The Relevance of Insulin Action in the Dopaminergic System

Abstract

The advances in medicine, together with lifestyle modifications, led to a rising life expectancy. Unfortunately, however, aging is accompanied by an alarming boost of age-associated chronic pathologies, including neurodegenerative and metabolic diseases. Interestingly, a non-negligible interplay between alterations of glucose homeostasis and brain dysfunction has clearly emerged. In particular, epidemiological studies have pointed out a possible association between Type 2 Diabetes (T2D) and Parkinson’s Disease (PD). Insulin resistance, one of the major hallmark for etiology of T2D, has a detrimental influence on PD, negatively affecting PD phenotype, accelerating its progression and worsening cognitive impairment. This review aims to provide an exhaustive analysis of the most recent evidences supporting the key role of insulin resistance in PD pathogenesis. It will focus on the relevance of insulin in the brain, working as pro-survival neurotrophic factor and as a master regulator of neuronal mitochondrial function and oxidative stress. Insulin action as a modulator of dopamine signaling and of alpha-synuclein degradation will be described in details, too. The intriguing idea that shared deregulated pathogenic pathways represent a link between PD and insulin resistance has clinical and therapeutic implications. Thus, ongoing studies about the promising healing potential of common antidiabetic drugs such as metformin, exenatide, DPP IV inhibitors, thiazolidinediones and bromocriptine, will be summarized and the rationale for their use to decelerate neurodegeneration will be critically assessed.

Diabetes Causes Dysfunctional Dopamine Neurotransmission Favoring Nigrostriatal Degeneration in Mice

“…This suggests that db/db mice activate compensatory mechanisms to deliver DAT to the plasmalemmal membrane, possibly related to differences between both mouse models in insulin levels known to impact dopaminergic neurotransmission. [81][82][83][84] Consistent with our data, decreased DAT binding sites have been observed in diabetic patients with or without PD. 15 Decreased VMAT2 levels may reflect decreased number or size of synaptic vesicles, in consonance with parallel low levels of Syb2, and suggest that the sequestration of axonal dopamine into vesicles is compromised in diabetic mice, favoring its accumulation in the cytosol, as indicated previously.…”

Diabetes Mellitus and Parkinson's Disease: Shared Pathophysiological Links and Possible Therapeutic Implications

“…Clinical manifestations of both diseases are caused by the destruction of specific cells, which are the pigmented dopaminergic cells in PD, and the beta-pancreatic cells in DM. The loss of these cells results in decreased insulin in DM and dopamine in PD [6].…”

Early Biomarkers of Neurodegenerative and Neurovascular Disorders in Diabetes

“…Insulin resistance also correlates with the progression of PD [ 35 ]. Finally, a recent study concluded that DM can possibly increase the risk of development of Parkinson-like pathology and aggravate the disease phenotype [ 102 ].…”

“…Some studies showed that EGF may be linked to the development of microvascular complications in diabetes [ 51 ]. For example, patients with type 1 DM and microangiopathy have higher serum EGF concentrations compared to those without [ 102 ]. VEGF, in turn, is mainly responsible for stimulating endothelial cell proliferation and migration, collagen production and macrophage chemotaxis [ 52 ].…”