Dopamine changes in retina and brain in a high fat diet (HFD)+STZ model of diabetes

Abstract

Purpose : Dopamine loss has been shown to underlie early retinal dysfunction in a Type I diabetes model, and treatment with the dopamine precursor, L-DOPA, ameliorated these deficits. Less is known about whether changes in dopamine occur in the brain with diabetes. Here, we investigated changes in monoamines in the diabetic retina and brain using high fat diet (HFD) + low dose STZ rat models of Type I and Type II diabetes.

Methods : Adult Long Evans rats were randomly assigned to the following groups: naïve controls (n=12), HFD (n=14), or HFD+STZ (n=17). HFD+STZ rats were further divided into Type I (n=8) and Type II (n=9) based on metabolic assessments (blood glucose, weight, blood insulin levels via ELISA, and glucose tolerance). Visual function was assessed via optomotor response every 2 weeks from baseline, and cognitive function was assessed via Y-maze every 4 weeks. Retinal function was assessed via electroretinogram (ERG) at 4 and 8 weeks post-STZ. After 8 weeks, rats were euthanized, and retina, cortex, hippocampus, and striatum were taken for HPLC analysis of monoamines and their metabolites: dopamine and DOPAC, 3-MT, and HVA; serotonin and 5-HIAA; and norepinephrine and MHPG.

Results : Type I and Type II rats showed distinct metabolic phenotypes based on blood glucose, glucose tolerance, body weight, and serum insulin. Both Type I and Type II rats exhibited deficits in spatial frequency and contrast sensitivity (p<0.05 to p<0.0001), and Type II rats showed ERG delays in oscillatory potential implicit times (p<0.05). No cognitive deficits were observed. Reduced monoamine levels, most prominently in Type I rats, were observed in the following areas: retina (dopamine and 3-MT, p<0.05 to p<0.0001), striatum (3-MT, p<0.01), hippocampus (DOPAC, p<0.05), and cortex (DOPAC, HVA, 3-MT, and 5-HIAA, p<0.05 to p<0.001). Additionally, decreases in dopamine turnover (DOPAC/dopamine) were observed in hippocampus (p<0.01) and cortex (p<0.01).

Conclusions : Our study determined that dopamine deficiency occurs in multiple systems with diabetes, prompting the question, can diabetes be thought of as a disease of dopamine disruption? Additionally, we showed that retinal changes appear before cognitive changes, suggesting the retina can be used as a biomarker to predict and provide earlier treatment for cognitive deficits with diabetes. Future research will assess therapeutics that target the dopamine system in diabetes.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.