Extending Arms of Insulin Resistance from Diabetes to Alzheimer's disease: Identification of Potential Therapeutic Targets.

Type 3 diabetes (T3D) is chronic brain insulin resistant state which has shared pathology with sporadic Alzheimer's disease (sAD). Insulin signaling is a highly conserved pathway in the living systems that orchestrate cell growth, repair, maintenance, energy homeostasis and reproduction. Although insulin is primarily studied as a key molecule in diabetes mellitus, its role has recently been implicated in the development of Alzheimer's disease (AD) pathology. Severe brain complications are observed in diabetic patients and metabolically compromised brain status is evident in AD patients. Underlying shared pathology of these two disorders draws a trajectory from peripheral insulin resistance to insulin unresponsiveness in the central nervous system (CNS). As insulin has a pivotal role in AD, it is not an overreach to address brain diabetic condition in AD as T3D. Insulin signaling is indispensable for nervous system and is vital for neuronal growth, repair, and maintenance of chemical milieu at synapses. Downstream mediators of insulin signaling pathway work as a regulatory hub for aggregation and clearance of unfolded proteins like Aβ and tau. In this review, we will discuss the regulatory roles of insulin as a pivotal molecule in brain with current understanding of defective insulin signaling as a key pathological mechanism in sAD. This also highlights ongoing trials of targeting insulin signaling as a therapeutic manifestation to treat brain diabetic condition.