AUTHOR=Fedotkina Olena , Jain Ruchi , Prasad Rashmi B. , Luk Andrea , García-Ramírez Marta , Özgümüs Türküler , Cherviakova Liubov , Khalimon Nadiya , Svietleisha Tetiana , Buldenko Tetiana , Kravchenko Victor , Jain Deepak , Vaag Allan , Chan Juliana , Khalangot Mykola D. , Hernández Cristina , Nilsson Peter M. , Simo Rafael , Artner Isabella , Lyssenko Valeriya 

TITLE=Neuronal Dysfunction Is Linked to the Famine-Associated Risk of Proliferative Retinopathy in Patients With Type 2 Diabetes

JOURNAL=Frontiers in Neuroscience

VOLUME=16

YEAR=2022

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.858049

DOI=10.3389/fnins.2022.858049

ISSN=1662-453X

ABSTRACT=<p>Persons with type 2 diabetes born in the regions of famine exposures have disproportionally elevated risk of vision-threatening proliferative diabetic retinopathy (PDR) in adulthood. However, the underlying mechanisms are not known. In the present study, we aimed to investigate the plausible molecular factors underlying progression to PDR. To study the association of genetic variants with PDR under the intrauterine famine exposure, we analyzed single nucleotide polymorphisms (SNPs) that were previously reported to be associated with type 2 diabetes, glucose, and pharmacogenetics. Analyses were performed in the population from northern Ukraine with a history of exposure to the Great Ukrainian Holodomor famine [the Diagnostic Optimization and Treatment of Diabetes and its Complications in the Chernihiv Region (DOLCE study), <italic>n</italic> = 3,583]. A validation of the top genetic findings was performed in the Hong Kong diabetes registry (HKDR, <italic>n</italic> = 730) with a history of famine as a consequence of the Japanese invasion during WWII. In DOLCE, the genetic risk for PDR was elevated for the variants in <italic>ADRA2A</italic>, <italic>PCSK</italic>9, and <italic>CYP2C19*2</italic> loci, but reduced at <italic>PROX1</italic> locus. The association of <italic>ADRA2A</italic> loci with the risk of advanced diabetic retinopathy in famine-exposed group was further replicated in HKDR. The exposure of embryonic retinal cells to starvation for glucose, mimicking the perinatal exposure to famine, resulted in sustained increased expression of <italic>Adra2a</italic> and <italic>Pcsk9</italic>, but decreased <italic>Prox1</italic>. The exposure to starvation exhibited a lasting inhibitory effects on neurite outgrowth, as determined by neurite length. In conclusion, a consistent genetic findings on the famine-linked risk of <italic>ADRA2A</italic> with PDR indicate that the nerves may likely to be responsible for communicating the effects of perinatal exposure to famine on the elevated risk of advanced stages of diabetic retinopathy in adults. These results suggest the possibility of utilizing neuroprotective drugs for the prevention and treatment of PDR.</p>