The failure of insulin signaling – a condition known as insulin resistance – is a key pathological feature of both type 2 diabetes (T2DM, systemic insulin resistance) and Alzheimer's disease and related dementias (ADRDs, brain insulin resistance) and greatly contribute to their development. Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of ADRDs and T2DM, thus proposing AD as type 3 diabetes.

Examination of postmortem AD and amnestic mild cognitive impairment brain uncovered key signs of brain insulin resistance, i.e., reduced insulin receptor (IR) and increased serine phosphorylation (inhibitory) of insulin receptor substrate 1 (IRS1), particularly in the hippocampus, cortex and hypothalamus. Higher levels of insulin resistance markers are associated with poorer performance on cognitive tests of episodic and working memory, independent of the senile plaques and tangles load, thus suggesting a role for insulin signalling in neuronal functions. At the cellular level, these dysfunctions might manifest as the impairment of neuroplasticity, receptor regulation or neurotransmitter release in neurons, or the impairment of processes more directly implicated in insulin metabolism, such as neuronal glucose uptake in neurons expressing GLUT4, or homeostatic or inflammatory responses to insulin. Further, intense research over the last two decades has highlighted the impact of insulin signalling, brain energy balance and their fluctuations on neurogenesis processes both during post-natal and adult life. Indeed, diabetes, obesity, and overweight are prevalent pregnancy complications that predispose offspring to neurodevelopmental disorders. Moreover, impaired neurogenesis compromises hippocampal function and plays a role in cognitive deficits in ADDRs. In those plastic neural tissues, activation of insulin signalling regulates birth, specification, migration, and integration of newly generated neurons, suggesting that alterations of this key signaling transduction pathway may have a role both in neurodevelopmental disorders and adult neurogenesis.

This Research Topic seeks contributions in the form of original research articles, short communication, review and opinion, addressing the major needs and challenges in the comprehension of the role of insulin signalling and its alterations in the brain.

Keywords: insulin resistance, neurodevelopment, neurodegeneration, metabolism, diabetes

Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.