Nigrostriatal Dopmaine Function and Insulin Resistance

Abstract

Clinical studies have linked Type 2 Diabetes (T2D) with neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD). Although the link between T2D and AD is relatively well established, the potential link between T2D and PD is less understood. The mechanism by which such a link is mediated is unknown. It is also unclear whether the comorbidity between these diseases is bidirectional: whether T2D predisposes individuals to develop PD, or whether it is actually PD that increases T2D risk. The purpose of this work was to investigate this potential link using preclinical models. We used a high fat feeding regimen to model early stage T2D and analyzed the effects of this model on the basal ganglia, which is affected in Parkinson's disease. We used the 6-hydroxydopamine (6-OHDA) lesion model of PD to analyze glucose tolerance and peripheral insulin resistance following dopamine (DA) depletion. Finally, we combined a high fat diet and low dose 6-OHDA model to determine whether a high fat diet can exacerbate DA depletion. We found that high fat diet-induced insulin resistance elicits profound functional effects in the striatum. DA release was severely blunted in high fat-fed animals, and DA uptake was markedly slower. Interestingly, magnetic resonance imaging revealed increased iron content in the substantia nigra of these same animals, and expression of several proteins involved in iron transport was altered. The effects of 6-OHDA mediated dopamine depletion on peripheral glucose tolerance were less impressive. Although severe unilateral DA depletion induced insulin resistance in the striatum in both young and middle aged rats, glucose tolerance and peripheral insulin signaling were not affected. Finally, we observed that a high fat diet significantly increased DA depletion in response to the same dose of 6-OHDA, indicating that high fat feeding may increase the vulnerability of nigrostriatal neurons to toxins. While our studies do not support a role for DA depletion in mediating peripheral glucose tolerance, they do provide evidence that high fat diet-induced insulin resistance may contribute to impaired dopaminergic function and potentially neurodegeneration.