Acute Hyperglycemia Induced by Hyperglycemic Clamp Affects Plasma Amyloid-β in Type 2 Diabetes

Article type: Research Article

Authors: Rolandsson, Olov^{a; *} | Tornevi, Andreas^b | Steneberg, Pär^c | Edlund, Helena^c | Olsson, Tommy^d | Andreasson, Ulf^{e; f} | Zetterberg, Henrik^{e; f; g; h; i; j} | Blennow, Kaj^{e; f; k; l}

Affiliations: [a] Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden | [b] Department of Public Health and Clinical Medicine, Sustainable Health, Umeå University, Umeå, Sweden | [c] Department of Medical and Translational Biology, Umeå University, Umeå, Sweden | [d] Public Health and Clinical Medicine, Internal Medicine, Umeå University, Umeå, Sweden | [e] Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden | [f] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [g] Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK | [h] Dementia Research Institute at UCL, London, UK | [i] Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China | [j] Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA | [k] Paris Brain Institute, ICM, Pitié-Salpetriere Hospital, Sorbonne University, Paris, France | [l] Department of Neurology, Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, China

Correspondence: [*] Correspondence to: Olov Rolandsson, MD, PhD, Department of Public Health and Clinical Medicine, Umeå University, 901 87 Umeå Sweden. Tel.: +46 0 90 785 35 71; E-mail: [email protected].

Abstract: Background: Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer’s disease (AD). Mis-metabolism with aggregation of amyloid-β peptides (Aβ) play a key role in AD pathophysiology. Therefore, human studies on Aβ metabolism and T2D are warranted. Objective: The objective of this study was to examine whether acute hyperglycemia affects plasma Aβ1–40 and Aβ1–42 concentrations in individuals with T2D and matched controls. Methods: Ten participants with T2D and 11 controls (median age, 69 years; range, 66–72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in a randomized order, each lasting 4 hours. Aβ1–40, Aβ1–42, and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aβ1–40 and Aβ1–42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration. Results:At baseline, Aβ1–40 and Aβ1–42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aβ decreased in the control group, compared to the placebo clamp (Aβ1–40: p = 0.034, Aβ1–42: p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aβ or IDE was noted in the T2D group. Conclusions:Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aβ40 and Aβ42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D.

Keywords: Alzheimer’s disease, amyloid-β, cognition, endocrinology and metabolism specialty, hyperglycemia, type 2 diabetes

DOI: 10.3233/JAD-230628

Journal: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 1033-1046, 2024