Department of Ophthalmology, Vision Research Center, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA.
Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri - Kansas City, Kansas City, MO, 64108, USA.
Sci Rep. 2023 Oct 13;13(1):17347. doi: 10.1038/s41598-023-44446-3.
The study was designed to quantify retina function in a spontaneous mutation mouse model of diabetes, in which sustained dyslipidemia was induced chemically. The goal of the study was to identify if dyslipidemia in the presence of hyperglycemia resulted in either a synergistic, or a merely additive, exacerbation of retinal and visual dysfunctions in diabetes. Two cohorts of mice, male C57BL/6 and C57BL/KsJ-db/db mice were divided into two groups each. One group of each strain received the triblock copolymer, poloxamer 407 (P-407), administered by intraperitoneal injection ("WT P-407" and "db/db P-407" groups) with saline as a control in the remaining two groups ("WT" and "db/db" groups). Blood glucose, total cholesterol (TC) and total triglyceride (TG) levels were quantified using enzyme-based colorimetric assays. Retina function was measured using electroretinography (ERG) and visual acuity was determined by behaviorally assessing parameters of the optomotor reflex. TC and TG levels were normal in both saline controls (WT) and db/db mice but were significantly elevated in the WT P-407 group (p < 0.01 for TC; p < 0.001 for TG), while levels of the same lipids were further elevated in the db/db P-407 group when compared to the WT P-407 group levels (p < 0.001 for both TC and TG). Behavioral assessment of the optomotor reflex indicated reduced visual acuity for the db/db P-407 group when compared to either the WT P-407 or the db/db groups (p < 0.001, p < 0.0001). ERG measurements of scotopic retina function showed a significant decline in the scotopic b-wave amplitude of the WT P-407 animals (p < 0.01) and a further reduction for the db/db P-407 group when compared to controls (p < 0.0001). Very significant, strong correlations between scotopic b-wave amplitude and implicit time to TC (r = - 0.8376, p = < 0.0001 and r = 0.7069, p = 0.0022, respectively) and TG levels (r = - 0.8554, p = < 0.0001 and r = 0.7150, p = 0.0019, respectively) were found. Dyslipidemia in the presence of hyperglycemia synergistically exacerbated the severity of retinal dysfunction in diabetes. P-407 administration significantly elevated plasma TC and TG levels in male wild-type (WT) and diabetic mice (db/db), but the resulting hyperlipidemia was more significantly pronounced in the diabetic mice. While elevated plasma lipid and blood glucose levels were individually correlated with a decline in retinal function, the combination of both exacerbated retinal dysfunction. This model of combined hyperglycemia and dyslipidemia can be used to dissect individual contributions of features of the metabolic syndrome to the pathogenesis of retinal dysfunction in diabetes.
这项研究旨在定量研究自发性突变糖尿病小鼠模型中的视网膜功能，该模型通过化学方法诱导持续的血脂异常。研究的目的是确定高血糖症存在时血脂异常是否会导致视网膜和视觉功能障碍在糖尿病中协同或仅仅是附加地恶化。将两批雄性 C57BL/6 和 C57BL/KsJ-db/db 小鼠分为两组。每组的一组接受三嵌段共聚物泊洛沙姆 407（P-407），通过腹腔内注射给药（“WT P-407”和“db/db P-407”组），其余两组（“WT”和“db/db”组）用生理盐水作为对照。使用基于酶的比色测定法来量化血糖、总胆固醇（TC）和总甘油三酯（TG）水平。使用视网膜电图（ERG）测量视网膜功能，通过行为评估光感受器反射的参数来确定视力。TC 和 TG 水平在生理盐水对照（WT）和 db/db 小鼠中均正常，但在 WT P-407 组中显著升高（TC 为 p < 0.01；TG 为 p < 0.001），而在 db/db P-407 组中，当与 WT P-407 组水平相比时，相同脂质的水平进一步升高（TC 和 TG 均为 p < 0.001）。光感受器反射的行为评估表明，与 WT P-407 或 db/db 组相比，db/db P-407 组的视力明显降低（p < 0.001，p < 0.0001）。暗适应视网膜功能的 ERG 测量显示，WT P-407 动物的暗适应 b 波振幅显著下降（p < 0.01），与对照组相比，db/db P-407 组的 b 波振幅进一步降低（p < 0.0001）。TC（r = -0.8376，p = <0.0001 和 r = 0.7069，p = 0.0022）和 TG 水平（r = -0.8554，p = <0.0001 和 r = 0.7150，p = 0.0019）之间存在非常显著的负相关。在高血糖症的情况下血脂异常协同加剧了糖尿病中视网膜功能障碍的严重程度。P-407 给药显著升高了雄性野生型（WT）和糖尿病（db/db）小鼠的血浆 TC 和 TG 水平，但在糖尿病小鼠中，由此产生的高脂血症更为显著。虽然升高的血浆脂质和血糖水平与视网膜功能下降单独相关，但两者的结合加剧了视网膜功能障碍。这种高血糖和血脂异常相结合的模型可用于剖析代谢综合征的特征对糖尿病中视网膜功能障碍发病机制的个别贡献。
