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Pathophysiology/complications
Insulin sensitivity predicts cognitive decline in individuals with prediabetes
  1. Caroline Willmann1,2,3,
  2. Kathrin Brockmann4,5,
  3. Robert Wagner1,2,3,
  4. Stephanie Kullmann2,3,
  5. Hubert Preissl1,2,3,6,7,
  6. Günter Schnauder1,
  7. Walter Maetzler8,
  8. Thomas Gasser4,5,
  9. Daniela Berg4,8,
  10. Gerhard W Eschweiler9,10,
  11. Florian Metzger9,10,11,
  12. Andreas J Fallgatter9,10,
  13. Hans-Ulrich Häring1,2,3,
  14. Andreas Fritsche1,2,3,
  15. Martin Heni1,2,3,12
  1. 1Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany
  2. 2Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Helmholtz Center Munich, Tübingen, Germany
  3. 3German Centre for Diabetes Research (DZD), Neuherberg, Germany
  4. 4Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, Center of Neurology, University of Tübingen, Tübingen, Germany
  5. 5German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany
  6. 6Institute for Diabetes and Obesity, Helmholtz Diabetes Centre at Helmholtz Zentrum München, German Research Centre for Environmental Health (GmbH), Neuherberg, Germany
  7. 7Department of Pharmacy and Biochemistry, Institute of Pharmaceutical Sciences, University of Tübingen, Tübingen, Germany
  8. 8Department of Neurology, Christian-Albrechts University, Kiel, Germany
  9. 9Department of Psychiatry and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
  10. 10Geriatric Center at the University Hospital of Tübingen, Tübingen, Germany
  11. 11Department of Psychiatry and Psychotherapy, Vitos Hospital Haina, Haina, Germany
  12. 12Department for Diagnostic Laboratory Medicine, Institute for Clinical Chemistry and Pathobiochemistry, University Hospital Tübingen, Tübingen, Germany
  1. Correspondence to Dr Martin Heni; martin.heni{at}med.uni-tuebingen.de

Abstract

Introduction Epidemiological studies indicate an association between type 2 diabetes and cognitive dysfunction that appear to start already in the prediabetic state. Although cross-sectional studies have linked insulin resistance to impaired cognition, the potential predictive value of insulin resistance has not yet been sufficiently studied longitudinally without confounding by overt diabetes (and its pharmacological treatment).

Research design and methods We investigated longitudinal data from participants of the ‘Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration’ Study. Subjects underwent a neurocognitive assessment battery (CERAD Plus battery; Consortium to Establish a Registry for Alzheimer’s Disease) at baseline and followed every 2 years (median follow-up 4.0 Q1–3: 2.2–4.3 years). Subjects within a pre-diabetic glycated hemoglobin range of 5.6%–6.5% underwent 5-point 75 g oral glucose tolerance tests (OGTTs) with assessment of insulin sensitivity and insulin secretion (n=175). Subjects with newly diagnosed diabetes mellitus or with major depressivity (Beck Depression Inventory >20) were excluded (n=15). Data were analyzed by mixed models using sex, age and glycemic trait as fixed effects. Subject and time since first measurement were used as random effects.

Results Insulin sensitivity was positively associated with the CERAD sum score (higher is better) in a time-dependent manner (p=0.0057). This result is mainly driven by a steeper decrease in the memory domain associated with lower insulin sensitivity (p=0.029). The interaction between age and insulin sensitivity was independent of glycemia (p=0.02). There was also no association between insulin secretion and cognition.

Conclusions Insulin resistance rather than sole elevation of blood glucose predicts cognitive decline, specifically in the memory domain, in persons with prediabetes. Treatments of diabetes that improve insulin sensitivity might therefore have the potential to postpone or even prevent cognitive decline in patients with diabetes.

  • insulin resistance
  • diabetes complications
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjdrc-2020-001741

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    Footnotes

    • Contributors CW researched and analyzed data and drafted the manuscript, KB researched data and contributed to discussion, RW analyzed data and contributed to discussion, SK, HP contributed to discussion, GS contributed to discussion, WM, TG, DB contributed to the design of the study and to discussion, GWE, FM contributed to discussion, H-UH, AF, MH contributed to the design of the study and to discussion. All authors approved the final version of the manuscript prior to submission.

    • Funding Part of this work was supported by a grant (01GI0925) from the Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.). The TREND Study has been, and still is supported by the Hertie Institute for Clinical Brain Research, the German Centre for Neurodegenerative Diseases (DZNE within the framework of iMed Helmholtz Association), the Centre for Integrative Neuroscience, TEVA Pharmaceutical Industries Ltd., Union Chimique Belge (UCB), Janssen Pharmaceuticals, Inc. and the International Parkinson Fonds. The supporting institutions had no influence on the design, conduct, or analysis of the study.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval Informed written consent was obtained from study participants prior inclusion in the study and the ethics committee of the University of Tübingen approved the protocol (90/2009BO2 and 350/2007BO1).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement The data are not publicly available because they contain information that could compromise research participant privacy/consent.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.