Peripheral insulin resistance moderates cerebral glucose metabolism and impairs working memory in healthy younger adults

Abstract

AbstractPeople with insulin resistance are at increased risk for cognitive decline. Historically, insulin resistance was considered a condition of ageing but it is increasingly seen in younger adults. It is possible that changes in insulin function in early adulthood have both proximal effects, and moderate or even accelerate cerebral metabolism changes in ageing. Thirty-six younger (mean 27.8 years) and 43 older (mean 75.5) participants completed a battery of tests, including blood sampling, cognitive assessment and a simultaneous PET/MR scan. Cortical thickness and cerebral metabolic rate of glucose were derived for 100 regions, 17 networks and subcortical structures. Insulin resistance was measured with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Older adults had lower rates of cerebral glucose metabolism than younger adults across the brain. In younger adults, higher insulin resistance was associated with attenuated rates of cerebral glucose metabolism, but this was not seen in older adults. The largest effects of insulin resistance in younger adults were in prefrontal, parietal and temporal regions; and in the control, salience ventral attention, default and somatomotor networks. Higher rates of network glucose metabolism were associated with lower reaction time and psychomotor speed. Higher levels of insulin resistance were associated with lower working memory. Our results underscore the importance of insulin sensitivity to brain health and cognitive function across the adult lifespan, even in early adulthood.Significance StatementGlucose is the primary source of energy for the brain. Decreased glucose metabolism in the brain due to clinically significant levels of insulin resistance is associated with cognitive impairment and neurodegenerative disease. Although sub-clinical levels of insulin resistance have also been associated with grey matter atrophy, white matter integrity and cognitive decline, their impact on cerebral metabolism in healthy individuals is unclear. We showed for the first time that – while older adults have lower rates of cerebral metabolism - peripheral insulin resistance attenuates cerebral metabolism in healthy younger but not older adults. Lower rates of glucose metabolism were also associated with reduced psychomotor speed, and higher insulin resistance with impaired working memory performance. Preventing insulin resistance in early adulthood is important for ensuring efficient fuel supply for the brain and the maintenance of cognitive health across the adult lifespan.