Potential approaches to prevent hypoglycemia-associated autonomic failure
Open accessAbstract
Clear health benefits are associated with intensive glucose control in type 1 diabetes mellitus (T1DM). However, maintaining near-normal glycemia remains an elusive goal for many patients, in large part owing to the risk of severe hypoglycemia. In fact, recurrent episodes of hypoglycemia lead to ‘hypoglycemia-associated autonomic failure’ (HAAF), characterized by defective counter-regulatory responses to hypoglycemia. Extensive studies to understand the mechanisms underlying HAAF have revealed multiple potential etiologies, suggesting various approaches to prevent the development of HAAF. In this review, we present an overview of the literature focused on pharmacological approaches that may prevent the development of HAAF. The purported underlying mechanisms of HAAF include: 1) central mechanisms (opioid receptors, ATP-sensitive K+(K ATP ) channels, adrenergic receptors, serotonin selective receptor inhibitors, γ-aminobuyric acid receptors, N-methyl D-aspartate receptors); 2) hormones (cortisol, estrogen, dehydroepiandrosterone (DHEA) or DHEA sulfate, glucagon-like peptide-1) and 3) nutrients (fructose, free fatty acids, ketones), all of which have been studied vis-à-vis their ability to impact the development of HAAF. A careful review of the current literature reveals many promising therapeutic approaches to treat or reduce this important limitation to optimal glycemic control.
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Multiple pathways in addition to the adrenergic system could be simultaneously involved in the pathogenesis of HAAF.
“suggesting that multiple pathways in addition to the adrenergic system could be simultaneously involved in the pathogenesis of HAAF (8, 33, 34).”
From Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure (2020) · cites this paper as [8]
None of the proposed mechanisms have been able to entirely explain the pathogenesis of HAAF, as multiple pathways may be simultaneously involved.
“However, none of the proposed mechanisms have been able to entirely explain the pathogenesis of HAAF, as it appears that multiple pathways may be simultaneously involved (8).”
From Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure (2020) · cites this paper as [8]
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Lontchi-Yimagou, E., Aleksic, S., Hulkower, R., Gospin, R., Goyal, A., Kuo, B., Mitchell, W. G., You, J. Y., Upadhyay, L., Carey, M., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa539 · Cited by 17 · see citing works
Self-citation
- Authors
- Lontchi-Yimagou, E., You, J. Y., Carey, M., Gabriely, I., Shamoon, H., & Hawkins, M.
- Affiliations
- Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York, USA
- Albert Einstein College of Medicine (US)
- Corresponding author
- Hawkins, Meredith
- Venue
- Journal of Investigative Medicine
- Publisher
- SAGE Publications
- Published
- 2018-03
- Volume
- 66
- Issue
- 3
- Pages
- 641-647
- ISSN
- 1081-5589 (ISSN-L)
- 1708-8267
- PMC
- PMC6338223
- OpenAlex
- W2769285216
- Semantic Scholar
- 4b2de84e635d5ad188c41b273b02cedbb1cbc953
- Cited by
- 12
- References
- 80
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 1
- FWCI
- 0.04
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Investigative Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR001073, UL1TR002556)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK069861, R01DK079974, R01DK048321, R37DK048321, R01DK069861, P30DK020541)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- hypoglycemia-associated autonomic failure, type 1 diabetes, recurrent hypoglycemia, pharmacological prophylaxis, opioid receptors, ATP-sensitive potassium channels, adrenergic receptors, GABA receptors, NMDA receptor, cortisol, estrogen, dehydroepiandrosterone, glucagon-like peptide-1, fructose, free fatty acids, ketones, glycemic control
- MeSH terms
- Animals, Autonomic Nervous System, Fatty Acids, Food, Hormones, Humans, Hypoglycemia, Ketones
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