Diabetologia · 2026
Unhealthy fat distribution as a sex-specific predictor of declining hippocampus insulin sensitivity.
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Sandforth Leontine, Veit Ralf, Machann Jürgen, Dannecker Corinna, Miller Gregor, Jiménez-Muñoz Marina, Peter Andreas, Jumpertz von Schwartzenberg Reiner, Fritsche Andreas, Heni Martin, Birkenfeld Andreas L, Preissl Hubert, Kullmann Stephanie
Аннотация
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/m2, 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 1H-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 HbA1c. 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; 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/INTERPRETATION: Unhealthy 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.
METHODS: In 260 non-diabetic participants (165 women, mean BMI 29.7 ± 6.2 kg/m2, 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 1H-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 HbA1c. 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; 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/INTERPRETATION: Unhealthy 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.