Brain insulin signaling and cerebrovascular disease in human postmortem brain.

Abstract

Diabetes is associated with impaired insulin metabolism and increased dementia risk. Insulin is important in brain function and alterations may be associated with neuropathology. We examined associations of insulin resistance in the human postmortem brain, as assessed by molecular signaling measures including insulin receptor substrate (IRS1) and serine/threonine-protein kinase [AKT], with pathologically-defined cerebrovascular disease. Subjects were 150 elderly deceased and autopsied persons with or without diabetes, matched 1:1 by sex on age-at-death and education. ELISA, immunohistochemistry, and ex vivo stimulation with insulin, of midfrontal gyrus cortex tissue, documented insulin signaling. Postmortem neuropathologic data identified cerebrovascular disease. We examined associations of brain insulin signaling measures with cerebrovascular pathology, and specifically with brain infarcts (including by size and location) and cerebral vessel pathologies including atherosclerosis, arteriolosclerosis, and amyloid angiopathy. We also examined whether diabetes affected associations of the insulin measures with cerebrovascular pathology. In a regression analysis, greater AKT1 phosphorylation at T308 following ex vivo stimulation of human postmortem brain tissue with insulin was associated with more cerebrovascular disease, and specifically more brain infarcts (OR=1.916; estimate=0.650; p=0.007). This association was present regardless of diabetes status. In secondary analyses, we also found that a greater pS616 IRS1 immunolabeling in neuronal cytoplasm was associated with more brain infarcts (OR=1.610; estimate=0.476; p=0.013), and that this association was higher among persons without diabetes. We also showed consistent results of pS616 IRS1 associations with each of gross infarcts and microinfarcts separately. No other association including by infarct location (cortical or subcortical) was found. No association was found between other measures of insulin resistance including levels of proteins by ELISA, with any of the infarct outcomes including cortical or subcortical infarct outcomes. Other analyses with vessel pathologies as outcomes showed no association of the insulin resistance and related markers with atherosclerosis or arteriolosclerosis, except for pS473 AKT1 following insulin stimulation being associated with less amyloid angiopathy. In this study of elderly autopsied persons with or without diabetes, we found that insulin resistance in the human brain is associated with cerebrovascular disease and especially infarcts (in number and different sizes), even among persons without diabetes. The underlying pathophysiologic mechanisms need further elucidation.