Introduction and Objective: Portal glucose sensing is key to glucose homeostasis, conveying metabolic information to the brain via vagal afferent pathways. In type 2 diabetes, this signaling is impaired due to reduced GLP-1R expression in portal afferent nerves. We evaluated whether restoration of portal GLP-1R expression by local low dose dihydrotestosterone (DHT) alters brain processing. Methods: In twelve minipigs, diabetes was induced using an obesogenic diet combined with a small dose of streptozotocin (80 mg/kg, IV). Animals were randomized to receive a peri-portal implant delivering dihydrotestosterone (DHT; 100 µg/day; n=6) to restore GLP-1R expression and vagal afferent signaling, or a sham implant (n=6). Five months later, peripheral GLP-1R expression was quantified by abdominal PET imaging using 68Ga-NODAGA-Exendin-4 and brain metabolic activity was assessed by 18F-FDG PET imaging. Brain images were normalized to a probabilistic pig brain atlas and analyzed using region-wise statistical parametric mapping (SPM 12). Network-level connectivity analyses were also performed (NetPET). Results: DHT-treated animals demonstrated a marked increase in portal GLP-1R expression compared with sham controls (Vt 3.12 ± 0.049 vs 0.16 ± 0.007 mL/cm3 for DHT vs sham, P 0.001). The engagement of central autonomic and limbic networks was strongly and positively correlated with increased GLP-1R expression (r²=0.88 and 0.87, P = 0.0002 and 0.0002 respectively), independent of treatment assignment. Conversely, higher GLP-1R expression was associated with reduced activation of the anterior prefrontal cortex (r2=0.78, P =0.021). Conclusion: Restoration of impaired portal GLP-1R-dependent glucose sensing selectively enhances autonomic and limbic network engagement while reducing recruitment of anterior prefrontal executive regions, indicative of central reprogramming capabilities linked to portal glucose sensing. Disclosure C. Malbert: Research Support; Current; Paltech. M.R. Allouche: Stock/Shareholder; Current; Paltech. M. Horowitz: None. K.L. Jones: None.
Malbert et al. (Fri,) studied this question.