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Stress, hypoglycemia, and the autonomic nervous system
Open accessAbstract
Stress can be classified as either psychosocial or physiologic. Physiologic stress refers to stresses due to acute illness, trauma, pain, hypoglycemia, and sleep deprivation-much less is known regarding its health consequences. This review focuses on hypoglycemia as a model to further investigate physiological stress. Experimental mild to moderate hypoglycemia is a paradigmatic physiological stress that evokes autonomic, neuroendocrine, and immune responses. Hypoglycemic stress is an ideal model to examine the interactions and consequences of physiological stress on the autonomic nervous system. Acute hypoglycemia has been demonstrated to increase inflammatory markers, prolong QTc, and impair cardiac-vagal baroreflex sensitivity. Some of these consequences may not reverse completely when euglycemia is restored. For example, there is attenuation of the cardiac-vagal baroreflex, attenuation of the vascular sympathetic baroreflex (muscle sympathetic nerve activity response to transient hypotension), and attenuation of the catecholamine response to lower body negative pressure that is present the next day after hypoglycemia has resolved.
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TL;DR
This review argues that experimentally induced mild-to-moderate hypoglycemia is a paradigmatic physiological stress model for studying autonomic, neuroendocrine, and immune responses. It summarizes evidence that acute and antecedent hypoglycemia impair cardiovascular autonomic function and counterregulation, with some effects persisting after euglycemia is restored.
Key findings
- Hypoglycemia activates the HPA axis, sympathoadrenal system, and immune/inflammatory responses; counterregulatory increases in glucagon, epinephrine, growth hormone, and cortisol restore glucose. Acute hypoglycemia increases inflammatory markers—most consistently IL-6—prolongs QTc, and impairs cardiac-vagal baroreflex sensitivity.
- In 17 healthy volunteers exposed to experimental hypoglycemia for 120 min, cardiac-vagal baroreflex sensitivity was significantly decreased, the blood pressure threshold for baroreflex activation increased, and maximum R-R interval responses decreased.
- Antecedent hypoglycemia produces hypoglycemia-associated autonomic failure (HAAF), including blunted hormonal and sympathoadrenal responses and hypoglycemia unawareness, which can increase severe hypoglycemia risk six-fold; HAAF can be reversed by strict avoidance of hypoglycemia for 2–3 weeks.
- After euglycemia is restored, antecedent hypoglycemia attenuates cardiac-vagal baroreflex, vascular sympathetic baroreflex (MSNA response to transient hypotension), and catecholamine response to lower body negative pressure for at least 16 h; prothrombotic effects have been shown to persist at least 7 days. In ACCORD, >10,000 patients with T2DM were randomized, and the trial was stopped early for increased mortality in the strict glycemic control arm, with post-hoc analysis associating hypoglycemia with mortality in both groups.
Methods
- Narrative review synthesizing experimental human studies of hypoglycemic stress, including hyperinsulinemic clamps (euglycemic, hypoglycemic, and stepped), modified Oxford baroreflex testing, muscle sympathetic nerve activity (MSNA), lower body negative pressure, ACTH infusion, and inflammatory/coagulation markers.
- No new primary data are reported; the review cites studies including 17 healthy volunteers, ACCORD with >10,000 T2DM participants, and other T1DM/T2DM and healthy-volunteer cohorts.
- Main analysis is qualitative synthesis of cited literature rather than systematic review or meta-analysis.
Limitations
- Stated: the mechanisms mediating HAAF are not fully delineated; it is not known when the vascular-sympathetic baroreflex decrease first occurs or how long these impairments persist.
- Evident: as a narrative review, it lacks a systematic search strategy or quantitative synthesis, and it relies on cited studies with heterogeneity—for example, the text notes heterogeneity in studies of inflammatory and immune markers affected by hypoglycemia.
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In the paper
“The study showed that during hypoglycemia, the baroreflex is significantly decreased.”
§ Stress, hypoglycemia, and the autonomic nervous system > Acute primarily maladaptive responses to hypoglycemic stress > Attenuated baroreflex function
What the sources say
- Not checked yetcites Rao et al., 2016 source
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plainstates a causen = 17- Asserted: passes — The authors put it forward as true.
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In the paper
“Antecedent hypoglycemia as compared to antecedent euglycemia impaired the MSNA response to transient hypotension during the modified Oxford procedure.”
- Also stated in: § Conclusion · plain
“For example, the morning after exposure to hypoglycemia, when individuals are euglycemic, there is attenuation of the cardiac-vagal baroreflex, attenuation of the sympathetic (MSNA response to transient hypotension), and attenuation of the catecholamine response to lower body negative pressure (cardiovascular hypoglycemia associated autonomic failure).”
§ Stress, hypoglycemia, and the autonomic nervous system > Consequences of repeated exposure to hypoglycemia > Hypoglycemia associated cardiovascular autonomic failure
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In the paper
“Furthermore, the blood pressure threshold for baroreflex activation is increased, and the maximum R-R interval response and maximal range of the R-R interval responses are decreased”
§ Stress, hypoglycemia, and the autonomic nervous system > Acute primarily maladaptive responses to hypoglycemic stress > Attenuated baroreflex function
What the sources say
- Not checked yetcites Rao et al., 2016 source
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plainstates a causen = 17- Asserted: passes — The authors put it forward as true.
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In the paper
“Cardiac-vagal baroreflex sensitivity in the final 30 min of the 2.5 hour ACTH infusion was significantly reduced compared to the final 30 min of a placebo infusion, and remained suppressed the following day (Fig. 7) (Leung et al., 2020).”
§ Stress, hypoglycemia, and the autonomic nervous system > ACTH infusion impairs baroreflex sensitivity
What the sources say
- Not checked yetcites Leung et al., 2020 source
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In the paper
“Antecedent hypoglycemia as compared to antecedent euglycemia reduced cardiac-vagal baroreflex sensitivity (assessed by the sequential pharmacological induction of hypotension and hypertension with the modified Oxford procedure).”
- Also stated in: § Conclusion · plain
“For example, the morning after exposure to hypoglycemia, when individuals are euglycemic, there is attenuation of the cardiac-vagal baroreflex, attenuation of the sympathetic (MSNA response to transient hypotension), and attenuation of the catecholamine response to lower body negative pressure (cardiovascular hypoglycemia associated autonomic failure).”
§ Stress, hypoglycemia, and the autonomic nervous system > Consequences of repeated exposure to hypoglycemia > Hypoglycemia associated cardiovascular autonomic failure
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Also stated in: § Conclusion · plain
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Metadata
- Authors
- Haas, A., Borsook, D., Adler, G., & Freeman, R.
- Affiliations
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Freeman, Roy
- Venue
- Autonomic Neuroscience
- Publisher
- Elsevier BV
- Published
- 2022-07
- Volume
- 240
- Pages
- 102983
- ISSN
- 1566-0702 (ISSN-L)
- PMC
- PMC12818488
- OpenAlex
- W4223959830
- Cited by
- 30
- References
- 113
- Citations by year
- 2026: 14 · 2025: 6 · 2024: 4 · 2023: 4 · 2022: 2
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 283 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Autonomic Neuroscience (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Syncope and Autonomic Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- hypoglycemia, physiological stress, autonomic nervous system, sympathetic baroreflex, QTc prolongation, inflammatory markers, catecholamine response, muscle sympathetic nerve activity, lower body negative pressure, neuroendocrine response, immune response
- MeSH terms
- Autonomic Nervous System, Blood Pressure, Heart Rate, Humans, Hypoglycemia, Sympathetic Nervous System, Baroreflex
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-14, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-14 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
