Effects on the expression of glutamic acid and gamma-aminobutyric acid in the retina of diabetic rats with insulin late intensive treatment_Chinese Journal of Ocular Fundus Diseases

Authors：

 ZhengWeidong , HuangYan , WanSong , 徐国兴

Department of Ophthalmology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China;

Corresponding author：

ZhengWeidong, Email: wdzheng1996@163.corn

Keywords：

Diabetic retinopathy/physiopathology; Glutamic acid; gamma-Aminobutyric acid; Glutamate decarboxylase

DOI：

10.3760/cma.j.issn.1005-1015.2015.06.018

Video：

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Objective To observe the expression of glutamate (Glu) andγ-aminobutyric acid (GABA) in the retina of diabetic rats which were intervened later by insulin intensive therapy, and to investigate the mechanism of metabolic memory of hyperglycemia which induced the retina neuropathy in diabetic rats. Methods 60 Brown Norway rats were randomly divided into normal control (NC) group, diabetes mellitus (DM) group (6 weeks at DM1, 12 weeks at DM2) and metabolic memory (MM) group, 15 rats in each group. Diabetes was induced by intraperitoneal injection of streptozocin. After 6 weeks, MM group was treated with insulin intensive therapy for 6 weeks. DM1 group was sacrificed at the end of 6 weeks and other groups were sacrificed at the end of 12 weeks. High performance liquid chromatography was used to detect the amount of Glu and GABA in the rat retina. Real-time polymerase chain reaction was applied to quantify the mRNA expressions of Glutamate decarboxylase (GAD). TdT mediated dUTP nick ending labelling was used to detect cell apoptosis. Results The concentration of Glu (t=6.963), GABA (t=4.385) and the ratio of Glu/GABA (t=4.163) in MM group were significantly higher than DM1 group, but the concentration of Glu (t=3.411) and GABA (t=3.709) were significantly lower than DM2 group (P < 0.05). And there was no significant difference in the ratio of Glu/GABA between MM and DM2 groups (t=1.199, P > 0.05). The level of expressions of GAD mRNA in MM group was significantly lower than DM1 group (t=3.496, P < 0.05), but higher than DM2 group (t=8.613, P < 0.05). The number of nerve cells apoptosis in MM group was significantly higher than DM1 group (t=2.584, P < 0.05), but lower than DM2 group (t=3.531, P < 0.05). Conclusions Intensive therapy later by insulin can partially reduce the content of Glu and GABA and the rate of nerve cells apoptosis, which cannot return to normal levels, and has no effect on the rise in the ratio of Glu/GABA caused by the hyperglycemia. The disorders of Glu and GABA may participate in the metabolic memory of hyperglycemia.

Citation： ZhengWeidong, HuangYan, WanSong. Effects on the expression of glutamic acid and gamma-aminobutyric acid in the retina of diabetic rats with insulin late intensive treatment. Chinese Journal of Ocular Fundus Diseases, 2015, 31(6): 586-590. doi: 10.3760/cma.j.issn.1005-1015.2015.06.018 Copy

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11.	Feit-Leichman RA, Kinouchi R, Takeda M, et al.Vascular damage in a mouse model of diabetic retinopathy: relation to neuronal and glial changes[J].Invest Ophthalmol Vis Sci, 2005, 46(11):4281-4287.
12.	Kumar S, Zhuo L.Longitudinal in vivo imaging of retinal gliosis in a diabetic mouse model[J].Exp Eye Res, 2010, 91(4):530-536.
13.	Yang Y, Mao D, Chen X, et al. Decrease in retinal neuronal cells in streptozotocin-induced diabetic mice[J].Molecular Vision, 2012, 18:1411-1420.
14.	Martin PM, Roon P, van Ells TK, et al.Death of retinal neurons in streptozotocin-induced diabetic mice[J].Invest Ophthalmol Vis Sci, 2004, 45(9): 3330-3336.
15.	Bixler GV, Vanguilder HD, Brucklacher RM, et al.Chronic insulin treatment of diabetes does not fully normalize alterations in the retinal transcriptome.[J].BMC Med Genomics, 2011, 4(1):40-54.
16.	Gu L, Xu H, Wang F, et al. Erythropoietin exerts a neuroprotective function against glutamate neurotoxicity in experimental diabetic retina [J].Invest Ophthalmol Vis Sci, 2014, 55(12):8208-8222.
17.	Cervantes-Villagrana AR, Garcia-Román J, González-Espinosa C, et al. Pharmacological inhibition of N-methyl d-aspartate receptor promotes secretion of vascular endothelial growth factor in Müller cells: effects of hyperglycemia and hypoxia[J].Curr Eye Res, 2010, 35(8):733-741.
18.	Kusari J, Zhou SX, Padillo E, et al. Inhibition of vitreoretinal VEGF elevation and blood-retinal barrier breakdown in streptozotocin-induced diabetic rats by brimonidine[J]. Invest Ophthalmol Vis Sci, 2010, 51(2): 1044-1051.

1. Ihnat MA, Thorpe JE, Ceriello A. Hypothesis: the 'metabolic memory', the new challenge of diabetes[J].Diabet Med, 2007, 24(6):582-586.
2. 万松, 郑卫东, 徐国兴, 等.高血糖"代谢记忆"与糖尿病视网膜病变的关系[J].国际眼科纵览, 2012, 36(6): 375-378.
3. Kowluru RA, Chan PS. Metabolic memory in diabetes-from in vitro oddity to in vivo problem: role of apoptosis[J].Brain Res Bull, 2010, 81(2):297-302.
4. Carrasco E, Hernández C, Miralles A, et al. Lower somatostatin expression is an early event in diabetic retinopathy and is associated with retinal neurodegeneration [J].Diabetes Care, 2007, 30(11):2902-2908.
5. Hernández C, Simó R. Neuroprotection in diabetic retinopathy[J].Curr Diab Rep, 2012, 12(4):329-337.
6. Barber AJ, Gardner TW, Abcouwer SF. The significance of vascular and neural apoptosis to the pathology of diabetic retinopathy[J].Invest Ophthalmol Vis Sci, 2011, 52(2): 1156-1163.
7. Stitt AW. AGEs and diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2010, 51(10): 4867-4874.
8. 郑卫东, 黄焱, 徐国兴, 等.色素上皮衍生因子对早期DM大鼠视网膜谷氨酸和γ-氨基丁酸的影响[J].福建医科大学学报, 2011, 45(5):327-330.
9. Diabetes Control and Complications Trial, Epidemiology of Diabetes Interventions and Complications Research Group. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial[J].Arch Ophthalmol, 2008, 126(12): 1707-1715.
10. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes[J].N Engl J Med, 2008, 359(15):1577-1589.
11. Feit-Leichman RA, Kinouchi R, Takeda M, et al.Vascular damage in a mouse model of diabetic retinopathy: relation to neuronal and glial changes[J].Invest Ophthalmol Vis Sci, 2005, 46(11):4281-4287.
12. Kumar S, Zhuo L.Longitudinal in vivo imaging of retinal gliosis in a diabetic mouse model[J].Exp Eye Res, 2010, 91(4):530-536.
13. Yang Y, Mao D, Chen X, et al. Decrease in retinal neuronal cells in streptozotocin-induced diabetic mice[J].Molecular Vision, 2012, 18:1411-1420.
14. Martin PM, Roon P, van Ells TK, et al.Death of retinal neurons in streptozotocin-induced diabetic mice[J].Invest Ophthalmol Vis Sci, 2004, 45(9): 3330-3336.
15. Bixler GV, Vanguilder HD, Brucklacher RM, et al.Chronic insulin treatment of diabetes does not fully normalize alterations in the retinal transcriptome.[J].BMC Med Genomics, 2011, 4(1):40-54.
16. Gu L, Xu H, Wang F, et al. Erythropoietin exerts a neuroprotective function against glutamate neurotoxicity in experimental diabetic retina [J].Invest Ophthalmol Vis Sci, 2014, 55(12):8208-8222.
17. Cervantes-Villagrana AR, Garcia-Román J, González-Espinosa C, et al. Pharmacological inhibition of N-methyl d-aspartate receptor promotes secretion of vascular endothelial growth factor in Müller cells: effects of hyperglycemia and hypoxia[J].Curr Eye Res, 2010, 35(8):733-741.
18. Kusari J, Zhou SX, Padillo E, et al. Inhibition of vitreoretinal VEGF elevation and blood-retinal barrier breakdown in streptozotocin-induced diabetic rats by brimonidine[J]. Invest Ophthalmol Vis Sci, 2010, 51(2): 1044-1051.

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