Brain Insulin Dysregulation: Implication for Neurological and Neuropsychiatric Disorders

Abstract

Arduous efforts have been made in the last three decades to elucidate the role of insulin in the brain. A growing number of evidences show that insulin is involved in several physiological function of the brain such as food intake and weight control, reproduction, learning and memory, neuromodulation and neuroprotection. In addition, it is now clear that insulin and insulin disturbances particularly diabetes mellitus may contribute or in some cases play the main role in development and progression of neurodegenerative and neuropsychiatric disorders. Focusing on the molecular mechanisms, this review summarizes the recent findings on the involvement of insulin dysfunction in neurological disorders like Alzheimer's disease, Parkinson's disease and Huntington's disease and also mental disorders like depression and psychosis sharing features of neuroinflammation and neurodegeneration.

Role of Adiposity-Driven Inflammation in Depressive Morbidity

“…Reciprocally, emerging evidence suggests that insulin may display antiinflammatory properties by preventing hyperglycemia and modulating key inflammatory molecules (for reviews, see Hyun et al, 2011;Scheen et al, 2015). Interestingly, recent reports on brain location of insulin receptors and their link with neuronal function and mood have introduced new ways of considering this hormone, in particular, regarding its potential role in obesity-related neuropsychiatric symptoms (Blazquez et al, 2014;Ghasemi et al, 2013a). In support of this notion, converging findings reveal dysfunctions of insulin signaling pathway in different neurological or neuropsychiatric disorders (Blazquez et al, 2014;Ghasemi et al, 2013b;Yates et al, 2012).…”

A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson's disease

“…Importantly, type 2 diabetes (T2DM) has been identified as a risk factor for PD (Hu et al, 2007;Schernhammer et al, 2011;Sun et al, 2012;Wahlqvist et al, 2012). Insulin signaling in the brain plays an important role in neuronal metabolism, repair, and synaptic efficacy (Freiherr et al, 2013;Ghasemi et al, 2013;van der Heide et al, 2006). Insulin desensitisation has been observed in the brains of patients with PD (Aviles-Olmos et al, 2013b;Moroo et al, 1994;Morris et al, 2011).…”

The Role of Insulin and Incretins in Neuroinflammation and Neurodegeneration

“…Insulin resistance and related insulin dysfunction has been pin-pointed in the pathogenesis of several neurodegenerative [86] -Decreased insulin signaling cascade activation [87] -Decreased insulin leads to an increase in neurofibrillary tangles and amyloid beta plaques [88] , the hallmarks of AD. Parkinson's disease -Decreased CNS insulin concentrations [86] may contribute to increased deposition of α-synuclein [89] , which make up PD Lewy bodies.…”

“…Parkinson's disease -Decreased CNS insulin concentrations [86] may contribute to increased deposition of α-synuclein [89] , which make up PD Lewy bodies. Huntington's disease -Reduced level of Akt, the molecule central to the insulin signaling pathway [86] .…”

“…-Insulin positively regulates dopamine neurotransmission [47,91] and synaptic clearance of dopamine [92] , which is the major neurotransmitter associated with feelings of happiness. Schizophrenia -Higher circulating insulin levels compared to healthy controls, which correlates with insulin resistance [86,93] .…”