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.

Keywords: Insulin; Parkinson’s disease; Pathophysiology; Therapeutics; Type 2 diabetes mellitus.

Fig. 1

Function of insulin in the brain. Insulin controls peripheral activities in the brain by autonomic nervous system (ANS) and the hypothalamic-pituitary axis (HPA). Insulin specifically acts in the hippocampus and prefrontal cortex to enhance cognitive function and lessen depression symptoms. Insulin reduces food intake and helps people lose weight by acting in the hypothalamic nuclei. Insulin functions in the brain to reduce hepatic glucose synthesis, enhance lipogenesis, reduce lipolysis, and boost the sympathoadrenal response to hypoglycemia via the efferent ANS to target organs. The hypothalamic-pituitary–gonadal axis is the pathway via which insulin improves reproductive competence

Fig. 2

Signalling pathways involved in insulin signals in the brain. When insulin ligand binds to its receptor, the receptor substrates IRS and Shc were phosphorylated. IRS activates PI3K-Akt pathway and insulin signalling cascade such as mTORC and FOXO1. PI3K first converts PIP₂ to PIP₃ that helps in engaging the Akt to the cell membrane. Shc activates MAPK pathway by activating the Ras protein through phosphorylation. Insulin binding also helps in the expression and recruitment of other receptors like GABA, NMDA, and AMPA. IRS, insulin receptor substrate; mTORC, mammalian target of rapamycin complex; FOXO1, Forkhead box protein O1; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol-3-kinase; PIP2, phosphatidylinositol (3,4)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; GABA, gamma-aminobutyric acid; NMDA, N-methyl-D-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

Fig. 3

Correlating the influence of methylglyoxal on T2DM and PD. This image depicts the possible influence of methylglyoxal on causing the T2DM and PD pathogenesis. In T2DM, glycolysis is the major factor for the release of MGO, whereas in PD in gets released due to low levels of GSH. Further in T2DM, it has a role in causing both phenotypic as well as genotypic changes. In PD, it impacts in two ways: (1) by increasing oxidative stress and (2) neuro-inflammation in the cells

Fig. 4

(a) Dysregulation of Insulin in PD pathogenesis. In PD, the production of insulin is hindered which directly or indirectly inhibits the IR-IRS-1-PI3K/AKT signalling pathway of insulin production. This results into consecutive production of either oxidative stress or aggregation of a-syn which is mostly observed in PD. (b) Impact of oxidative stress on T2DM and PD. This image lets us to easily compare the similarities and differences amongst the impact of oxidative stress on T2DM and PD. In both the cases, inflammation is the major role of disease pathogenesis. (c) Importance of microglia in T2DM and PD. Generally, the activation of microglia causes morphological as well as functional changes which results into disease conditions. This image enables us to understand the role of microglia activation in both T2DM and PD and how it triggers inflammation more easily

Fig. 5

Metformin: anti-diabetic and neuroprotective role. Metformin has a neuroprotective role through the AMPK pathway which is also their anti-diabetic pathway. AMPK is activated through inhibition of mitochondrial complex I and it drastically reduces the ROS levels causing neuronal survival. Metformin enhances autophagy by inhibiting mTORC1 which was phosphorylated by AMPK, anti-apoptosis by increasing anti-apoptotic protein Bcl-2, reduces DNA damage, and neuroinflammation hence accounting for neuronal protection. Metformin reduces the αSyn aggregates by increasing PP2A. AMPK, AMP-activated protein kinase; ROS, reactive oxygen species; mTORC1, mammalian target of rapamycin complex 1; Bcl-2, B-cell lymphoma 2; PP2A, protein phosphatase 2