Table 5. Studies that revealed the impact of insulin and insulin resistance on PD.

Abbreviations: PD: Parkinson's disease; mTORC1/S6K1 pathway: mechanistic target of rapamycin complex 1/ribosomal protein kinase 1 pathway; FOXO1/HMOX1: forkhead box protein O1/heme oxygenase 1; IDE: insulin-degrading enzyme

Author’s name	Year of publication	Study design	Main points
Fiory et al. [6]	2019	Review article	Increased prevalence of PD in diabetic patients. Insulin plays a vital role in the dopaminergic cells. There are shared pathways between insulin resistance and PD. Insulin treatment has a neuroprotective role in PD. Insulin could impact dopamine synthesis and clearance through its effect on tyrosine hydroxylase. Anti-diabetic drugs that treat insulin-resistant could have a protective function.
Hong et al. [19]	2020	Basic science study	Insulin resistance contributed to PD progression through mitochondrial dysfunction and increased oxidative stress. It also leads to the synthesis of aberrant alpha-synuclein and leads to dopaminergic neurons' destruction.
Gao et al. [20]	2015	Basic science study	Alpha-synuclein has a negative effect on the insulin signaling pathway via the mTORC1/S6K1 pathway.
Ramalingam et al. [21]	2014	Essential science research	Insulin could protect the cell against hydrogen peroxide-induced oxidative stress.
Ramalingam et al. [22]	2016	Basic science study	Insulin decreases the BAX/BAL2 ratio by activating phosphoinositide-3-kinase/protein kinase B (PI3K/Akt/GSK3) pathways.
Heras-Sandoval et al. [23]	2014	Review article	Insulin enhanced autophagy and decreased toxic proteins in the brain. And hence reduced the alpha-synuclein aggregation in the brain.
Tokutake et al. [24]	2012	Basic science study	Insulin also found to inhibit the neurotoxicity of tau proteins by inhibiting the glycogen synthase kinase 3 (GSK3) beta.
Sharma et al. [25]	2015	Basic science study	Insulin through IDE can prevent aggregation of alpha-synuclein. IDE binds to alpha-synuclein oligomers and prevents amyloid formation.
Cheng et al. [26]	2010	Review article	Insulin plays a vital role in the biogenesis and function of the mitochondria. This action carried out by inhibition of FOXO1/HMOX1 and keeping the NAD(+)/NADH ratio.
Aghanoori et al. [27]	2017	Basic science study	Insulin improves the activity of respiratory chain activity in diabetic rats. Increase gen expression of the mitochondria in dorsal root ganglia culture.