A growing pool of evidence suggests that Type 2 diabetes mellitus (T2DM) and Parkinson’s disease (PD) may share common pathological mechanisms, and that the presence of T2DM increases the risk of developing PD by 40%.
Measuring blood sugar level. Image Credit: Neirfy / Shutterstock
How is T2DM Connected to PD?
PD, the second most common neurodegenerative disorder after Alzheimer’s disease, is primarily caused by the loss of dopaminergic neurons in the substantia nigra of the midbrain. Although the exact etiology of this particular type of neurodegeneration is still unknown, accumulating evidence suggests that mitochondrial disruption, inflammation, oxidative stress, and impaired autophagy-related pathways are among the important contributors. T2DM, which primarily develops from insulin resistance, also shares similar dysregulated pathways as PD.
Insulin resistance is defined as a condition wherein tissues in the body stop responding to insulin, resulting in impaired glucose and energy metabolism. A growing pool of evidence suggests that a similar pattern of metabolic dysregulation is also observed in patients with PD.
Although mainly known for its role in regulating peripheral glucose metabolism, insulin also acts as a neuroprotective factor and regulates the growth and survival of neurons, dopaminergic transmission, and synaptic connections in the central nervous system, especially the basal ganglia and substantia nigra. In this regard, one recent study has shown that about two-thirds of PD patients who are non-diabetic and have normal glucose metabolism may have undiagnosed insulin resistance.
Possible Mechanisms of T2DM-Mediated PD Progression
Insulin resistance associated with T2DM can increase the risk of developing PD in multiple ways. For instance, loss of AKT signaling, which is one of the main downstream targets of the insulin signaling pathway that regulates cell survival, is associated with the pathogenesis of several age-related disorders, including T2DM, Alzheimer’s disease, and PD. Post-mortem analysis showed that the brains of individuals who had PD had reduced levels of both total and phosphorylated AKT and single nucleotide polymorphism of the AKT gene. In addition, loss of AKT signaling also leads to apoptosis (cell death) of dopaminergic neurons in PD patients.
Impaired insulin signaling negatively regulates lysosomal systems that are responsible for the degradation of structurally/functionally abnormal cellular components, leading to increased aggregation of alpha-synuclein, a protein which is highly related to the pathology of PD-related dementia. Under normal physiological condition, activation of insulin-AKT signaling causes inhibition of GSK-3B, which in turn triggers autophagy and reduces the aggregation of alpha-synuclein. However, in the case of PD, significantly higher levels of GSK-3B and alpha-synuclein aggregates have been observed.
Disruption of mitochondrial functioning contributes significantly to the pathogenesis of PD in terms of defective mitochondrial autophagy, dysregulated calcium homeostasis, impaired mitochondrial electron transport chain, increased oxidative stress, and increased mitochondrial DNA mutation. Under physiological condition, the insulin-AKT signaling pathway acts as a master regulator of mitochondrial biogenesis and integrity. However, in the case of PD, insulin resistance has been shown to alter mitochondrial protein levels, calcium homeostasis, and mitochondrial complex I functioning in the substantia nigra. All these events ultimately result in reduced mitochondrial biogenesis, altered mitochondrial membrane depolarization, excessive free radical generation, increased oxidative stress, and cell death.
Another major pathology in PD patients is reduced cerebral glucose metabolism, which increases intracellular ATP/ADP, inhibits potassium channels, and reduces the release of dopamine from dopaminergic neurons. All these events ultimately result in motor and cognitive decline in PD patients.
Inflammation plays an important role in the pathogenesis of PD. Increased levels of pro-inflammatory mediators and enhanced microglial activation have been observed in PD patients. Although microglia play a protective role in the initial phase of inflammation, prolonged activation of these cells can cause severe brain damage. It has been found that the activity of NF-kB, an important downstream target of insulin signaling and a master regulator of microglial pro-inflammatory responses, is significantly higher in PD patients.
This increased activation might result from suppressed insulin-AKT signaling, as AKT is known to inhibit NF-kB by upregulating IkBα. Another possible reason is the formation of advanced glycation end products (AGEs) due to long-term reduced glucose metabolism. Increased levels of AGE and their receptors have been found in the frontal cortex of PD patients. AGE-receptor interactions can cause activation of NF-kB, which can in turn increase inflammation, oxidative stress, and nerve cell death. AGEs can also trigger alpha-synuclein aggregation and Lewy body formation.