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

Fedotkina, Olena LU ; Jain, Ruchi LU ; Prasad, Rashmi B LU ; Luk, Andrea ; García-Ramírez, Marta ; Özgümüs, Türküler ; Cherviakova, Liubov ; Khalimon, Nadiya ; Svietleisha, Tetiana and Buldenko, Tetiana , et al. (2022) In Frontiers in Neuroscience 16. p.858049-858049
Abstract

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... (More)

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), n = 3,583]. A validation of the top genetic findings was performed in the Hong Kong diabetes registry (HKDR, n = 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 ADRA2A, PCSK9, and CYP2C19*2 loci, but reduced at PROX1 locus. The association of ADRA2A 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 Adra2a and Pcsk9, but decreased Prox1. 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 ADRA2A 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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Frontiers in Neuroscience
volume
16
pages
858049 - 858049
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85130729265
  • pmid:35600617
ISSN
1662-4548
DOI
10.3389/fnins.2022.858049
language
English
LU publication?
yes
id
22338813-ec8d-4169-8fa6-b6474e6ea987
date added to LUP
2022-08-03 19:05:50
date last changed
2024-03-21 04:11:57
@article{22338813-ec8d-4169-8fa6-b6474e6ea987,
  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), n = 3,583]. A validation of the top genetic findings was performed in the Hong Kong diabetes registry (HKDR, n = 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 ADRA2A, PCSK9, and CYP2C19*2 loci, but reduced at PROX1 locus. The association of ADRA2A 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 Adra2a and Pcsk9, but decreased Prox1. 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 ADRA2A 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>}},
  author       = {{Fedotkina, Olena and Jain, Ruchi and Prasad, Rashmi B and Luk, Andrea and García-Ramírez, Marta and Özgümüs, Türküler and Cherviakova, Liubov and Khalimon, Nadiya and Svietleisha, Tetiana and Buldenko, Tetiana and Kravchenko, Victor and Jain, Deepak and Vaag, Allan and Chan, Juliana and Khalangot, Mykola D and Hernández, Cristina and Nilsson, Peter M and Simo, Rafael and Artner, Isabella and Lyssenko, Valeriya}},
  issn         = {{1662-4548}},
  language     = {{eng}},
  pages        = {{858049--858049}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Neuroscience}},
  title        = {{Neuronal Dysfunction Is Linked to the Famine-Associated Risk of Proliferative Retinopathy in Patients With Type 2 Diabetes}},
  url          = {{http://dx.doi.org/10.3389/fnins.2022.858049}},
  doi          = {{10.3389/fnins.2022.858049}},
  volume       = {{16}},
  year         = {{2022}},
}