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Amyloid-related protein changes associated with dementia differ according to severity of hypoglycemia

Moin, Abu Saleh Md; Kahal, Hassan; Al-Qaissi, Ahmed; Kumar, Nitya; Sathyapalan, Thozhukat; Atkin, Stephen L; Butler, Alexandra E.


Abu Saleh Md Moin

Hassan Kahal

Ahmed Al-Qaissi

Nitya Kumar

Thozhukat Sathyapalan

Stephen L Atkin

Alexandra E. Butler


Introduction Hypoglycemia in type 2 diabetes (T2D) may increase risk for Alzheimer’s disease (AD), but no data on changes in AD-related proteins with differing degrees of hypoglycemia exist. We hypothesized that milder prolonged hypoglycemia would cause greater AD-related protein changes versus severe transient hypoglycemia.

Research design and methods Two prospective case-control induced hypoglycemia studies were compared: study 1, hypoglycemic clamp to 2.8 mmol/L (50 mg/dL) for 1 hour in 17 subjects (T2D (n=10), controls (n=7)); study 2, hypoglycemic clamp to 2.0 mmol/L (36 mg/dL) undertaken transiently and reversed in 46 subjects (T2D (n=23), controls (n=23)). Blood sampling at baseline, hypoglycemia and 24-hour post-hypoglycemia, with proteomic analysis of amyloid-related proteins performed.

Results In control subjects, the percentage change from baseline to hypoglycemia differed between study 1 and study 2 for 5 of 11 proteins in the AD-related panel: serum amyloid A1 (SAA1) (p=0.009), pappalysin (PAPPA) (p=0.002), apolipoprotein E2 (p=0.02), apolipoprotein E3 (p=0.03) and apolipoprotein E4 (p=0.02). In controls, the percentage change from baseline to 24 hours differed between studies for two proteins: SAA1 (p=0.003) and PAPPA (p=0.004); however, after Bonferroni correction only SAA1 and PAPPA remain significant. In T2D, there were no differential protein changes between the studies.

Conclusions The differential changes in AD-related proteins were seen only in control subjects in response to iatrogenic induction of hypoglycemic insults of differing length and severity and may reflect a protective response that was absent in subjects with T2D. Milder prolonged hypoglycemia caused greater AD-related protein changes than severe acute hypoglycemia in control subjects.


Atkin, S. L., Moin, A. S. M., Kahal, H., Al-Qaissi, A., Kumar, N., Sathyapalan, T., …Butler, A. E. (2021). Amyloid-related protein changes associated with dementia differ according to severity of hypoglycemia. BMJ Open Diabetes Research and Care, 9(1),

Journal Article Type Article
Acceptance Date Apr 6, 2021
Online Publication Date Apr 30, 2021
Publication Date Apr 30, 2021
Deposit Date May 12, 2021
Publicly Available Date May 12, 2021
Journal BMJ Open Diabetes Research and Care
Print ISSN 2052-4897
Electronic ISSN 2052-4897
Publisher BMJ Publishing Group
Peer Reviewed Peer Reviewed
Volume 9
Issue 1
Article Number e002211
Public URL


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© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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