Type 2 Diabetes (T2DM) and Parkinson’s Disease (PD): a Mechanistic Approach

Abstract

Growing evidence suggest that there is a connection between Parkinson’s disease (PD) and insulin dysregulation in the brain, whilst the connection between PD and type 2 diabetes mellitus (T2DM) is still up for debate. Insulin is widely recognised to play a crucial role in neuronal survival and brain function; any changes in insulin metabolism and signalling in the central nervous system (CNS) can lead to the development of various brain disorders. There is accumulating evidence linking T2DM to PD and other neurodegenerative diseases. In fact, they have a lot in common patho-physiologically, including insulin dysregulation, oxidative stress resulting in mitochondrial dysfunction, microglial activation, and inflammation. As a result, initial research should focus on the role of insulin and its molecular mechanism in order to develop therapeutic outcomes. In this current review, we will look into the link between T2DM and PD, the function of insulin in the brain, and studies related to impact of insulin in causing T2DM and PD. Further, we have also highlighted the role of various insulin signalling pathway in both T2DM and PD. We have also suggested that T2DM-targeting pharmacological strategies as potential therapeutic approach for individuals with cognitive impairment, and we have demonstrated the effectiveness of T2DM-prescribed drugs through current PD treatment trials. In conclusion, this investigation would fill a research gap in T2DM-associated Parkinson’s disease (PD) with a potential therapy option. Graphical Abstract

Causal relationships between type 1 diabetes mellitus and Alzheimer’s disease and Parkinson’s disease: a bidirectional two-sample Mendelian randomization study

“…While there is mounting evidence linkingT2DM with PD [ 41 , 42 ], and suggesting antidiabetic agents as a novel treatment for PD [ 5 ], less is known about the association between PD and T1DM. For PD, the changes in brain insulin resistance (BIR) and α-synuclein protein at synapses, as well as the dopaminergic loss in specific brain regions, eventually yield to the manifestation of the classic motor symptoms corresponding to the typical PD phenotype [ 43 ].…”

The Contribution of Type 2 Diabetes to Parkinson’s Disease Aetiology

“…Cell survival effects of the PI3K-AKT signalling pathway are promoted by (a) inhibiting excessive apoptosis and (b) attenuating the pro-inflammatory NF.κB-dependent signalling pathways, (c) attenuating FOXO1-mediated MT oxidative stress, (d) reducing α-syn aggregation by preventing the GSK3β inhibition of IDEs that break down the α-syn protein, and (e) promoting synapse regeneration by mTORC1/2 activation [1,233,234]. All four signalling pathways support neuronal growth and survival [2,192,[235][236][237].…”

“…In PD, the high metabolic rate of brain dopaminergic neurons increases their vulnerability to the combined detrimental effects of increased MT oxidant stress and the MT accumulation of toxic α-synO. Brain IR further compounds the damaging impact of MT oxidant stress and toxic α-synO forms [2,28,235,237]. Insulin signalling supports normal MT biogenesis (i.e., oxidative function) via the modulation of the mTORC and FOXO1 signalling pathways, which converge and adjust the activity of peroxisome proliferatoractivated receptor-γ coactivator 1-α (PGC1α).…”

“…PD inhibits autolysosome cargo degradation and retrograde trafficking, and T2Dassociated IR and hyperglycemia inhibit autophagosome synthesis; both disorders reduce the efficiency of autophagy. Therefore, T2D in patients with PD further degrades the proteostasis of these patients [28,237,[293][294][295][296][297][298][299]. Regular insulin signalling balances autophagy activity within physiological limits by (a) AKT-mediated activation of the mTOR and the inhibition of the FOXO1/3 signalling pathways and (b) preventing α-syn fibril formation from α-synO with the phosphatidylinositol 3-kinase (PI3K)-signalling pathway-activated IDEs.…”

Insulin resistance compromises midbrain organoid neural activity and metabolic efficiency predisposing to Parkinson’s disease pathology

“…It has also been shown that patients affected by PD and T2D comorbidity, suffer from more severe motor symptoms and cognitive decline (6)(7)(8)(9). Moreover, it has been suggested that T2D and PD share underlying pathophysiological mechanisms (5,10,11). Along with the dysregulated energy metabolism, aberrant protein aggregation, accumulation of reactive oxygen species and inflammation, insulin resistance seems to play a pivotal role in converging most of these common mechanisms.…”