Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

• Published in: Nature reviews. Neurology Vol. 14; no. 3; pp. 168 - 181
• Main Authors: Arnold, Steven E., Arvanitakis, Zoe, Macauley-Rambach, Shannon L., Koenig, Aaron M., Wang, Hoau-Yan, Ahima, Rexford S., Craft, Suzanne, Gandy, Sam, Buettner, Christoph, Stoeckel, Luke E., Holtzman, David M., Nathan, David M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2018; Nature Publishing Group
• Subjects: 692/420; 692/699/2743/137; 692/699/375/365/1283; 692/700/478/174; Alzheimer's disease; Brain; Brain - metabolism; Dementia - metabolism; Development and progression; Diabetes; Diabetes Mellitus, Type 2 - metabolism; Health aspects; Humans; Insulin - metabolism; Insulin Resistance; Medicine & Public Health; Neurology; review-article; Type 2 diabetes
• ISSN: 1759-4758; 1759-4766; 1759-4766
• DOI: 10.1038/nrneurol.2017.185

Key Points The molecular signalling pathways through which insulin exerts its actions in the body also mediate its roles in synaptic neurotransmission, neuronal and glial metabolism, and the neuroinflammatory response in the brain The actions of insulin in the brains of healthy individuals include central modulation of body metabolism and enhancement or regulation of memory and other cognitive and emotional functions Insulin resistance is a core feature of type 2 diabetes mellitus (T2DM) and contributes not only to the hyperglycaemia that defines diabetes mellitus but also to the hyperlipidaemia, inflammation, oxidative stress and atherosclerosis that accompany it T2DM substantially increases risk of not only cerebrovascular disease and stroke but also neurodegenerative dementias of late life, especially Alzheimer disease (AD) Brain insulin resistance can be defined as the failure of brain cells to respond to insulin as they normally would, resulting in impairments in synaptic, metabolic and immune response functions T2DM is associated with brain insulin resistance, and studies suggest that brain insulin resistance is a feature of AD; however, whether the two conditions are mechanistically linked or represent unrelated occurrences in ageing is unclear Alzheimer disease (AD) and related dementias share numerous mechanistic and epidemiological similarities with type 2 diabetes mellitus (T2DM). However, whether these associations result from synergistic interactions between the disorders is unclear. This Review summarizes our current knowledge regarding insulin signalling and resistance in the brain and discusses current evidence concerning neurological impairment in T2DM and insulin resistance in AD. Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.