Evolution, Development, and the Incoherence of Sex: A Framework for Multiple Sex Concepts.

The brain relies on a continuous and tightly regulated glucose supply to meet its energy demands. Increasing evidence suggests that aberrant glucose homeostasis, characterized by hyperglycemia, insulin resistance, and reduced cellular glucose uptake, occurring both peripherally and within the brain itself, play a crucial role in age-related cognitive decline and neurodegeneration. In the periphery, longitudinal and cross-sectional studies have found that even among healthy adults without diabetes, higher normal blood glucose levels are associated with a greater risk of developing dementia , Alzheimer’s disease , increased brain atrophy , and lower cognitive performance , while decreased peripheral glucose regulation was found to be associated with decreased cognitive performance, memory impairments, and hippocampal atrophy . Notably, the brain regions affected by elevated blood glucose, including the PCC, frontal cortex, and hippocampus, overlap substantially with areas showing early vulnerability in Alzheimer's disease, highlighting the importance of glycemic control for brain health and the need to better under the impact of glucose metabolism on neurodegeneration. One major cause of peripheral glucose dysregulation is insulin resistance. Insulin is the primary hormone by which glucose is taken up into insulin-sensitive cells, a process mediated by the GLUT4 glucose transporter in GLUT4-dependent tissues like skeletal muscle, cardiac muscle, and adipose tissue . When insulin signaling is impaired, these cells cannot import glucose from the bloodstream, resulting in hyperglycemia alongside hypometabolism, and eventual atrophy . The peripheral oral glucose tolerance test (OGTT) has proven invaluable for detecting impaired glucose regulation . By measuring peripheral glucose accumulation after a standardized glucose challenge, elevated blood glucose levels following the OGTT indicate impaired glucose clearance and utilization rather than merely increased supply. Recent evidence suggests that similar principles may apply to brain glucose homeostasis, where just as peripheral glucose accumulation in the OGTT reflects insulin resistance and metabolic dysfunction, brain glucose accumulation may serve as an indicator of impaired cerebral glucose utilization and neuronal insulin resistance . The concept of “brain insulin resistance” has emerged as a key mechanism linking metabolic dysfunction to neurodegeneration, with studies showing that brain insulin resistance can be detected long before clinical symptoms appear and may drive early pathological changes . The temporal relationship between peripheral and cerebral glucose dysregulation is complex and may reveal a sequence of changes in metabolism that begin well in advance of clinical symptom onset. Longitudinal findings from up to an eight-year period suggest that altered peripheral glucose metabolism in midlife may precede brain-specific changes, with impaired glucose tolerance in midlife leading to decreases in regional cerebral blood flow (rCBF) in the frontal, parietal, and temporal cortices compared to those with normal glucose tolerance . In a shorter-term study, older adults whose fasting glucose increased over one year displayed regional atrophy in the hippocampus and inferior parietal cortex, as well as increased amyloid accumulation in the precuneus, despite remaining cognitively normal . These findings support the idea that peripheral glucose dysregulation may signal emerging brain vulnerability, but the sequence and directionality of this relationship is unclear. There are three possible patterns: 1) brain and peripheral glucose levels tightly track each other, reflecting a direct coupling of systemic and cerebral glucose metabolism, 2) elevations in brain glucose precede elevations in the periphery if buffering mechanisms fail early enough, or 3) elevations in brain glucose could lag behind the periphery, implying that the brain is initially protected and its homeostasis is prioritized. Alterations in blood-brain barrier (BBB) transporters and astrocytic metabolic buffering observed with aging support the latter pattern, suggesting that the brain may preserve glucose homeostasis even under conditions of peripheral hyperglycemia.