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Hypoglycemia-associated autonomic failure in diabetes

Cryer, Philip E.·2001·American Journal of Physiology-Endocrinology and Metabolism

DOI 10.1152/ajpendo.2001.281.6.e1115

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Abstract

Hypoglycemia is the limiting factor in the glycemic management of diabetes. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response to falling glucose levels in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic and the resulting neurogenic symptom responses) and thus a vicious cycle of recurrent hypoglycemia. Perhaps the most compelling support for HAAF is the finding that as little as 2-3 wk of scrupulous avoidance of hypoglycemia reverses hypoglycemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected individuals. Insight into this pathophysiology has led to a broader view of the clinical risk factors for hypoglycemia to include indexes of compromised glucose counterregulation and provided a framework for the study of the mechanisms of iatrogenic hypoglycemia and, ultimately, its elimination from the lives of people with diabetes.

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The Role of Glucosensing Neurons in the Detection of Hypoglycemia
Routh, V. H., Song, Z., & Liu, X. (2004) · Diabetes Technology & Therapeutics · doi:10.1089/152091504774198133 · Cited by 21
2. Hypoglycemia Detection
Routh, V. H., Donovan, C. M., & Ritter, S. (2012) · Translational endocrinology & metabolism · doi:10.1210/team.9781936704200.ch2 · Cited by 19
Repetitive and profound insulin-induced hypoglycemia results in brain damage in newborn rats: an approach to establish an animal model of brain injury induced by neonatal hypoglycemia
Zhou, D., Qian, J., Liu, C., Chang, H. H., & Sun, R. (2008) · European Journal of Pediatrics · doi:10.1007/s00431-007-0653-2 · Cited by 19
“The sequel of recurrent hypoglycemia is termed “hypoglycemia-associated autonomic failure” (HAAF) [4].”
Potential role of hypothalamic microRNAs in regulation of FOS and FTO expression in response to hypoglycemia
Mussa, B. M., Taneera, J., Mohammed, A. K., Srivastava, A., Mukhopadhyay, D., & Sulaiman, N. D. (2019) · The Journal of Physiological Sciences · doi:10.1007/s12576-019-00718-0 · Cited by 17
Role of dorsal vagal motor nucleus orexin-receptor-1 in glycemic responses to acute versus repeated insulin administration
Paranjape, S., Vavaiya, K. V., Kale, A. Y., & Briski, K. P. (2007) · Neuropeptides · doi:10.1016/j.npep.2006.11.001 · Cited by 17
“by diminished hypoglycemic awareness and impaired glucose counterregulation (Cryer, 2001).”
Background
Recognition and Management of Diabetic Neuropathy
Unger, J., & Cole, B. E. (2007) · Primary Care Clinics in Office Practice · doi:10.1016/j.pop.2007.07.003 · Cited by 17
Direct effects of recurrent hypoglycaemia on adrenal catecholamine release
Orban, B., Routh, V. H., Levin, B. E., & Berlin, J. R. (2014) · Diabetes and Vascular Disease Research · doi:10.1177/1479164114549755 · Cited by 16
Orexin signaling is necessary for hypoglycemia-induced prevention of conditioned place preference
Otlivanchik, O., Sanders, N. M., Dunn-Meynell, A. A., & Levin, B. E. (2015) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00066.2015 · Cited by 16
“HYPOGLYCEMIA UNAWARENESS AND concomitant failure to activate behavioral defenses against hypoglycemia (such as feeding) contribute to the problem of hypoglycemia-associated autonomic failure and the vicious cycle of insulin-induced hypoglycemia (IIH) in Type 1 diabetes mellitus and advanced Type 2 diabetes mellitus pa…”
Background
Recurrent Hypoglycemia Increases Anxiety and Amygdala Norepinephrine Release During Subsequent Hypoglycemia
McNay, E. C. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00175 · Cited by 17
Insulin actions on hypothalamic glucose‐sensing neurones
Garcia, S. M., Hirschberg, P. R., Sarkar, P., Siegel, D. M., Teegala, S. B., Vail, G. M., & Routh, V. H. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12937 · Cited by 16
Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats
LaGamma, E. F., Kirtok, N., Chan, O. T. M., & Nankova, B. B. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00237.2014 · Cited by 15
“Despite the well-established role of hypoglycemia per se in the development of HAAF, the mechanism(s) underlying the key feature of the pathogenesis of HAAF in diabetes, the attenuated sympathoadrenal epinephrine response to falling plasma glucose levels in a background of imperfect insulin replacement and impaired gl…”
Background
Hypoglycaemic bradycardia and circulatory collapse in a dog and a cat
Little, C. J. L. (2005) · Journal of Small Animal Practice · doi:10.1111/j.1748-5827.2005.tb00344.x · Cited by 14
Glycemia-Induced miRNA Changes: A Review
Al-Mahayni, S., Ali, M. K., Khan, M. A., Jamsheer, F., Moin, A. S. M., & Butler, A. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087488 · Cited by 13
“CRR, occurs due to metabolic changes that lead to increased responsiveness to inhibitory signals generated by recurrent hypoglycemia [11,12,18,57].”
Background
Carvedilol prevents counterregulatory failure and impaired hypoglycaemia awareness in non-diabetic recurrently hypoglycaemic rats
Farhat, R., Su, G., Sejling, A.-S., Knight, N., Fisher, S. J., & Chan, O. (2019) · Diabetologia · doi:10.1007/s00125-018-4802-0 · Cited by 12
Evaluation of the counter‐regulatory responses to hypoglycaemia in patients with type 1 diabetes during opiate receptor blockade with naltrexone
Naik, S., Belfort‐DeAguiar, R., Sejling, A., Szepietowska, B., & Sherwin, R. S. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12855 · Cited by 11
“However, intensive insulin regimens increase the risk of recurrent hypoglycaemia, which commonly induces a diminished ability to recognize hypoglycaemia (hypoglycaemia unawareness) and an impairment in the patient’s hormonal counter-regulatory response, a phenomenon known as hypoglycaemia-associated autonomic failure…”
Background
Hypoglycemia unawareness in type 1 diabetes patients using intermittent continuous glucose monitoring: Identification of risk factors and glycemic patterns
Vieira, I. H., Barros, L. M., Baptista, C. F., Melo, M., Rodrigues, D. M., & Paiva, I. (2022) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2022.102525 · Cited by 11
Hypoglycemia, Hypoglycemia Unawareness and Counterregulation in Children and Adolescents with Type 1 Diabetes Mellitus
Böber, E., Büyükgebiz, A., Verrotti, A., & Chiarelli, F. (2005) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem.2005.18.9.831 · Cited by 10
The Antinarcolepsy Drug Modafinil Reverses Hypoglycemia Unawareness and Normalizes Glucose Sensing of Orexin Neurons in Male Mice
Patel, V., Sarkar, P., Siegel, D. M., Teegala, S. B., Hirschberg, P. R., Wajid, H., Itani, O., & Routh, V. H. (2022) · Diabetes · doi:10.2337/db22-0639 · Cited by 10
Hypothalamic-Pituitary-Adrenal Axis Function in Fibromyalgia and Chronic Fatigue Syndrome
Adler, G. K., Manfredsdottir, V. F., & Rackow, R. M. (2002) · The Endocrinologist · doi:10.1097/00019616-200211000-00008 · Cited by 8
Hypoglycaemia in elderly patients with type 2 diabetes mellitus: a review of risk factors, consequences and prevention
Jafari, B., & Britton, M. E. (2015) · Journal of Pharmacy Practice and Research · doi:10.1002/jppr.1163 · Cited by 11
Sex Differences and Role of Estradiol in Hypoglycemia-Associated Counter-Regulation
Briski, K. P., Alhamami, H. N., Alshamrani, A. A., Mandal, S. K., Shakya, M., & Ibrahim, M. H. H. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-70178-3_17 · Cited by 10
Hypoglycemic unawareness: challenges, triggers, and recommendations in patients with hypoglycemic unawareness: a case report
Sharifi, Y., Ebrahimpur, M., & Tamehrizadeh, S. S. (2022) · Journal of Medical Case Reports · doi:10.1186/s13256-022-03498-1 · Cited by 12
“A prior study showed that diabetic patients with reduced beta-adrenergic sensitivity may be unaware of hypoglycemia, and the best suggestion for these patients is to strictly avoid hypoglycemia [35, 36].”
Background
Pancreas and Islet Transplant Population
Sutherland, D. E. R. (2004) · Springer eBooks · doi:10.1007/978-1-4757-4371-5_6 · Cited by 9
Experimentally Induced Hypoglycemia-associated Autonomic Failure in Humans: Determinants, Designs, and Drawbacks
Bengtsen, M. B., & Møller, N. (2022) · Journal of the Endocrine Society · doi:10.1210/jendso/bvac123 · Cited by 9
“Though the term impaired awareness of hypoglycemia (IAH) [14] is related to HAAF, studies merely investigating IAH were excluded, as we opted for the HAAF definition coined by Philip Cryer predicating the coexistence of defective hormonal counterregulatory response and hypoglycemia unawareness [15].”
The role of central nervous system on hypoglycemia and the feasibility of the brain theory in traditional Chinese medicine on treatment of diabetes mellitus
Jiang, H., Niu, J.-J., Zhang, W., Huang, W., Zhou, M.-Y., Sha, W., Li, J., Li, F., Zhu, T., Xia, X., et al. (2014) · Journal of Chinese Integrative Medicine · doi:10.1016/s2095-4964(14)60008-x · Cited by 8
Hypoglycemia during moderate intensity exercise reduces counterregulatory responses to subsequent hypoglycemia
Cade, W. T., Khoury, N., Nelson, S., Shackleford, A. M., Semenkovich, K. A., Krauss, M. J., & Arbeláez, A. M. (2016) · Physiological Reports · doi:10.14814/phy2.12848 · Cited by 8
“…of hypoglycemia, such as the one seen during exercise in our experiment, can reduce the sympathoadrenal and symptomatic responses to subsequent hypoglycemia (Davis et al. 2000; Cryer 2012), causing defective glucose counterregulation and hypoglycemia unawareness (Gold et al. 1994; Cryer 2001).”
Background
Combined corticotropin-releasing hormone and glucocorticoid deficiency does not enhance counterregulatory responses after recurrent hypoglycemia in mice
Jacobson, L., & Pacák, K. (2005) · Metabolism · doi:10.1016/j.metabol.2005.04.013 · Cited by 7
“Inadequate glucagon secretion renders the sympathetic nervous system response to hypoglycemia more important because after glucagon, epinephrine has the most rapid action to restore blood sugar [1].”
Background
Impact of recurring intermediate insulin-induced hypoglycemia on hypothalamic paraventricular corticotropin-releasing hormone, oxytocin, vasopressin and glucokinase gene profiles: role of type II glucocorticoid receptors
Briski, K. P., Kale, A. Y., & Vavaiya, K. V. (2009) · Experimental Brain Research · doi:10.1007/s00221-009-1787-4 · Cited by 7
Hypoglycemia-Dependent β2-Adrenoceptor Downregulation: A Contributing Factor to Hypoglycemia Unawareness in Patients with Type-1 Diabetes?
Schwab, K., Menche, U., Schmeisl, G., & Lohse, M. J. (2004) · Hormone Research in Paediatrics · doi:10.1159/000080064 · Cited by 7
Associations Between Hypoglycemia Awareness Status and Symptoms of Hypoglycemia Among Adults with Type 1 or Insulin-Treated Type 2 Diabetes Using the Hypo-METRICS Smartphone Application
Martine‐Edith, G., Zaremba, N., Divilly, P., Søholm, U., Broadley, M. M., Baumann, P. M., MAHMOUDI, Z., Gomes, M., Ali, N., Abbink, E. J., et al. (2024) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2023.0596 · Cited by 6
“2,3 Hypoglycemia symptoms are often grouped into autonomic symptoms such as heart palpitations, shaking, and sweating, resulting from the activation of the autonomic nervous sys-tem 4,5 and neuroglycopenic symptoms, including headache, confusion, and dizziness, typically considered to manifest as a…”
Metabolomic, hormonal and physiological responses to hypoglycemia versus euglycemia during exercise in adults with type 1 diabetes
McCarthy, O. M., Pitt, J. P., Churm, R., Dunseath, G. J., Jones, C., Bally, L., Nakas, C. T., Deere, R., Eckstein, M. L., Bain, S. C., et al. (2020) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2020-001577 · Cited by 8
Insulin enhances contextual fear memory independently of its effect in increasing plasma adrenaline
Oliveira, A., Seixas, R., Pereira, F., Azevedo, M., Martinho, R., Serrão, P., & Moreira-Rodrigues, M. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.121881 · Cited by 6
Leptin acts in the brain to influence hypoglycemic counterregulation: disparate effects of acute and recurrent hypoglycemia on glucagon release
Reno, C. M., Ding, Y., & Sherwin, R. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00361.2015 · Cited by 6
A Model of Self-Treatment Behavior, Glucose Variability, and Hypoglycemia-Associated Autonomic Failure in Type 1 Diabetes
Breton, M. D., Clarke, W. L., Farhy, L. S., & Kovatchev, B. P. (2007) · Journal of Diabetes Science and Technology · doi:10.1177/193229680700100304 · Cited by 6
Carvedilol prevents impairment of the counterregulatory response in recurrently hypoglycaemic diabetic rats
Farhat, R., Vliet, E. D. S. V., Su, G., Neely, L., Benally, T., & Chan, O. T. M. (2021) · Endocrinology Diabetes & Metabolism · doi:10.1002/edm2.226 · Cited by 5

Authors: Cryer, P. E.
Affiliations: Washington University in St. Louis (US)
Corresponding author: Cryer, Philip E.
Venue: American Journal of Physiology-Endocrinology and Metabolism
Publisher: American Physiological Society
Published: 2001-12-01
Volume: 281
Issue: 6
Pages: E1115-E1121
ISSN: 0193-1849 (ISSN-L)
1522-1555
DOI: 10.1152/ajpendo.2001.281.6.e1115
OpenAlex: W1931223844
Cited by: 152
References: 76
Citations by year: 2026: 4 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 5 · 2021: 8 · 2020: 10 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 10 · 2014: 10 · 2013: 9 · 2012: 8
FWCI: 1.17
Type: journal article
Language: en
Open access: closed
Locations: American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5p60dk020579-35)
National Institute of Diabetes and Digestive and Kidney Diseases (R37DK027085, P60-DK20579, R37-DK27085, T32 DK07120, T32DK007120)
National Center for Research Resources (M01-RR00036, M01RR000036)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Education
Keywords: hypoglycemia-associated autonomic failure, iatrogenic hypoglycemia, diabetes mellitus, glucose counterregulation, hypoglycemia unawareness, epinephrine response, glucagon response, neurogenic symptoms, glycemic control, hypoglycemia risk factors
MeSH terms: Animals, Autonomic Nervous System Diseases, Diabetes Mellitus, Glucose, Humans, Hypoglycemia, Diabetes Complications

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Hypoglycemia-associated autonomic failure in diabetes

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