Brain insulin resistance mediated cognitive impairment and neurodegeneration: Type-3 diabetes or Alzheimer's Disease.

Insulin resistance is a condition characterized by the attenuated biological response in the presence of normal or elevated insulin level and therefore is characterized by the impaired sensitivity to insulin and impaired glucose disposal and utilization. Insulin resistance in brain/Brain insulin resistance (BIR) is accompanied by the various manifestations including alteration in glucose sensing by hypothalamic neurons, impaired sympathetic outflow in response to hypoglycemia, increased ROS production, impaired mitochondrial oxygen consumption in the brain, cognitive deficits and neuronal cell damage. It has been reported that the disrupted insulin signaling is accompanied by the reduced expression of insulin receptor (IR)/insulin receptor substrate 1 (IRS1)/PI3K/AKT and IGF-1 receptor (IGF-1R)/IRS2/PI3K pathways. Insulin resistance and impaired insulin signaling interferes with the degradation and transportation of Aβ leading to Aβ deposition. Aβ promotes the hyperphosphorylation of tau, accumulation of neurofibrillary tangles and the later promotes the neuro-inflammation, apoptosis, oxidative stress, impairments of energy metabolism, synaptic disconnections, and hippocampus atrophy. Therefore, the impaired insulin signaling and the insulin promote cognitive deficits and neuronal cell death in the affected individuals. BIR is mainly responsible for the cognitive deficits and the neuronal damage in the patients of Alzheimer's disease (AD). In the present work, authors describe the BIR, and its role in the emergence of cognitive deficits and neurodegeneration. Further, the emphasis has been given on the pharmacological agents that may alleviate the BIR and its deleterious effects.