Research Paper Volume 13, Issue 21 pp 23936—23952

Impaired glucose metabolism reduces the neuroprotective action of adipocytokines in cognitively normal older adults with insulin resistance

Karel M. Lopez-Vilaret1, , Jose L. Cantero1,2, , Marina Fernandez-Alvarez1,2, , Miguel Calero2,3, , Olga Calero2,3, , Mónica Lindín4, , Montserrat Zurrón4, , Fernando Díaz4, , Mercedes Atienza1,2, ,

  • 1 Laboratory of Functional Neuroscience, Universidad Pablo de Olavide, Seville, Spain
  • 2 CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, Madrid, Spain
  • 3 Chronic Disease Programme, Instituto de Salud Carlos III, Madrid, Spain
  • 4 Cognitive Neuroscience Laboratory, Universidade de Santiago de Compostela, Santiago de Compostela, Spain

Received: July 12, 2021       Accepted: October 26, 2021       Published: November 3, 2021
How to Cite

Copyright: © 2021 Lopez-Vilaret et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Evidence suggests that aging-related dysfunctions of adipose tissue and metabolic disturbances increase the risk of diabetes and metabolic syndrome (MtbS), eventually leading to cognitive impairment and dementia. However, the neuroprotective role of adipocytokines in this process has not been specifically investigated. The present study aims to identify metabolic alterations that may prevent adipocytokines from exerting their neuroprotective action in normal ageing. We hypothesize that neuroprotection may occur under insulin resistance (IR) conditions as long as there are no other metabolic alterations that indirectly impair the action of adipocytokines, such as hyperglycemia. This hypothesis was tested in 239 cognitively normal older adults (149 females) aged 52 to 87 years (67.4 ± 5.9 yr). We assessed whether the homeostasis model assessment-estimated insulin resistance (HOMA-IR) and the presence of different components of MtbS moderated the association of plasma adipocytokines (i.e., adiponectin, leptin and the adiponectin to leptin [Ad/L] ratio) with cognitive functioning and cortical thickness. The results showed that HOMA-IR, circulating triglyceride and glucose levels moderated the neuroprotective effect of adipocytokines. In particular, elevated triglyceride levels reduced the beneficial effect of Ad/L ratio on cognitive functioning in insulin-sensitive individuals; whereas under high IR conditions, it was elevated glucose levels that weakened the association of the Ad/L ratio with cognitive functioning and with cortical thickness of prefrontal regions. Taken together, these findings suggest that the neuroprotective action of adipocytokines is conditioned not only by whether cognitively normal older adults are insulin-sensitive or not, but also by the circulating levels of triglycerides and glucose, respectively.


AD: Alzheimer’s disease; Ad/L: adiponectin to leptin ratio; BBB: blood brain barrier; BMI: body mass index; BNT: Boston naming test; CI0.95 = 95%: confidence intervals; CRF: cardiorespiratory fitness; HOMA-IR: homeostasis model assessment-estimated insulin resistance; IR: insulin resistance; MetS: metabolic syndrome; rACC: rostral anterior cingulate cortex; TMT-A/TMT-B: trail making test (form A and form B).