The Effect of GLP-1 Receptor Agonist Lixisenatide on Experimental Diabetic Retinopathy

Overview

Journal Acta Diabetol

Specialty Endocrinology

Date 2023 Jul 9

PMID 37423944

Authors

Kuebra Oezer

Matthias Kolibabka

Johann Gassenhuber

Nadine Dietrich

Thomas Fleming

Andrea Schlotterer

Michael Morcos

Paulus Wohlfart

Hans-Peter Hammes

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Glucagon-like peptide-1 receptor: mechanisms and advances in therapy.

Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C Signal Transduct Target Ther. 2024; 9(1):234.

PMID: 39289339 PMC: 11408715. DOI: 10.1038/s41392-024-01931-z.

Hyperglycemia-induced oxidative stress exacerbates mitochondrial apoptosis damage to cochlear stria vascularis pericytes via the ROS-mediated Bcl-2/CytC/AIF pathway.

Shi T, Zhou Z, Jiang W, Huang T, Si J, Li L Redox Rep. 2024; 29(1):2382943.

PMID: 39092597 PMC: 11299461. DOI: 10.1080/13510002.2024.2382943.

References

Yuan T, Yang T, Chen H, Fu D, Hu Y, Wang J . New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis. Redox Biol. 2018; 20:247-260. PMC: 6205410. DOI: 10.1016/j.redox.2018.09.025. View

Hammes H, Welp R, Kempe H, Wagner C, Siegel E, Holl R . Risk Factors for Retinopathy and DME in Type 2 Diabetes-Results from the German/Austrian DPV Database. PLoS One. 2015; 10(7):e0132492. PMC: 4503301. DOI: 10.1371/journal.pone.0132492. View

Hammes H . Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond. Diabetologia. 2017; 61(1):29-38. DOI: 10.1007/s00125-017-4435-8. View

Kilhovd B, Giardino I, Torjesen P, Birkeland K, Berg T, Thornalley P . Increased serum levels of the specific AGE-compound methylglyoxal-derived hydroimidazolone in patients with type 2 diabetes. Metabolism. 2003; 52(2):163-7. DOI: 10.1053/meta.2003.50035. View

Fosmark D, Berg J, Jensen A, Sandvik L, Agardh E, Agardh C . Increased retinopathy occurrence in type 1 diabetes patients with increased serum levels of the advanced glycation endproduct hydroimidazolone. Acta Ophthalmol. 2008; 87(5):498-500. DOI: 10.1111/j.1755-3768.2008.01300.x. View

Fosmark D, Torjesen P, Kilhovd B, Berg T, Sandvik L, Hanssen K . 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. 2006; 55(2):232-6. DOI: 10.1016/j.metabol.2005.08.017. View

Hammes H, Martin S, Federlin K, Geisen K, Brownlee M . Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy. Proc Natl Acad Sci U S A. 1991; 88(24):11555-8. PMC: 53174. DOI: 10.1073/pnas.88.24.11555. View

McVicar C, Ward M, Colhoun L, Guduric-Fuchs J, Bierhaus A, Fleming T . Role of the receptor for advanced glycation endproducts (RAGE) in retinal vasodegenerative pathology during diabetes in mice. Diabetologia. 2015; 58(5):1129-37. PMC: 4392170. DOI: 10.1007/s00125-015-3523-x. View

Chen M, Curtis T, Stitt A . Advanced glycation end products and diabetic retinopathy. Curr Med Chem. 2013; 20(26):3234-40. DOI: 10.2174/09298673113209990025. View

10.

Kolibabka M, Friedrichs P, Dietrich N, Fleming T, Schlotterer A, Hammes H . Dicarbonyl Stress Mimics Diabetic Neurovascular Damage in the Retina. Exp Clin Endocrinol Diabetes. 2016; 124(7):437-9. DOI: 10.1055/s-0042-106081. View

11.

Pongrac Barlovic D, Soro-Paavonen A, Jandeleit-Dahm K . RAGE biology, atherosclerosis and diabetes. Clin Sci (Lond). 2011; 121(2):43-55. DOI: 10.1042/CS20100501. View

12.

Andersen A, Lund A, Knop F, Vilsboll T . Glucagon-like peptide 1 in health and disease. Nat Rev Endocrinol. 2018; 14(7):390-403. DOI: 10.1038/s41574-018-0016-2. View

13.

Aroda V . A review of GLP-1 receptor agonists: Evolution and advancement, through the lens of randomised controlled trials. Diabetes Obes Metab. 2018; 20 Suppl 1:22-33. DOI: 10.1111/dom.13162. View

14.

Werner U, Haschke G, Herling A, Kramer W . Pharmacological profile of lixisenatide: A new GLP-1 receptor agonist for the treatment of type 2 diabetes. Regul Pept. 2010; 164(2-3):58-64. DOI: 10.1016/j.regpep.2010.05.008. View

15.

Bolli G, Owens D . Lixisenatide, a novel GLP-1 receptor agonist: efficacy, safety and clinical implications for type 2 diabetes mellitus. Diabetes Obes Metab. 2013; 16(7):588-601. DOI: 10.1111/dom.12253. View

16.

Calsolaro V, Edison P . Novel GLP-1 (Glucagon-Like Peptide-1) Analogues and Insulin in the Treatment for Alzheimer's Disease and Other Neurodegenerative Diseases. CNS Drugs. 2015; 29(12):1023-39. DOI: 10.1007/s40263-015-0301-8. View

17.

Dietrich N, Kolibabka M, Busch S, Bugert P, Kaiser U, Lin J . The DPP4 Inhibitor Linagliptin Protects from Experimental Diabetic Retinopathy. PLoS One. 2016; 11(12):e0167853. PMC: 5152931. DOI: 10.1371/journal.pone.0167853. View

18.

Dietrich N, Hammes H . Retinal digest preparation: a method to study diabetic retinopathy. Methods Mol Biol. 2012; 933:291-302. DOI: 10.1007/978-1-62703-068-7_19. View

19.

Rabbani N, Thornalley P . Measurement of methylglyoxal by stable isotopic dilution analysis LC-MS/MS with corroborative prediction in physiological samples. Nat Protoc. 2014; 9(8):1969-79. DOI: 10.1038/nprot.2014.129. View

20.

Anders S, Huber W . Differential expression analysis for sequence count data. Genome Biol. 2010; 11(10):R106. PMC: 3218662. DOI: 10.1186/gb-2010-11-10-r106. View