, atherosclerosis and diabetes. Clin Sci (Lond) 121(2):43–55. (PMID: 2145714510.1042/CS20100501)
Andersen A et al (2018) Glucagon-like peptide 1 in health and disease. Nat Rev Endocrinol 14(7):390–403. (PMID: 2972859810.1038/s41574-018-0016-2)
Aroda VR (2018) A review of GLP-1 receptor agonists: evolution and advancement, through the lens of randomised controlled trials. Diabetes Obes Metab 20(Suppl 1):22–33. (PMID: 2936458610.1111/dom.13162)
Werner U et al (2010) Pharmacological profile of lixisenatide: a new GLP-1 receptor agonist for the treatment of type 2 diabetes. Regul Pept 164(2–3):58–64. (PMID: 2057059710.1016/j.regpep.2010.05.008)
Bolli GB, Owens DR (2014) Lixisenatide, a novel GLP-1 receptor agonist: efficacy, safety and clinical implications for type 2 diabetes mellitus. Diabetes Obes Metab 16(7):588–601. (PMID: 2437319010.1111/dom.12253)
Calsolaro V, Edison P (2015) Novel GLP-1 (Glucagon-Like Peptide-1) analogues and insulin in the treatment for Alzheimer’s disease and other neurodegenerative diseases. CNS Drugs 29(12):1023–1039. (PMID: 2666623010.1007/s40263-015-0301-8)
Dietrich N et al (2016) The DPP4 inhibitor linagliptin protects from experimental diabetic retinopathy. PLoS ONE 11(12):e0167853. (PMID: 27942008515293110.1371/journal.pone.0167853)
Zhang Y et al (2011) Intravitreal injection of exendin-4 analogue protects retinal cells in early diabetic rats. Investig Ophthalmol Vis Sci 52(1):278–285. (PMID: 10.1167/iovs.09-4727)
Dietrich N, Hammes HP (2012) Retinal digest preparation: a method to study diabetic retinopathy. Methods Mol Biol 933:291–302. (PMID: 2289341510.1007/978-1-62703-068-7_19)
Dutescu RM et al (2013) Multifocal ERG recordings under visual control of the stimulated fundus in mice. Investig Ophthalmol Vis Sci 54(4):2582–2589. (PMID: 10.1167/iovs.12-11446)
Abràmoff MD, Magalhães PJ, Ram SJ (2004) Image processing with ImageJ. Biophotonics Int 11(7):36–42.
Rabbani N, Thornalley PJ (2014) Measurement of methylglyoxal by stable isotopic dilution analysis LC-MS/MS with corroborative prediction in physiological samples. Nat Protoc 9(8):1969–1979. (PMID: 2505864410.1038/nprot.2014.129)
Anders S, Huber W (2010) Differential expression analysis for sequence count data. Genome Biol 11(10):R106. (PMID: 20979621321866210.1186/gb-2010-11-10-r106)
Schlotterer A et al (2010) Apurinic/apyrimidinic endonuclease 1, p53, and thioredoxin are linked in control of aging in C. elegans. Aging Cell 9(3):420–432. (PMID: 2034607110.1111/j.1474-9726.2010.00572.x)
Kimura KD et al (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277(5328):942–946. (PMID: 925232310.1126/science.277.5328.942)
Schlotterer A et al (2009) C. elegans as model for the study of high glucose- mediated life span reduction. Diabetes 58(11):2450–2456. (PMID: 19675139276817910.2337/db09-0567)
Torgovnick A et al (2013) Healthy aging: what can we learn from Caenorhabditis elegans? Z Gerontol Geriatr 46(7):623–628. (PMID: 2394901210.1007/s00391-013-0533-5)
Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54(6):1615–1625. (PMID: 1591978110.2337/diabetes.54.6.1615)
Hammes HP (2018) Medikamentöse therapie der diabetischen retinopathie – Die diabetologische perspektive. Diabetologe 14(8):568–576. (PMID: 10.1007/s11428-018-0372-5)
MD TM, MD MB (2008) Unifying hypothesis of diabetic complications. In: LeRoith D, Vinik AI (eds.), Controversies in treating diabetes: contemporary endocrinology. Humana Press. https://doi.org/10.1007/978-1-59745-572-5_12.
Rolev KD, Shu X-S, Ying Y (2021) Targeted pharmacotherapy against neurodegeneration and neuroinflammation in early diabetic retinopathy. Neuropharmacology 187:108498. (PMID: 3358215010.1016/j.neuropharm.2021.108498)
Usuelli V, La Rocca E (2015) Novel therapeutic approaches for diabetic nephropathy and retinopathy. Pharmacol Res 98:39–44. (PMID: 2544779410.1016/j.phrs.2014.10.003)
UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPD 33). Lancet 352(9131):837–853. (PMID: 10.1016/S0140-6736(98)07019-6)
Nishikawa T et al (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404(6779):787–790. (PMID: 1078389510.1038/35008121)
Giacco F et al (2015) GLP-1 cleavage product reverses persistent ROS generation after transient hyperglycemia by disrupting an ROS-generating feedback loop. Diabetes 64(9):3273–3284. (PMID: 26294429454244910.2337/db15-0084)
Simó R, Hernández C (2017) GLP-1R as a target for the treatment of diabetic retinopathy: friend or foe? Diabetes 66(6):1453–1460. (PMID: 2853329610.2337/db16-1364)
Wei L et al (2022) GLP-1 RA improves diabetic retinopathy by protecting the blood-retinal barrier through GLP-1R-ROCK-p-MLC signaling pathway. J Diabetes Res 2022:1861940. (PMID: 36387940964932410.1155/2022/1861940)
Regard JB, Sato IT, Coughlin SR (2008) Anatomical profiling of G protein-coupled receptor expression. Cell 135(3):561–571. (PMID: 18984166259094310.1016/j.cell.2008.08.040)
Hebsgaard JB et al (2018) Glucagon-like peptide-1 receptor expression in the human eye. Diabetes Obes Metab 20(9):2304–2308. (PMID: 29707863609950710.1111/dom.13339)
Behl T, Kaur I, Kotwani A (2016) Implication of oxidative stress in progression of diabetic retinopathy. Surv Ophthalmol 61(2):187–196. (PMID: 2607435410.1016/j.survophthal.2015.06.001)
Bartlett HE, Eperjesi F (2008) Nutritional supplementation for type 2 diabetes: a systematic review. Ophthalmic Physiol Opt 28(6):503–523. (PMID: 1907655310.1111/j.1475-1313.2008.00595.x)
Lee CT et al (2010) Micronutrients and diabetic retinopathy a systematic review. Ophthalmology 117(1):71–78. (PMID: 1990070910.1016/j.ophtha.2009.06.040)
West AL, Oren GA, Moroi SE (2006) Evidence for the use of nutritional supplements and herbal medicines in common eye diseases. Am J Ophthalmol 141(1):157–166. (PMID: 1638699210.1016/j.ajo.2005.07.033)
Wilkinson JT, Fraunfelder FW (2011) Use of herbal medicines and nutritional supplements in ocular disorders: an evidence-based review. Drugs 71(18):2421–2434. (PMID: 2214138510.2165/11596840-000000000-00000)
Lopes de Jesus CC et al (2008) Vitamin C and superoxide dismutase (SOD) for diabetic retinopathy. Cochrane Database Syst Rev (1): Cd006695. https://doi.org/10.1002/14651858.CD006695.pub2.
Da Silva S et al (2010) Antioxidants in the prevention and treatment of diabetic retinopathy a review. J Diabet Metabol 1:111. https://doi.org/10.4172/2155-6156.100011. (PMID: 10.4172/2155-6156.100011)
Hammes HP et al (2003) Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 9(3):294–299. (PMID: 1259240310.1038/nm834)
Berrone E et al (2006) Regulation of intracellular glucose and polyol pathway by thiamine and benfotiamine in vascular cells cultured in high glucose. J Biol Chem 281(14):9307–9313. (PMID: 1645246810.1074/jbc.M600418200)
Krady JK et al (2005) Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes 54(5):1559–1565. (PMID: 1585534610.2337/diabetes.54.5.1559)
Cheng C et al (2011) Ets2 determines the inflammatory state of endothelial cells in advanced atherosclerotic lesions. Circ Res 109(4):382–395. (PMID: 2170092910.1161/CIRCRESAHA.111.243444)
Chung YW et al (2020) The anti-inflammatory effects of glucagon-like peptide receptor agonist Lixisenatide on the retinal nuclear and nerve fiber layers in an animal model of early type 2 diabetes. Am J Pathol 190(5):1080–1094. (PMID: 3235457110.1016/j.ajpath.2020.01.011)
Reichenbach A, Bringmann A (2020) Glia of the human retina. Glia 68(4):768–796. (PMID: 3179369310.1002/glia.23727)
Kettenmann H, Verkhratsky A (2011) Neuroglia–living nerve glue. Fortschr Neurol Psychiatr 79(10):588–597. (PMID: 2198951110.1055/s-0031-1281704)
Kugler EC, Greenwood J, MacDonald RB (2021) The “Neuro-Glial-Vascular” unit: the role of glia in neurovascular unit formation and dysfunction. Front Cell Dev Biol 9:732820–732820. (PMID: 34646826850292310.3389/fcell.2021.732820)
Shin ES et al (2014) High glucose alters retinal astrocytes phenotype through increased production of inflammatory cytokines and oxidative stress. PLoS ONE 9(7):e103148. (PMID: 25068294411337710.1371/journal.pone.0103148)
Suryavanshi SV, Kulkarni YA (2017) NF-κβ: a potential target in the management of vascular complications of diabetes. Front Pharmacol 8:798. (PMID: 29163178568199410.3389/fphar.2017.00798)
Rinaldi C et al (2021) Oxidative stress and the neurovascular unit. Life 11(8):767. (PMID: 34440511839897810.3390/life11080767)
Edgar R, Domrachev M, Lash AE (2002) Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30(1): 207–210. (PMID: 117522959912210.1093/nar/30.1.207)

Keywords: Diabetic retinopathy; Ets2; GLP-1RA; Lixisenatide; Neurovascular unit; ROS

74O62BB01U (lixisenatide)
0 (Hypoglycemic Agents)
0 (Glucagon-Like Peptide-1 Receptor)
0 (Antioxidants)
IY9XDZ35W2 (Glucose)

Date Created: 20230709 Date Completed: 20231004 Latest Revision: 20240402

20240403

PMC10520173

10.1007/s00592-023-02135-7

37423944