Open Access 11-04-2025 | Type 2 Diabetes | Article

Alterations in cerebral perfusion and substrate metabolism in type 2 diabetes: interactions with APOE-ε4

Authors: Martin Schain, Edvin Johansson, Iina Laitinen, Anna Frödén Löwenmark, Mark Lubberink, Anders Gummesson, Torsten Danfors, Pirjo Nuutila, Russell Esterline, Lars Johansson, Jan Oscarsson, Kerstin Heurling

Published in: Diabetologia

Abstract

Aims/hypothesis

Epidemiological studies indicate that type 2 diabetes increases the risk for Alzheimer’s disease. Alterations in cerebral metabolism have been proposed as a potential mechanism underlying this association. A better understanding of these metabolic changes may elucidate potential pathways linking type 2 diabetes to Alzheimer’s disease. The aim of the current exploratory study was to investigate whether cerebral metabolism, including glucose and fatty acid uptake as well as cerebral blood flow, is altered in individuals with type 2 diabetes compared with both overweight individuals and lean control individuals.

Methods

This exploratory study included 38 participants (ten with type 2 diabetes, 13 overweight individuals and 15 lean control individuals). Brain metabolism was assessed using multiple imaging techniques: [¹⁸F]fluorodeoxyglucose and [¹⁸F]fluoro-6-thiaheptadecanoic acid positron emission tomography for glucose and fatty acid uptake; arterial spin-labelling MRI for cerebral perfusion; and ¹H-magnetic resonance spectroscopy for specific metabolites. Neurodegeneration markers were evaluated from lumbar puncture samples. Group comparisons were assessed using one-way ANOVA and unpaired t tests, and correlations were assessed with linear regression.

Results

Individuals with type 2 diabetes exhibited lower cerebral glucose uptake compared with both lean and overweight groups (p<0.01). Cerebral perfusion was reduced in both participants with type 2 diabetes and overweight participants relative to lean control participants (p<0.01). Both glucose uptake and perfusion correlated negatively with HOMA-IR, insulin and HbA_1c levels (p<0.001–p<0.05). White matter fatty acid uptake was elevated in the diabetes group compared with the lean group (p<0.05). Post hoc analyses revealed that lean APOE-ε4 carriers had increased fatty acid uptake in the entire brain relative to lean non-carriers. Among non-carriers of APOE-ε4, those with type 2 diabetes showed higher fatty acid uptake than lean control individuals (p<0.01–p<0.05), and this uptake correlated positively with HOMA-IR, insulin and HbA_1c levels (p<0.05).

Conclusions/interpretation

Type 2 diabetes was associated with decreased cerebral perfusion and glucose uptake but increased fatty acid uptake in white matter. The elevated fatty acid uptake observed both in individuals with type 2 diabetes and in APOE-ε4 carriers suggests a common metabolic dysfunction for these Alzheimer’s disease risk factors and suggests that targeting cerebral metabolic dysfunction, particularly fatty acid metabolism, could be a potential strategy for reducing the risk for neurodegeneration in individuals with type 2 diabetes.

Graphical Abstract

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Title: Alterations in cerebral perfusion and substrate metabolism in type 2 diabetes: interactions with APOE-ε4
Authors: Martin Schain
Edvin Johansson
Iina Laitinen
Anna Frödén Löwenmark
Mark Lubberink
Anders Gummesson
Torsten Danfors
Pirjo Nuutila
Russell Esterline
Lars Johansson
Jan Oscarsson
Kerstin Heurling
Publication date: 11-04-2025
Publisher: Springer Berlin Heidelberg
Keywords: Type 2 Diabetes
Alzheimer's Disease
Alzheimer Disease
Positron Emission Tomography
Overweight
Published in: Diabetologia
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-025-06405-7

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Alterations in cerebral perfusion and substrate metabolism in type 2 diabetes: interactions with APOE-ε4

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