ArticleDiabetologia2026
Unhealthy fat distribution as a sex-specific predictor of declining hippocampus insulin sensitivity.
Article in Diabetologia, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
aims/hypothesisImpairments 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.
methodsIn 260 non-diabetic participants (165 women, mean BMI 29.7 ± 6.2 kg/m
resultsFasting 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; visceral adipose tissue [VAT]: estimate 0.007, p=0.013; intrahepatic lipid content [IHL]: estimate 0.003, p=0.010). In women, higher WHR, VAT and IHL were predictors of lower hippocampal insulin responsiveness with increasing age. These effects remained significant after adjusting for BMI. Postmenopausal women showed lower hippocampal insulin responsiveness with higher WHR and IHL (p<0.05), and women in high-risk Tübingen prediabetes clusters also showed lower hippocampal insulin responsiveness than men (sex × cluster type: estimate 0.39, p=0.02). The hippocampal insulin response did not correlate with hippocampal volume (p>0.05). CONCLUSIONS/
interpretationUnhealthy body fat distribution was a sex-dependent predictor for decreased hippocampal insulin sensitivity with increasing age. Older women with high abdominal fat and/or those assigned to high-risk clusters were most vulnerable to impaired insulin responsiveness in the hippocampus. These findings may contribute to explaining sex differences in the development of type 2 diabetes and neurodegenerative diseases.
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