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. Author manuscript; available in PMC: 2021 Jun 1.
Published in final edited form as: Exp Eye Res. 2020 Apr 29;195:108040. doi: 10.1016/j.exer.2020.108040

Dopamine metabolite levels in the vitreous of diabetic and non-diabetic humans

Andrew Hendrick a, Jesse Smith a,*, Chris Stelton a, Scott Barb a, Jiong Yan a, Blaine Cribbs a, Nieraj Jain a, Steve Yeh a, G Baker Hubbard a, Li He a, Susov Dhakal a,**, P Michael Iuvone a,b
PMCID: PMC7282952  NIHMSID: NIHMS1591454  PMID: 32360553

Abstract

Animal studies suggest that the retinal dysfunction in diabetic subjects that precedes overt clinical vasculopathy may be due to a retinal dopamine deficit. We analyzed levels of dopamine (DA) and its primary metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the vitreous of diabetic and non-diabetic human subjects. Adult patients undergoing pars plana vitrectomy for non-hemorrhagic indications were prospectively recruited from the Emory Eye Center in Atlanta, GA. Vitreous samples were analyzed using high performance liquid chromatography (HPLC) to measure levels of DOPAC and DA in the vitreous specimens. Vitreous samples from 9 diabetic patients and 20 from non-diabetic patients were analyzed. No eyes had apparent diabetic retinopathy. Mean normalized DA concentration in vitreous of diabetic subjects was 0.76 ± 0.12 pg/pL vs. 0.73 ± 0.08 pg/pL in non-diabetic vitreous (p=0.849). DOPAC concentration was 8.84 ± 0.74 pg/pL in vitreous of diabetic subjects vs. 9.22 ± 0.56 pg/pL in vitreous of non-diabetic subjects (p=0.691). No difference was observed in the concentrations of DA and DOPAC in the vitreous of people without diabetes compared to those with diabetes without retinopathy.

Keywords: dopamine, diabetes, diabetic retinopathy, vitreous

Short Communication (WC<4000)

Diabetic retinopathy (DR) is a complication of diabetes mellitus and a leading cause of blindness in working age adults; affecting millions of people in the United States (Zhang et al., 2010). Standard treatment for initial stages of diabetic retinopathy involves rigorous management of hyperglycemia (UKPDS, 1998), but at later stages laser photocoagulation, intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors (Gross et al., 2018), and surgery can become necessary. Prevention of blinding complications can be effective under ideal circumstances (Liew et al., 2014), but many patients are unaware or unable to comply with screening and management guidelines (Bressler et al., 2014; Obeid et al., 2019). A broad opportunity exists to treat diabetes and diabetic retinopathy to specifically curtail stages prior to the development of visually threatening disease.

Dopamine (DA) is an endogenous catecholamine neurotransmitter commonly associated with Parkinson’s disease pathophysiology and psychopathology (Brandies and Yehuda, 2008). However, the role of DA in obesity, addiction, circadian rhythms, and diabetes mellitus (DM) has become more evident within the past several years. In fact, bromocriptine, a dopaminergic (D2 receptor) agonist, is FDA approved for treatment of type 2 DM (Gaziano et al., 2010; Gaziano et al., 2012).

Abnormalities in dopaminergic neurotransmission in the retina may have an association with the pathogenesis of DR, but this relationship has not been investigated previously in humans. In diabetic rats and mice, DA levels are reduced in the retina 1 month after DM induction (Nishimura and Kuriyama, 1985). In a mouse model of type 1 DM where DA is reduced, treatment with 3,4-L-dihydroxyphenylalanine (L-DOPA, a DA precursor) improved metrics of visual function using electroretinography and the optomotor reflex (Aung et al., 2014). Dopamine and its metabolites may serve as a biomarker for DR and may play a role in its pathogenesis, and thus present a novel pathway for treatment at earlier stages than in current use. This study compares vitreous levels of dopamine in people with and without type II diabetes.

This study was approved by the Emory University Institutional Review Board and adhered to the tenets of the Declaration of Helsinki. All patients provided signed informed consent prior to participation in the study. Subjects were 18 years of age or older and already consented to undergo pars plana vitrectomy for non-hemorrhagic indications for surgery such as macular holes and epiretinal membranes. Subjects were excluded if vitreous hemorrhage was present. Subjects were also excluded with a history of psychosis, Parkinson’s disease, or with use of medications that may alter systemic dopamine levels (e.g., bromocriptine, levodopa, antipsychotic medications). A total of 31 individuals were recruited, 9 with diabetes and 21 without. One sample of the non-diabetic cohort was excluded because the dopamine and DHBA (internal standard) peaks were undetectable and DOPAC levels were extremely high (~2 times the group mean). At the start of each case, an undiluted sample of vitreous was obtained by their surgeons and samples were immediately frozen on dry ice. Samples were analyzed for dopamine and a metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), using HPLC with electrochemical detection (Stone et al., 2016). Statistical analysis was performed using Microsoft Excel (Office 365; Microsoft Corp.) and Sigma Stat 3.5 (Aspire Software International). Results were normalized to volume of vitreous sample and compared using unpaired Student’s t-test to analyze for between group differences per metabolite in vitreous specimens. All analyses were performed with a priori significance set at a<0.05.

Thirty samples were analyzed, 9 from eyes of people with diabetes and 21 from non-diabetic eyes. Individuals with diabetes did not have clinically detectable diabetic retinopathy. The average sample was 0.52 grams of undiluted vitreous. Mean normalized DA concentration in diabetic vitreous was 0.76 pg/pL (SEM 0.12) vs. 0.73 pg/pL (SEM 0.08) in non-diabetic vitreous (p=0.85). DOPAC concentration was 8.84 pg/pL (SEM 0.74) in diabetic vitreous vs. 9.22 pg/pL (SEM 0.56) in non-diabetic vitreous (p=0.69). Results are presented in Figures 1 and 2.

Figure 1.

Figure 1.

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Dopamine levels in vitreous of human subjects with or without type II

DM. The levels of dopamine were compared in vitreous from type II DM subjects without DR and vitreous of subjects without diabetes. No diffence was found (t27=− 0.192, p=0.849; N=20 non-DM samples and N=9 DM samples).

Figure 2.

Figure 2.

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DOPAC levels in vitreous of human subjects with or without type II DM.

The levels of dopamine were compared in vitreous from type II DM subjects without DR and vitreous of subjects without diabetes. No diffence was found (t27=0.401, p=0.691; N=20 non-DM samples and N=9 DM samples).

This study did not detect a difference in the vitreous levels of DA and DOPAC in people with and without type II diabetes. Low dopamine levels are associated with development of diabetic retinopathy in rodent models of type 1 diabetes (Akimov and Renteria, 2012; Aung et al., 2013; Aung et al., 2014; Kirwin et al., 2011; Muir et al., 2012). A literature search did not reveal prior published research on this topic in humans.

Dopamine may play an early and even causative role in some of the visual defects associated with diabetes, such as color vision abnormalities, impaired contrast sensitivity (Jackson and Barber, 2010), and ERG abnormalities (Ghirlanda et al., 1997; Shirao and Kawasaki, 1998). These consequences are likely time-dependent but occur prior to manifestations of overt clinical diabetic retinopathy. It is possible that our study did not find a difference in vitreous levels of dopamine due to testing before dopamine abnormalities occur, as none of our subjects had diabetic retinopathy. Perhaps differences exist in the pathophysiology in rodent models of type 1 diabetes that are dissimilar to human type 2 diabetes. Further study will be necessary to test these possibilities.

Much interest exists in reducing blinding consequences of diabetes at earlier stages. At the low levels of diabetic retinopathy severity, the current practice involves systemic optimization. Fenofibrate has not been widely adopted despite demonstrating effectively reduced progression of retinopathy severity (Chew et al., 2014; Keech et al., 2007). Trials are underway to evaluate the effectiveness of serial anti-VEGF injections in patients with categorically severe (ETDRS level 43/57) non-proliferative diabetic retinopathy (ClinicalTrials.gov Identifier: NCT02718326, NCT02634333). The dopaminergic pathway is a compelling consideration for treatment and further study is necessary to determine optimal conditions for the therapeutic potential.

Highlights.

  • Animal models of diabetes mellitus (DM) indicate that deficits in retinal dopamine precede vascular dysfunction and contribute to compromised visual function.

  • Levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in vitreous of human subjects were analyzed.

  • No statistically significant differences in dopamine or DOPAC levels were found between samples from type II DM subjects and non-diabetic subjects.

Acknowledgments

Funding: This project was supported by an unrestricted departmental grant from Research to Prevent Blindness to the Emory Eye Center; and grants from the National Institutes of Health P30 EY006360, R01 EY004864 and R01 EY027711. The sponsors had no role in the design or conduct of this research.

Abbreviations

DA

dopamine

DOPAC

3,4-dihydroxyphenylacetic acid

L-DOPA

3,4-L- dihydroxyphenylalanine

HPLC

high performance liquid chromatography

DM

diabetes mellitus

DR

diabetic retinopathy

OU

both eyes

OD

right eye

OS

left eye

Footnotes

A preliminary report of this study was presented at the Association for Research in Vision and Ophthalmology (ARVO) meeting in May of 2018

No conflicting interest exists for any author.

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