Scientists identify a potential treatment candidate for early type 2 diabetic retinopathy

Results of a study on lixisenatide in the retina and the optic nerve head in a mouse model of type 2 diabetes show promise for treating diabetic retinopathy before its clinical manifestation, report scientists in The American Journal of Pathology


Philadelphia, April 27, 2020

Diabetic retinopathy is one of the main vascular complications of type 2 diabetes, and the most common cause of visual deterioration in adults. A new study in The American Journal of Pathology, published by Elsevier, reports on the efficacy of a possible treatment candidate that showed anti-inflammatory and neuroprotective effects on the retina and optic nerve head in early type 2 diabetic retinopathy using a diabetic mouse model.

Diabetic retinopathy is caused by damage to the blood vessels of the light-sensitive tissue at the back of the eye. The cause is usually attributed to high blood sugar (hyperglycemia), but several studies have shown that inflammation is also an important factor in the progression of the disorder.

“Inflammation causes neurodegeneration as well as microvascular abnormalities in the retina,” explained lead investigator Jin A. Choi, PhD, Department of Ophthalmology and Visual Science, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. “Diabetic retinal neurodegeneration can occur before the onset of clinical diabetic retinal microvascular abnormalities. Therefore, therapeutics for neurodegeneration may provide a novel interventional strategy in the window period between the diagnosis of type 2 diabetes and the onset of clinically manifested diabetic retinopathy.”

Investigators analyzed and compared the anti-inflammatory and neuroprotective effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide in the retina and the optic nerve head with those of insulin in a mouse model of type 2 diabetes. They divided diabetic mice into three groups; GLP-1RA (LIX); insulin (INS) with controlled hyperglycemia based on the glucose concentration of LIX; and a control group (D-CON). Nondiabetic control mice were also characterized for comparison.

After eight weeks of treatment, neuroinflammation caused by type 2 diabetes was significantly reduced in GLP-1RA–treated retinas and optic nerve heads compared with untreated or even insulin-treated retinas of early type 2 diabetic mice, showing that the outcomes are independent of the glucose-lowering effect of GLP-1RA.

qPCR results
Relative mRNA expression levels of thioredoxin-interacting protein (TXNIP) (A),and glial fibrillary acidic protein (GFAP) (B) based on the average expression levels of the nondiabetic mice group (db/dm) (set as 1.0); P=0.047. (C): TXNIP and GFAP assessment by Western blotting (top panel), statistical analysis of relative optic density of TXNIP (bottom left panel) and GFAP (bottom right panel) to beta-actin among the groups based on the Western blot immunoreactive bands in the neurosensory retina. Data are expressed as means ± SEM. n=5 db/dm. n=7 D-CON, INS, and LIX. *P < 0.05, ***P < 0.001. db/dm, nondiabetic mice; D-CON, untreated diabetic mice; INS, diabetic mice treated with insulin; LIX, diabetic mice treated with lixisenatide; qPCR, quantitative PCR.

“This study can provide a possible therapeutic strategy to prevent visual deterioration by using GLP-1RA in early type 2 diabetic retinopathy,” noted first author Yeon Woong Chung, MD, Department of Ophthalmology and Visual Science, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. “GLP-1RA significantly suppressed neuroinflammation in the early diabetic retinopathy, whereas insulin had little or no suppressive effect in this study.”

“Retinal ganglion cells start to die even before clinical changes such as hemorrhages in diabetic retinopathy occur,” commented Dr. Choi. “Thus, for better visual prognosis, we need to focus on the treatment of the retina in early type 2 diabetes before the clinical onset of diabetic retinopathy. The diabetic mouse group in our study who were treated with GLP-1RA showed significantly decreased cell death compared to those with insulin treatment.”

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Notes for editors
The article is “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,” by Yeon Woong Chung, Jae Hyung, Lee, Ji Young Lee, Hyun Hee Ju, Ye-Jee Lee, Dong Hyun Jee, Seung-Hyun Ko, and Jin A. Choi (https://doi.org/10.1016/j.ajpath.2020.01.011). It will appear in The American Journal of Pathology, volume 190, Issue 5 (May 2020) published by Elsevier.

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant number: NRF-2016R1A2B4008487 and 2016R1A6A1A03010528, recipient: SHK), and the development fund of Catholic Institute for Visual Science of 2019 (grant number: 5-2019-B0001-00242, recipient: JAC).

Full text of the study is available to credentialed journalists upon request; contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com. Journalists wishing to interview the authors should contact Jin A. Choi, at +82 318818971 or jinah616@catholic.ac.kr.

About The American Journal of Pathology
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.org

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