Acute Insulin Boosts Dulaglutide Blood-Brain Barrier Transport, while Chronic Semaglutide Reduces Insulin Brain Entry in a Sex-Specific Manner

Incretin receptor agonists (IRAs), including GLP-1-based therapies, are increasingly recognized for their positive impact on metabolic and cognitive outcomes, alongside enhancing brain insulin signaling. While their peripheral effects are well-documented, the precise mechanisms by which IRAs influence the blood-brain barrier (BBB) remain poorly understood. Understanding these interactions is crucial, as the BBB regulates the entry of therapeutic compounds and metabolic signals into the brain, directly impacting neurological and metabolic health. This study addresses a critical gap in how insulin and IRAs mutually affect their transport across this vital barrier.

Researchers investigated the reciprocal effects of insulin and IRAs on BBB permeability in lean mice. They acutely administered intracerebroventricular (ICV) insulin receptor antagonist S961 or intravenous (IV) insulin alongside 125I-dulaglutide (BAF) to assess acute transport. Separately, mice received chronic treatment with semaglutide for two weeks. Primary endpoints included measuring 125I-dulaglutide (BAF) and 125I-insulin BBB transport rates (Ki), reversible insulin binding (Vi) at the BBB, and serum levels of insulin and GLP-1. An in situ perfusion procedure was used to study chronic effects independent of immediate serum factors.

The study revealed significant and sex-specific reciprocal interactions between insulin and IRAs at the BBB. ICV S961 did not affect 125I-dulaglutide (BAF) blood-to-brain transport. In contrast, IV insulin co-administration significantly enhanced 125I-dulaglutide (BAF) BBB transport into whole brain, olfactory bulb, parietal cortex, and pons. Regional transport rates for 125I-dulaglutide (BAF) varied by ~2.5-fold, with the fastest transport observed in the olfactory bulb, frontal cortex, cerebellum, and pons. Acute IV dulaglutide (BAF) did not alter 125I-insulin BBB transport rates (Ki), but it did reduce reversible insulin binding (Vi) at the BBB by >50%. Chronic semaglutide treatment for two weeks yielded distinct sex-specific outcomes:

Female mice showed reduced fasting serum insulin and GLP-1 levels, alongside decreased insulin transport into the whole brain. This reduction in 125I-insulin BBB transport in female mice was further confirmed using in situ perfusion. Male mice, however, primarily exhibited a reduction in insulin binding at the BBB. These findings collectively demonstrate a complex interplay where acute insulin can facilitate IRA brain entry, while chronic IRA exposure can modulate insulin's access to the brain, with notable sex-dependent differences.