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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In 260 non-diabetic participants (165 women, mean BMI 29.7\u00a0\u00b1\u00a06.2\u2009kg\/m\n                      <jats:sup>2<\/jats:sup>\n                      , mean age 44.2\u00a0\u00b1\u00a016.6 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\n                      <jats:sup>1<\/jats:sup>\n                      H-MRS. In addition, participants were assigned to high- and low-risk prediabetes clusters using the T\u00fcbingen risk cluster tool. Prediabetes was defined as impaired fasting glucose and\/or impaired glucose tolerance and\/or elevated HbA\n                      <jats:sub>1<\/jats:sub>\n                      c. We used linear regression models to select the most relevant predictors, including interactions with sex and age.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Fasting plasma glucose levels predicted lower hippocampal insulin response with age independently of sex (estimate 0.533,\n                      <jats:italic>p<\/jats:italic>\n                      =0.016). Significant interactions were present between age, sex and body fat distribution (waist-to-hip ratio [WHR]: estimate 0.233,\n                      <jats:italic>p<\/jats:italic>\n                      =0.010; visceral adipose tissue [VAT]: estimate 0.007,\n                      <jats:italic>p<\/jats:italic>\n                      =0.013; intrahepatic lipid content [IHL]: estimate 0.003,\n                      <jats:italic>p<\/jats:italic>\n                      =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 (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.05), and women in high-risk T\u00fcbingen prediabetes clusters also showed lower hippocampal insulin responsiveness than men (sex \u00d7 cluster type: estimate 0.39,\n                      <jats:italic>p<\/jats:italic>\n                      =0.02). The hippocampal insulin response did not correlate with hippocampal volume (\n                      <jats:italic>p<\/jats:italic>\n                      &gt;0.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06787-2","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T19:51:13Z","timestamp":1783108273000},"page":"2957-2969","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unhealthy fat distribution as a sex-specific predictor of declining hippocampus insulin sensitivity"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7136-6397","authenticated-orcid":false,"given":"Leontine","family":"Sandforth","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9860-642X","authenticated-orcid":false,"given":"Ralf","family":"Veit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4458-5886","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Machann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5689-9084","authenticated-orcid":false,"given":"Corinna","family":"Dannecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4281-4905","authenticated-orcid":false,"given":"Gregor","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4543-2929","authenticated-orcid":false,"given":"Marina","family":"Jim\u00e9nez-Mu\u00f1oz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5732-2287","authenticated-orcid":false,"given":"Andreas","family":"Peter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5544-099X","authenticated-orcid":false,"given":"Reiner","family":"Jumpertz von Schwartzenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4987-1961","authenticated-orcid":false,"given":"Andreas","family":"Fritsche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8462-3832","authenticated-orcid":false,"given":"Martin","family":"Heni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1407-9023","authenticated-orcid":false,"given":"Andreas L.","family":"Birkenfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8859-4661","authenticated-orcid":false,"given":"Hubert","family":"Preissl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9951-923X","authenticated-orcid":false,"given":"Stephanie","family":"Kullmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"issue":"10","key":"6787_CR1","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/j.tem.2025.01.004","volume":"36","author":"L Sandforth","year":"2025","unstructured":"Sandforth L, Kullmann S, Sandforth A et al (2025) Prediabetes remission to reduce the global burden of type 2 diabetes. 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Borutta and D. Loeffler (both Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of T\u00fcbingen; T\u00fcbingen, Germany) for recruitment of study participants and excellent technical assistance. Parts of the data were presented at the 60th EASD Annual Meeting in 2024. We acknowledge support by Open Access Publishing Fund of University of T\u00fcbingen.","order":1,"name":"Ethics","label":"Acknowledgements","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"Data are under the supervision of the Data Access Steering Committee of the Institute for Diabetes Research and Metabolic Diseases; T\u00fcbingen, Germany. Data can be made available upon reasonable request in a pseudonymised form. Requests should include a brief research proposal, intended use of the data and research plan. Access is subject to applicable data protection regulations and institutional data-sharing agreements. No custom code was used in this study.","order":2,"name":"Ethics","label":"Data availability","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"This project was supported by the German Center for Diabetes Research (DZD, 01GI0925) via the Federal Ministry of Education and Research, and Helmholtz Munich. LS is supported by the German Research\u00a0Foundation (Deutsche Forschungsgemeinschaft) as a clinician scientist.","order":3,"name":"Ethics","label":"Funding","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"RJvS and LS serve as clinical investigators for studies funded by Eli Lilly and Boehringer Ingelheim, and all compensations go to the University Hospital T\u00fcbingen. LS receives honoraria from Sciarc GmbH; all compensations go to the University Hospital T\u00fcbingen. ALB declines all personal compensation from pharma or device companies; all compensations go to the University Hospital T\u00fcbingen. ALB received unrestricted research support from AstraZeneca and Daiichi Sankyo. He has served as principal investigator for studies funded by Novo Nordisk and Boehringer Ingelheim. MH reports lecture fees from Chiesi\/Amryt, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Novo Nordisk and Sanofi. SK reports lecture fees from Eli Lilly and Novo Nordisk. The remaining authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","label":"Authors\u2019 relationships and activities","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"SK and LS conceptualised the work. Acquisition of data was performed by SK, RV, JM and AP and data analysis was performed by LS, GM, MJ-M and SK. LS, SK, JM, CD, AP, RJvS, AF, MH, ALB and HP interpreted the data. LS drafted the article. LS, RV, JM, CD, GM, MJ-M, AP, RJvS, AF, MH, ALB, HP and SK reviewed the article critically for important intellectual content and approved the final version of the work. SK and LS are the guarantors of the current work and take full responsibility for the data presented.","order":5,"name":"Ethics","label":"Contribution statement","group":{"name":"EthicsHeading","label":"Ethics"}}]}}