NF‐κB/NLRP3 inflammasome axis and risk of Parkinson's disease in Type 2 diabetes mellitus: A narrative review and new perspective

Abstract Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Genetic predisposition and immune dysfunction are involved in the pathogenesis of PD. Notably, peripheral inflammatory disorders and neuroinflammation are associated with PD neuropathology. Type 2 diabetes mellitus (T2DM) is associated with inflammatory disorders due to hyperglycaemia‐induced oxidative stress and the release of pro‐inflammatory cytokines. Particularly, insulin resistance (IR) in T2DM promotes the degeneration of dopaminergic neurons in the substantia nigra (SN). Thus, T2DM‐induced inflammatory disorders predispose to the development and progression of PD, and their targeting may reduce PD risk in T2DM. Therefore, this narrative review aims to find the potential link between T2DM and PD by investigating the role of inflammatory signalling pathways, mainly the nuclear factor kappa B (NF‐κB) and the nod‐like receptor pyrin 3 (NLRP3) inflammasome. NF‐κB is implicated in the pathogenesis of T2DM, and activation of NF‐κB with induction of neuronal apoptosis was also confirmed in PD patients. Systemic activation of NLRP3 inflammasome promotes the accumulation of α‐synuclein and degeneration of dopaminergic neurons in the SN. Increasing α‐synuclein in PD patients enhances NLRP3 inflammasome activation and the release of interleukin (IL)‐1β followed by the development of systemic inflammation and neuroinflammation. In conclusion, activation of the NF‐κB/NLRP3 inflammasome axis in T2DM patients could be the causal pathway in the development of PD. The inflammatory mechanisms triggered by activated NLRP3 inflammasome lead to pancreatic β‐cell dysfunction and the development of T2DM. Therefore, attenuation of inflammatory changes by inhibiting the NF‐κB/NLRP3 inflammasome axis in the early T2DM may reduce future PD risk.

Therefore, this narrative review aims to find the potential link between T2DM and PD by investigating the role of inflammatory signalling pathways, mainly the nuclear factor kappa B (NF-κB) and the nod-like receptor pyrin 3 (NLRP3) inflammasome. NF-κB is implicated in the pathogenesis of T2DM, and activation of NF-κB with induction of neuronal apoptosis was also confirmed in PD patients. Systemic activation of NLRP3 inflammasome promotes the accumulation of α-synuclein and degeneration of dopaminergic neurons in the SN. Increasing α-synuclein in PD patients enhances NLRP3 inflammasome activation and the release of interleukin (IL)-1β followed by the development of systemic inflammation and neuroinflammation. In conclusion, activation of the NF-κB/NLRP3 inflammasome axis in T2DM patients could be the causal pathway in the development of PD. The inflammatory mechanisms triggered by activated NLRP3 inflammasome lead to pancreatic β-cell dysfunction and the development of T2DM. Therefore, attenuation of inflammatory changes by inhibiting the NF-κB/ NLRP3 inflammasome axis in the early T2DM may reduce future PD risk.

| INTRODUC TI ON
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). 1 PD was initially identified in 1817 by Doctor James Parkinson who described shaking palsy. 2 PD is progressing due to the loss of dopaminergic neurons in the substantia nigra (SN) followed by a considerable dopamine deficiency in the caudate nucleus and putamen. 1 These changes lead to the development of motor dysfunctions including rigidity, resting tremors, bradykinesia and walking difficulty. 3 In addition, numerous non-motor disorders are developed including apathy, depression, anxiety, autonomic disorders, dementia, neuropsychiatric disorders, cognitive dysfunction and sleep disturbances. 4 The incidence of PD in the general population is 0.3% and reaches 4% above the age of 80 years. 5 The mean age of PD onset is around 60 years; though, new-onset PD may develop in the younger age group of 20-50 years. 6 The annual incidence of PD is 8-18 per 100,000. 6 PD is more common in China and it is expected that 50% of total PD patients will be in this country by 2030. 7 Higher incidence of PD could be related to population growth and aging, genetic predisposition, lifestyle changes, single gene polymorphism and environmental pollution. Moreover, the improved diagnostic methods also led to better identification of disease, especially in early stages. 7,8 Males are more affected by PD than females with a ratio of 3:2. 9 In 2040, the number of PD patients will extend to 14 million people with a risk for the progress of the Parkinson's pandemic. 9 PD may be genetic or non-genetic due to exposure to pesticides, and manganese. 10,11 The neuropathological characteristic of PD is the deposition of Lewy bodies from aggregated α-synuclein ( Figure 1). 12 Deposition of α-synuclein is not limited to the SN but throughout the entire brain such as the autonomic nervous system (ANS). 12 Deposition of α-synuclein is progressive for many years before the development of a symptomatic period. 12 Deposition of α-synuclein is starting initially in the ANS mainly in the dorsal motor nucleus of glossopharyngeal and vagus nerves and then spreads to the other brain areas in stage I PD. 13 Stage of α-synucleinopathy is characterized by spreading to the brain stem area including medulla oblongata, locus coeruleus and pontine tegmentum. In stage α-synucleinopathy, the SN is affected. During stage IV α-synucleinopathy, there is profound degeneration of dopaminergic neurons in the SN and the pathology of Lewy bodies extends to the temporal cortex. In the advanced V and VI stages, Lewy bodies are highly deposited in the neocortex leading to the development of cognitive dysfunction. 13 These findings suggest that PD neuropathology is not limited to SN degeneration. Notably, in the prodromal phase, non-motor symptoms including anosmia, constipation, sleep disorders and depression are developing before dopaminergic degeneration in the SN. Following the development of motor symptoms due to dopaminergic degeneration in the SN, cognitive dysfunctions are propagated due to the involvement of the temporal cortex. [13][14][15] Besides, PD is associated with the progression of various inflammatory disorders which are linked with the progression of PD neuropathology. 16 Genetic and environmental factors have been described as of major importance in T2DM development such as obesity, which is directly correlated with the development of insulin resistance (IR) and inflammatory state in metabolic activated adipose tissue. 17 Inflammatory responses may have a dual role in T2DM, as it may have either a causal relationship leading to IR or may be intensified by the hyperglycaemic state, resulting in T2DM complications. 18

K E Y W O R D S
NF-κB, NLRP3 inflammasome, Parkinson disease, T2DM Hyperglycaemia is the major risk factor for microvascular complications and reduction in glycated haemoglobin (HbA1c) decreases the incidence of retinopathy, nephropathy and neuropathy. 19 For every 1% decrement in HbA1c, the incidence of microvascular complications is reduced by about 25%-35%. 20 The incidence of T2DM is increasing worldwide and has become a significant public health problem. It is associated with mortality and significant morbidity, including neurological disability. 21 Although the effects of diabetes on the peripheral nervous system are well established, its effects on higher mental and specific neurological functions are often overlooked. Various studies reported that T2DM could be a risk factor for the development of PD. 22,23 However, the underlying mechanisms linking T2DM and PD are not fully elucidated. Therefore, this narrative review aimed to find the potential link between T2DM and PD regarding the potential role of inflammatory signalling pathways.

| T2DM AND INFL AMMATORY DISORDER S
T2DM is associated with inflammatory disorders and end-organ damage due to hyperglycaemia-induced oxidative stress and the release of pro-inflammatory cytokines. 24 IR and relative insulin deficiency due to pancreatic β-cell dysfunction is the major feature of T2DM. 25 The triggering of inflammatory disorders in T2DM is not fully elucidated, although it has been shown that immune cell dysregulation and infiltration into adipose tissue promote the expression of pro-inflammatory cytokines with the development of systemic inflammation. 26 Prolonged low-grade inflammation in T2DM due to hyperglycaemia and adipose tissue activation leads to the development of IR and the propagation of several related complications. 27 Inflammatory disorders seem to play a critical role in the progression of IR, T2DM and systemic complications. 26,27 Both hypoglycaemia and hyperglycaemia as well as glucose variability (daily changes of blood glucose with controlled glycated haemoglobin) trigger oxidative stress which in turn promotes inflammatory disorders. 28 Besides, environmental and genetic factors such as stress, diet and smoking are engaged in the activation of chronic inflammation in T2DM. 28 A population-based study illustrated that the risk of T2DM is increased with the presence of systemic inflammatory disorders. 26 A systematic review and meta-analysis on 10 prospective studies and 22 cohort studies showed that higher serum levels of IL-6 and C reactive protein (CRP) increase the risk for the development of T2DM. 29 Thus, anti-inflammatory agents may reduce the risk. 25 These observations suggest a close relationship between T2DM and immunoinflammatory disorders in a feedback loop ( Figure 2).

| PD and inflammatory disorders
Progression of PD is associated with high inflammatory changes and systemic inflammatory disorders. 30 For example, PD is more common in inflammatory bowel diseases (IBDs), as shown by a systematic review illustrating that PD is more common in patients with Crohn's disease and ulcerative colitis. 30 A retrospective study indicated that patients with IBDs had a higher risk for the development of PD. 30 Numerous cytokines like interleukin-1β (IL-1β) and tumour necrosis factor-alpha (TNFα) which are higher in IBDs and other inflammatory disorders are involved in the pathogenesis of PD. 30 These data indicated that higher inflammatory changes may increase for development of PD.
Of note, dysfunction of the immune system with genetic susceptibility impairs cellular immune responses in PD. 31 Deregulation of the innate/adaptive immune response is implicated in the development of neurodegenerative diseases including PD. 31 In PD, both central and peripheral immune responses are disturbed with increased risk for the development of an autoimmune response. 31 A 33% overall excess risk of PD was noted among patients with autoimmune disorders like Graves's disease, multiple sclerosis, pernicious anaemia and polymyalgia rheumatica; the risk being increased during the first 10 years of follow-up after hospitalisation of autoimmune disorders. 32 Of note, leucine-rich repeat kinase 2 (LRRK2) which regulates B-lymphocyte function, is regarded as a potential link between cell-mediated immunity and PD neuropathology. Peripheral inflammatory biomarkers may be augmented and correlated with motor severity in PD patients. 34 A case-control study on 58 PD patients compared to 20 healthy controls showed that IL-1β, TNFα, IL-6, CRP and IL-12 are increased in PD patients compared to healthy controls. 34 There was no positive correlation between the levels of inflammatory biomarkers and non-motor symptoms in PD patients. 34 Meanwhile, Chen et al. 35 36 These findings indicated that the progression of PD is highly correlated with the severity of peripheral and local inflammatory disorders ( Figure 3).

| T2DM and the risk of PD
Interestingly, PD is linked with T2DM, particularly in aetiology, epidemiology and pathogenesis. T2DM is regarded as a risk factor for PD. Notably, subjects with impaired glucose tolerance were shown to be at higher risk for the development of cognitive decline. 23 Thus, T2DM patients may have PD-like symptoms such as motor dysfunction as both PD and T2DM share overlapping pathology. Therefore, T2DM may predispose toward a PD-like pathology, and, when present in PD patients, can induce a more aggressive phenotype. 22 Various studies revealed the association between T2DM and PD ( Table 1). Evidences from epidemiological and observational studies showed a potential controversy regarding the association between T2DM and PD. 23,[37][38][39][40][41] In an observational study, T2DM patients appear to be at increased risk of developing PD, as well as experiencing faster progression and a more severe phenotype of PD, with the effects being potentially mediated by several common cellular pathways. The insulin signalling pathway, for example, may be responsible for neurodegeneration via insulin dysregulation, aggregation of amyloids, neuroinflammation, mitochondrial dysfunction and altered synaptic plasticity. 37 However, there are studies that showed the opposite or no relation between these diseases. 40,41 Of note, IR in T2DM promotes the degeneration of dopaminergic neurons in the SN and other PD neuropathological processes since; insulin signalling regulates dopaminergic synaptic plasticity and neurotransmission in the SN. 23 An experimental study observed that T2DM mice not only showed IR and impairment of insulin signalling in the pancreatic β cells and liver but also in the midbrain DNs. 42 These changes are developed due to the deposition of α-synuclein and associated endoplasmic reticulum stress. 42 Therefore, metabolic inflammation exacerbates the degeneration of DNs and contributes to the degeneration of DNs and the progress of PD.
Indeed, preclinical and clinical evidence indicated that T2DM is associated with an increased risk for the development of PD. 22,43 The connection between T2DM and risk for the development of PD was primarily reported in 1993 by Sanyk, who showed that PD patients with T2DM had severe motor dysfunction and respond less to PD pharmacotherapies. 44 Afterward, Marques et al. 44 illustrated that PD patients had abnormal glucose tolerance which could be due to the development of dysautonomia and impairment of insulin response. It has been revealed that degeneration of dopaminergic neurons in the SN influences glycaemic control since SN regulates the feeding behaviour during hypoglycaemia. 45 This conclusion anticipated the mutual relationship between T2DM and PD. 37,46 A prospective study on 25 PD patients with T2DM compared to 25 PD patients without T2DM followed for 36 months showed that T2DM patients with PD experience more motor dysfunctions. 22 The incidence of PD in the general population is 0.03% though this percentage is augmented to 18% in T2DM patients. 47 Thus, T2DM predisposes to more complications and a more aggressive phenotype of PD. A population-based study performed by Yang et al. 48 showed that T2DM augments the risk for PD. A meta-analysis demonstrated that T2DM increases the risk for PD by 38%. 49 As well, PD and T2DM share matching dysregulated pathways like genetic vulnerability and exposure to environmental risk factors. 43 It has been observed that systemic exposure to environmental toxins induces several pathological features of PD such as mitochondrial dysfunction, oxidative stress, inflammation, and α-synuclein misfolding, thereby indicating environmental exposure as a contributor to the PD disease process.
Exposure to environmental toxins may interact with polymorphisms in genes involved in free radical scavenging and protein degradation, leading to an increased risk to develop PD in some individuals. 50 The progress of peripheral IR and brain IR due to mitochondrial F I G U R E 3 PD and inflammatory disorders.
dysfunction, endoplasmic reticulum stress and chronic inflammation alterations could be a possible pathway linking PD and T2DM. 43 The probable link between PD and T2DM is the age factor, as both of these diseases are amplified by aging due to mitochondrial dysfunction and endoplasmic reticulum stress. 51 A retrospective study showed that T2DM patients increase PD risk mainly in younger women. 51 In addition, dysregulation of the brain insulin signalling pathway in T2DM reduces dopaminergic activity in the SN. 52 Brain IR is augmented in both PD and T2DM patients compared to the control. 53 These findings emphasized that T2DM increases the risk for the progression of PD. Notably, insulin signalling has been found to be de-sensitized in the brains of PD patients, and drugs that can re-sensitize insulin signalling may control disease progression. Insulin signalling plays important roles in neuronal growth, synaptic development, energy utilisation, mitogenesis, inhibition of apoptosis and more. Insulin binds to the α-subunit of the receptor. This activates the tyrosine kinase phosphorylation of the β-subunit. 54 Preclinical studies have shown that animal models of AD and PD show impaired insulin signalling and a range of downstream effects that contribute to the pathology. 54 Thus, improvement of insulin signalling in the brains of AD or PD patients has clear disease-modifying effects. Not only are symptoms such as attention, memory impairments, or other cognitive impairments much reduced in AD and PD patients, and motor coordination improved in PD patients, but the improvements long outlast drug treatment duration and support the rationale for repurposing anti-diabetic drugs for PD treatment. 55,56 At the cellular level, long-term elevated levels of glucose have been shown to lead to nigrostriatal degeneration and an increase of α-synuclein accumulation through induction of neuroinflammation in PD models. 57 Furthermore, pre-diabetes also boosts the risk for the development of PD. 17 58 Nevertheless, the use of oral hypoglycaemic agents in T2DM patients with anti-inflammatory properties like metformin may reduce PD risk in T2DM patients. 59,60 It has been shown that T2DM accelerates the development of cognitive dysfunction and motor deficits in PD via the reduction of the accessibility and expression of dopamine transporters. 22 Further on, Chung et al. 61 established that T2DM has detrimental effects on the dopaminergic transporters and brain cortical thickness.
However, Bohnen et al. 62 illustrated that T2DM is independently associated with the development of the severe form of PD via a mechanism other than PD-specific neurodegeneration like dopamine depletion and NS degeneration. Consequently, PD appears to be more brutal when linked with comorbid T2DM as PD patients with T2DM have more frontotemporal cortical atrophy compared with PD patients without T2DM. 62 Of note, tau protein which is a biomarker of NBDs as in AD and PD is augmented in the CSF of PD patients with T2DM compared to PD without T2DM. 22,45 Peripheral IR and hyperglycaemia provoke the development of chronic inflammation, microvascular dysfunction, neuroinflammation and impairment of the blood-brain barrier (BBB) function. 63 Notably, IR increases glutamate excitotoxicity and the development of synaptic dysfunction in the SN with the development of PD. 64 Brain IR promotes as well abnormal protein aggregation and impairment of amyloid protein clearance. 63 It has been reported that insulin receptors  These results have anticipated the mutual relationship between T2DM and PD; in particular, T2DM could be a risk factor in the development of PD ( Figure 4).

F I G U R E 4
The mutual relationship between T2DM and PD.  Furthermore, α-synuclein plasma level which is a major constituent of Lewy bodies had been reported to be increased in PD patients F I G U R E 5 NF-κB signalling pathway is activated in both T2DM and PD.

| NLRP3 inflammasome
compared to the healthy controls. 116 In turn, α-synuclein can trigger the activation of the NLRP3 inflammasome with subsequent release of IL-1β and the development of systemic inflammation and neuroinflammation 117 (Figure 7).
Accordingly, the NLRP3 inflammasome could be a potential link between PD and T2DM. A previous study revealed that T2DM was associated with higher α-synuclein plasma levels which induce sys-

| Crosstalk between oxidative stress and inflammation in PD and T2DM
The inflammation process in the human body plays a central role in the pathogenesis of many chronic diseases including T2DM and Metformin has been shown to inhibit α-synuclein phosphorylation and aggregation, prevent mitochondrial dysfunction, attenuate oxidative stress and modulate autophagy mainly through AMP-activated protein kinase (AMPK) activation, as well as prevent neurodegeneration and neuroinflammation. 135 Metformin has been shown to ameliorate motor and cognitive dysfunction, by inhibiting α-synuclein aggregation. 135 Together, the neuroprotective effects of metformin in PD pathogenesis present a novel promising therapeutic strategy that might overcome the limitations of current PD treatment. NF-kB is increased in a variety of tissues with aging, thus the inhibition of NF-kB leads to delayed onset of aging-related symptoms and pathologies such as diabetes, atherosclerosis, and PD. 136 In virtue of its antioxidant, and anti-inflammatory properties, metformin has become a possible candidate drug, improving in the context of aging and aging-related diseases by inhibiting the expression of the NF-kB gene, and eliminating the susceptibility to common diseases. 136 Likewise, metformin has been reported to inhibit NLRP3 by activating autophagy through the AMPK-dependent pathway. 137 Particularly, AMPK activation attenuates NLRP3 inflammasome upregulation in some pathological At a molecular level, insulin signaling impairment, abnormally higher activity of glycogen synthase kinase-3 (GSK-3) and the subsequent deregulated protein phosphorylation have been detected both in AD and T2DM patients. 141 Consequently, it has been proposed that pharmacological agents against T2DM could also be beneficial for the prevention and/or treatment of AD. In this bargain, the association between T2DM and PD extends to antidiabetic drugs. Small clinical trials repurposing antidiabetic drugs in PD have yielded positive results with exenatide a glucagon-like-peptide 1 receptor agonist, but not with pioglitazone. 142 A recent prospective study found strong evidence for a lower incidence of PD in users of DPP4 inhibitors and GLP-1 agonists compared to users of control medications, and an inverse association between the use of these drugs and the onset of PD. 143 Furthermore, these results were seen in both short-term and long-term >3 years users of GLP-1 agonists and DPP4 inhibitors. While glitazone usage was associated with a lower PD risk, this finding was not significant in the adjusted models. 143 Additional analyses showed that diabetes is associated with increased PD risk, the risk was highest for untreated diabetic patients and did not vary significantly between index and control medication groups for insulin-user diabetics. 143 It has been shown that DPP4 inhibitors can reduce vascular inflammation in metabolic disorders through the inhibition of NF-kB. 144,145 Similarly, DPP4 inhibitors repress NLRP3 inflammasome activation in diabetic nephropathy and acute kidney injury. 144,146,147 These observations proposed that antidiabetic agents can mitigate inflammatory disorders which are implicated in the pathogenesis of PD.

ACK N O WLE D G E M ENTS
The authors would like to thank the Deanship of Scientific Research at Shaqra University for supporting this work. Open Access funding enabled and organized by Projekt DEAL.

This work was supported by the University of Witten-Herdecke
Germany.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analysed in this study.