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
Department of Clinical Science, Center for Diabetes Research, University of Bergen, Bergen, Norway.
Department of Clinical Sciences, Lund University Diabetes Center, Skane University Hospital, Malmö, Sweden.
Front Neurosci. 2022 May 5;16:858049. doi: 10.3389/fnins.2022.858049. eCollection 2022.
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), = 3,583]. A validation of the top genetic findings was performed in the Hong Kong diabetes registry (HKDR, = 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 , 9, and loci, but reduced at locus. The association of 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 and , but decreased . 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 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.
出生于饥荒暴露地区的2型糖尿病患者在成年后患威胁视力的增殖性糖尿病视网膜病变（PDR）的风险异常升高。然而，其潜在机制尚不清楚。在本研究中，我们旨在探究PDR进展的潜在分子因素。为研究宫内饥荒暴露情况下基因变异与PDR的关联，我们分析了先前报道的与2型糖尿病、血糖及药物遗传学相关的单核苷酸多态性（SNP）。分析在乌克兰北部有乌克兰大饥荒暴露史的人群中进行[切尔尼戈夫地区糖尿病及其并发症的诊断优化与治疗（DOLCE研究），n = 3583]。在有二战期间日本入侵导致饥荒史的香港糖尿病登记处（HKDR，n = 730）对首要基因发现进行了验证。在DOLCE研究中，PDR的遗传风险在、9和位点的变异中升高，但在位点降低。位点与饥荒暴露组晚期糖尿病视网膜病变风险的关联在HKDR中得到进一步验证。使胚胎视网膜细胞暴露于葡萄糖饥饿状态，模拟围产期饥荒暴露，导致和的表达持续增加，但减少。饥饿暴露对神经突生长表现出持久的抑制作用，由神经突长度确定。总之，关于与PDR的饥荒相关风险的一致基因发现表明神经可能负责传递围产期饥荒暴露对成人糖尿病视网膜病变晚期风险升高的影响。这些结果提示利用神经保护药物预防和治疗PDR的可能性。
