2453-P: Long-Term Intranasal Insulin Enhances Hypothalamic Insulin Sensitivity and Reduces Adiposity in Adults with Overweight or Obesity

Introduction and Objective: Brain insulin sensitivity plays a central role in coordinating whole-body metabolism. In humans, reduced brain insulin responsiveness is linked to weight gain, visceral adiposity, and impaired metabolic control. Experimental work shows that intranasal insulin (INI) delivers insulin to the brain with minimal systemic effects. Building on this concept, we aimed to enhance central insulin signaling in humans through long-term INI treatment. We hypothesized that INI treatment enhances brain insulin sensitivity while leading to a more favorable body fat distribution. Methods: In this randomized, controlled, blinded study, 39 healthy individuals (age 60.6 ± 7.4 years; 67% women) were randomized to daily INI (160 IU, n=19) or placebo (PLA, n=20) spray treatment for 8 weeks. Before (t=0) and after (t=8wk) the treatment period, individuals were deeply phenotyped, including whole-body MRI for body fat quantification and functional MRI combined with acute INI to assess brain insulin sensitivity. Data are displayed as median ± 95% CI. Results: Body mass index (BMI) was similar between groups at baseline (t=0, INI: 28.2 ± 2.3 vs PLA 29.7 ± 3.1 kg/m2; p=0.51) and decreased only in the INI group (t=8wk, BMI: INI 27.3 ± 2.3, vs t=0; p=0.046, PLA: 30.2 ± 3.0 kg/m2, vs t=0; p=0.14). This was paralleled by a reduction in subcutaneous adipose tissue in the INI but not in the PLA group (Time point X Treatment p=0.01; t=0 vs t=8wk: INI 13.3 ± 2.2 L vs 12.5 ± 2.3 L; p=0.03; PLA 14.0 ± 2.7 L vs 15.4 ± 3.0 L; p=0.93). Hypothalamic insulin sensitivity increased in the INI but not in the placebo group (Time point X Treatment p=0.01; t=0 vs t=8wk: INI p=0.007; PLA p>0.99). Conclusion: Chronic INI treatment improves hypothalamic insulin sensitivity in adults with overweight or obesity, and this effect is accompanied by a reduction in BMI and subcutaneous fat. These findings highlight brain insulin responsiveness as a therapeutic target to counteract elevated body weight and body fat content. Disclosure L. Sandforth: None. R. Veit: None. C. Dannecker: None. R.J. von Schwartzenberg: None. A. Vosseler: None. M. Hallschmid: None. R. Wagner: Advisory Panel; Current; Sanofi. Speaker's Bureau; Ended; Daiichi Sankyo, Novo Nordisk. A.L. Birkenfeld: None. P. Hubert: None. A. Fritsche: None. M. Heni: Advisory Panel; Ended; Chiesi USA, Inc. Speaker's Bureau; Ended; Chiesi USA, Inc. Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Speaker's Bureau; Ended; Boehringer Ingelheim International GmbH, AstraZeneca, Lilly, Novartis AG, Novo Nordisk, Bayer AG. S. Kullmann: None.