Unhealthy fat distribution as a sex-specific predictor of declining hippocampus insulin sensitivity

作者：Leontine Sandforth, Ralf Veit, Jürgen Machann, Corinna Dannecker, Gregor Miller, Marina Jiménez‐Muñoz, Andreas Peter, Reiner Jumpertz von Schwartzenberg, Andreas Fritsche, Martin Heni, Andreas L. Birkenfeld, Hubert Preißl, Stephanie Kullmann · 发表于：Diabetologia · 年份：2026 · DOI：10.1007/s00125-026-06787-2 · 研究领域：Regulation of Appetite and Obesity、Diabetes, Cardiovascular Risks, and Lipoproteins、Advanced Neuroimaging Techniques and Applications

Abstract Aims/hypothesis Impairments in peripheral glucose metabolism and reduced brain insulin sensitivity are linked to an increased risk of both metabolic and neurodegenerative diseases. Brain insulin resistance represents a shared pathological mechanism underlying these disorders. Notably, hippocampal insulin responsiveness declines with age and differs between men and women. This study aimed to identify clinically relevant metabolic predictors of hippocampal insulin sensitivity in the context of age and sex. Methods In 260 non-diabetic participants (165 women, mean BMI 29.7 ± 6.2 kg/m 2 , mean age 44.2 ± 16.6 years), functional MRI was performed before and after intranasal insulin administration to assess hippocampal insulin response. Metabolic phenotyping comprised laboratory assessments including oral glucose tolerance tests, whole-body MRI and 1 H-MRS. In addition, participants were assigned to high- and low-risk prediabetes clusters using the Tübingen risk cluster tool. Prediabetes was defined as impaired fasting glucose and/or impaired glucose tolerance and/or elevated HbA 1 c. We used linear regression models to select the most relevant predictors, including interactions with sex and age. Results Fasting plasma glucose levels predicted lower hippocampal insulin response with age independently of sex (estimate 0.533, p =0.016). Significant interactions were present between age, sex and body fat distribution (waist-to-hip ratio [WHR]: estimate 0.233, p =0.010; viscer...