Hypoglycemia-associated autonomic failure in diabetes

Cryer, Philip E.

doi:10.1152/ajpendo.2001.281.6.e1115

Cited by 152Diabetes Management and ResearchDiabetes Treatment and ManagementDiabetes Management and Education

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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Recent antecedent hypoglycemic episodes do not increase blood-to-brain glucose transport.
“However, recent antecedent hypoglycemic episodes do not increase these mechanisms with a higher blood-to-brain glucose transport.”
From Hypoglycemia Unawareness—A Review on Pathophysiology and Clinical Implications (2024) · cites this paper as [18]
Dysfunction in brain glucose sensing processes can contribute to hypoglycemia unawareness syndrome.
“Dysfunction in these processes can lead to altered brain glucose sensing, which has far-reaching consequences on neuronal activity and overall brain physiology and can contribute to hypoglycemia unawareness syndrome [ 10 , 18 ].”
From Hypoglycemia Unawareness—A Review on Pathophysiology and Clinical Implications (2024) · cites this paper as [18]
A vicious cycle of recurrent hypoglycemia with the potential for serious complications can occur.
“Consequently, a vicious cycle of recurrent hypoglycemia with the potential for serious complications can occur [ 18 , 19 ].”
From Hypoglycemia Unawareness—A Review on Pathophysiology and Clinical Implications (2024) · cites this paper as [18]
Recurrent hypoglycemic episodes disrupt the normal release of counterregulatory hormones, such as glucagon, growth hormone (GH), and epinephrine.
“Hypoglycemia unawareness syndrome is commonly observed in individuals with recurrent hypoglycemic episodes disrupting the normal release of counterregulatory hormones, such as glucagon, growth hormone (GH), and epinephrine.”
From Hypoglycemia Unawareness—A Review on Pathophysiology and Clinical Implications (2024) · cites this paper as [18]

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“Hypoglycemia impairs hormonal and autonomic responses to subsequent hypoglycemia (51).”
Background
Effects of Cardiac Autonomic Dysfunction on Mortality Risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial
Pop-Busui, R., Evans, G. W., Gerstein, H. C., Fonseca, V., Fleg, J. L., Hoogwerf, B. J., Genuth, S., Grimm, R. H., Corson, M. A., Prineas, R., et al. (2010) · Diabetes Care · doi:10.2337/dc10-0125 · Cited by 540 · see citing works
“Hypoglycemia can impair hormonal and autonomic responses to subsequent hypoglycemia (8), and hypoglycemia may promote a reduced threshold for malignant arrhythmias and subsequent sudden cardiac death.”
Background
Glucose-sensing neurons
Routh, V. H. (2002) · Physiology & Behavior · doi:10.1016/s0031-9384(02)00761-8 · Cited by 237 · see citing works
Sleep-Related Hypoglycemia-Associated Autonomic Failure in Type 1 Diabetes
Banarer, S., & Cryer, P. E. (2003) · Diabetes · doi:10.2337/diabetes.52.5.1195 · Cited by 186 · see citing works
“The reduced cortisol response to hypoglycemia during sleep in diabetic subjects is relevant to the suggestion that it is the cortisol response to prior hypoglycemia that mediates reduced autonomic (including epinephrine) and symptomatic responses to subsequent hypoglycemia (25– 26), that is, that cortisol is the media…”
Influential
The importance of hypoglycemia in diabetic patients
Shafiee, G., Mohajeri‐Tehrani, M. R., Pajouhi, M., & Larijani, B. A. (2012) · Journal of Diabetes & Metabolic Disorders · doi:10.1186/2251-6581-11-17 · Cited by 166 · see citing works
“The mechanisms of defect in glucose counter-regulation in type 2 diabetes are the same as type 1diabetes which includes both defect in hypoglycemia counter-regulation mechanism and deficiency of sense of hypoglycemia [6].”
Background
Hypoglycemia in type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73.
Wright, A. D., Cull, C. A., Macleod, K. M., & Holman, R. R. (2006) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2005.08.010 · Cited by 153 · see citing works
“Information about hypoglycemia in diabetes is largely confined to Type 1 diabetes (Cryer, 2001) and insulin requiring Type 2 diabetes, where fear of hypoglycemia is often cited as a factor-limiting attempts to intensify therapy (Cryer, 2002).”
Background
Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats
Han, S. M., NamKoong, C., Jang, P., Park, I.-S., Hong, S. W., Katakami, H., Chun, S., Kim, S., Park, J.-Y., Lee, K.-U., et al. (2005) · Diabetologia · doi:10.1007/s00125-005-1913-1 · Cited by 147 · see citing works
“Therefore, it will be interesting to study if repeated hypoglycaemia can cause a reduction in PVN AMPK activation and if a manoeuvre activating PVN AMPK can prevent HAAF.”
BackgroundInfluential
Effects of Low and Moderate Antecedent Exercise on Counterregulatory Responses to Subsequent Hypoglycemia in Type 1 Diabetes
Sandoval, D. A., Guy, D. L. A., Richardson, M. A., Ertl, A. C., & Davis, S. N. (2004) · Diabetes · doi:10.2337/diabetes.53.7.1798 · Cited by 134 · see citing works
“This has been termed hypoglycemia-associated autonomic failure (8,9) and is proposed to create a vicious cycle of hypoglycemia for the type 1 diabetic patient.”
Background
Diabetic autonomic neuropathy
Freeman, R. L. (2014) · Handbook of clinical neurology · doi:10.1016/b978-0-444-53480-4.00006-0 · Cited by 133 · see citing works
Exercise and Type 1 Diabetes (T1DM)
Galassetti, P. R., & Riddell, M. C. (2013) · Comprehensive physiology · doi:10.1002/cphy.c110040 · Cited by 135 · see citing works
What Do We Know and We Do Not Know About Cardiovascular Autonomic Neuropathy in Diabetes
Pop‐Busui, R. (2012) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-012-9367-6 · Cited by 102 · see citing works
“hypoglycemia [24] and hypoglycemia unawareness may promote a reduced threshold for malignant arrhythmias and subsequent sudden cardiac death.”
Background
Recurrent/moderate hypoglycemia induces hippocampal dendritic injury, microglial activation, and cognitive impairment in diabetic rats
Won, S. J., Yoo, B. H., Kauppinen, T. M., Choi, B. Y., Kim, J. H., Jang, B. G., Lee, M., Sohn, M., Liu, J., Swanson, R. A., et al. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-182 · Cited by 99 · see citing works
Metabolic Pathways That Mediate Inhibition of Hypothalamic Neurons by Glucose
Yang, X.-J., Kow, L., Pfaff, D. W., & Mobbs, C. V. (2004) · Diabetes · doi:10.2337/diabetes.53.1.67 · Cited by 95 · see citing works
“Failure in the counterregulatory responses to hypoglycemia, secondary to previous hypoglycemic episodes, constitutes a major complication in type 1 diabetes (1).”
Background
Exercise: Applications to Childhood ADHD
Wigal, S. B., Emmerson, N., Gehricke, J.-G., & Galassetti, P. (2013) · Journal of Attention Disorders · doi:10.1177/1087054712454192 · Cited by 93 · see citing works
“Even these patients, however, may experience transient reductions in catecholamine responses after specific blunting stimuli, of which the best described is hypoglycemia (Cryer, 2001).”
Background
Concomitant Diabetes Mellitus and Heart Failure
Dei, A., Fonarow, G. C., Gheorghiade, M., & Butler, J. (2014) · Current Problems in Cardiology · doi:10.1016/j.cpcardiol.2014.09.002 · Cited by 92 · see citing works
Recurrent hypoglycemia reduces the glucose sensitivity of glucose-inhibited neurons in the ventromedial hypothalamus nucleus
Song, Z., & Routh, V. H. (2006) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00148.2006 · Cited by 78 · see citing works
“Thus brain glucose levels are allowed to fall to dangerous or even lethal levels before the CRR is initiated (1, 5).”
Background
Análisis psicométrico de las versiones en lengua castellana y catalana de un cuestionario de percepción de la hipoglucemia
Jansà, M., Quirós, C., Giménez, M., Vidal, M., Galindo, M., & Conget, I. (2014) · Medicina Clínica · doi:10.1016/j.medcli.2013.11.036 · Cited by 75 · see citing works
Association Between Impaired Cardiovascular Autonomic Function and Hypoglycemia in Patients With Type 1 Diabetes
Jaiswal, M., McKeon, K., Comment, N., Henderson, J., Swanson, S., Plunkett, C. D., Nelson, P. W., & Pop‐Busui, R. (2014) · Diabetes Care · doi:10.2337/dc14-0445 · Cited by 69 · see citing works
“, epinephrine, glucagon, and adrenocorticotropic hormone) and blunts autonomic nervous system responses to subsequent hypoglycemia (21).”
Background
Elevated endogenous cortisol reduces autonomic neuroendocrine and symptom responses to subsequent hypoglycemia
McGregor, V. P., Banarer, S., & Cryer, P. E. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00447.2001 · Cited by 66 · see citing works
Pancreas Transplantation
Han, D. J., & Sutherland, D. E. R. (2010) · Gut and Liver · doi:10.5009/gnl.2010.4.4.450 · Cited by 61 · see citing works
“Patients with hypoglycemic unawareness with frequent reactions to exogenous insulin lead a dangerous existence.(46) Patients with progressive secondary complications of diabetes are also destined for blindness, amputations, and kidney failure that exceeds the usual side effects of immunosuppression.”
Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes.
de Galan, B. E., Schouwenberg, B. J. J. W., Tack, C. J., & Smits, P. (2006) · PubMed · Cited by 61 · see citing works
Ventromedial hypothalamus glucose‐inhibited neurones: A role in glucose and energy homeostasis?
Hirschberg, P. R., Sarkar, P., Teegala, S. B., & Routh, V. H. (2019) · Journal of Neuroendocrinology · doi:10.1111/jne.12773 · Cited by 59 · see citing works
Physiological glucose is critical for optimized neuronal viability and AMPK responsiveness in vitro
Kleman, A. M., Yuan, J., Aja, S. M., Ronnett, G. V., & Landree, L. E. (2007) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2007.08.028 · Cited by 58 · see citing works
“…in pathways that regulate energy metabolism are incurred from exposure to dysregulated metabolic environments such as during diabetes, obesity or hypoglycemia (Sango, et al., 1991; Sango, et al., 1994; Cryer, 2001; Chen, et al., 2005; Song, et al., 2006; Martin, et al., 2006; Somoza, et al., 2007).”
Background
Prevention of Hypoglycemia While Achieving Good Glycemic Control in Type 1 Diabetes
Rossetti, P., Porcellati, F., Bolli, G. B., & Fanelli, C. G. (2008) · Diabetes Care · doi:10.2337/dc08-s227 · Cited by 55 · see citing works
Defective Counterregulation and Hypoglycemia Unawareness in Diabetes
Reno, C. M., Litvin, M., Clark, A. L., & Fisher, S. J. (2012) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2012.11.005 · Cited by 53 · see citing works
Hypoglycemia in Patients with Type 1 Diabetes: Epidemiology, Pathogenesis, and Prevention
Awoniyi, O., Rehman, R., & Dagogo-Jack, S. E. (2013) · Current Diabetes Reports · doi:10.1007/s11892-013-0411-y · Cited by 53 · see citing works
Cortisol Elevations Comparable to Those That Occur During Hypoglycemia Do Not Cause Hypoglycemia-Associated Autonomic Failure
Raju, B., McGregor, V. P., & Cryer, P. E. (2003) · Diabetes · doi:10.2337/diabetes.52.8.2083 · Cited by 44 · see citing works
“The clinical impact of HAAF, including the finding that as little as 2–3 weeks of scrupulous avoidance of hypoglycemia reverses hypoglycemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected patients is well documented (1,4).”
Background
Hypoglycemia-Associated Changes in the Electroencephalogram in Patients With Type 1 Diabetes and Normal Hypoglycemia Awareness or Unawareness
Sejling, A., Kjær, T. W., Pedersen‐Bjergaard, U., Diemar, S. S., Frandsen, C. S., Hilsted, L., Faber, J. O., Holst, J. J., Tarnow, L., Nielsen, M. N., et al. (2014) · Diabetes · doi:10.2337/db14-1359 · Cited by 45 · see citing works
Hypoglycemia Unawareness—A Review on Pathophysiology and Clinical Implications
Hölzen, L., Schultes, B., Meyhöfer, S. M., & Meyhöfer, S. (2024) · Biomedicines · doi:10.3390/biomedicines12020391 · Cited by 44 · see citing works
“An thus hypoglycemia incretin-driven hyperinsulinemic response to undigested carbohydrates can result in a hypoglycemic episode [12,13]. awareness [18].”
Background
Cortical Fluoro-Jade Staining and Blunted Adrenomedullary Response to Hypoglycemia after Noncoma Hypoglycemia in Rats
Tkacs, N. C., Pan, Y., Raghupathi, R., Dunn-Meynell, A. A., & Levin, B. E. (2005) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600152 · Cited by 43 · see citing works
“These sequelae of recurrent hypoglycemia are termed ‘hypoglycemia unawareness’ and ‘hypoglycemiaassociated autonomic failure’ (HAAF), respectively (Gerich et al, 1991; Cryer, 2001).”
Background
Telemedicine for diabetes care: An Indian perspective - feasibility and efficacy
Kesavadev, J., Saboo, B., Shankar, A., Krishnan, G., & Jothydev, S. (2015) · Indian journal of endocrinology and metabolism · doi:10.4103/2230-8210.167560 · Cited by 33 · see citing works
Butyrate, a gut-derived environmental signal, regulates tyrosine hydroxylase gene expression via a novel promoter element
Patel, P., Nankova, B. B., & LaGamma, E. F. (2005) · Developmental Brain Research · doi:10.1016/j.devbrainres.2005.08.005 · Cited by 41 · see citing works
Hypoglycemia-Associated Autonomic Failure Is Prevented by Opioid Receptor Blockade
Leu, J. P., Cui, M., Shamoon, H., & Gabriely, I. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0882 · Cited by 39 · see citing works
“compromised hypoglycemia awareness (5).”
The Impact of Nocturnal Hypoglycemia on Clinical and Cost-Related Issues in Patients With Type 1 and Type 2 Diabetes
Edelman, S. V., & Blose, J. S. (2014) · The Science of Diabetes Self-Management and Care · doi:10.1177/0145721714529608 · Cited by 37 · see citing works
Type 1 Diabetes Mellitus
Eisenbarth, G. S., & Buse, J. B. (2011) · Elsevier eBooks · doi:10.1016/b978-1-4377-0324-5.00032-8 · Cited by 39 · see citing works
Plasma catecholamines and the counterregulatory responses to hypoglycemia in infants: a critical role for epinephrine and cortisol
Jackson, L., Williams, F. L. R., Burchell, A., Coughtrie, M. W. H., & Hume, R. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0550 · Cited by 36 · see citing works
Revisiting tight glycemic control in perioperative and critically ill patients: when one size may not fit all
Abdelmalak, B., & Lansang, M. C. (2013) · Journal of Clinical Anesthesia · doi:10.1016/j.jclinane.2012.09.006 · Cited by 35 · see citing works
“For instance, it is likely that diabetic patients with lower blood glucose have an increased risk of hypoglycemia during the ensuing year [36,37].”
Background
Effect of chronic hypoglycaemia on glucose concentration and glycogen content in rat brain: a localized 13C NMR study
Lei, H., & Rolf Gruetter, A. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04115.x · Cited by 37 · see citing works
Differential regulation of the tyrosine hydroxylase and enkephalin neuropeptide transmitter genes in rat PC12 cells by short chain fatty acids: Concentration-dependent effects on transcription and RNA stability
Parab, S., Nankova, B. B., & Gamma, E. F. L. (2006) · Brain Research · doi:10.1016/j.brainres.2006.11.013 · Cited by 37 · see citing works
The impact of metabolic control and QTc prolongation on all-cause mortality in patients with type 2 diabetes and foot ulcers
Fagher, K., & Löndahl, M. (2013) · Diabetologia · doi:10.1007/s00125-013-2860-x · Cited by 37 · see citing works
“Autonomic neuropathy, which might not only lead to decreased adrenergic awareness of hypoglycaemia but also to increased risk of cardiac arrhythmia, may have been more frequently present in those patients with prolonged QTc time[45].”
Background
Naloxone, but Not Valsartan, Preserves Responses to Hypoglycemia After Antecedent Hypoglycemia
Poplawski, M. M., Mastaitis, J. W., & Mobbs, C. V. (2010) · Diabetes · doi:10.2337/db10-0326 · Cited by 34 · see citing works
“Diabetes 60:39–46, 2011 Hypoglycemia-associated autonomic failure (HAAF) is thought to constitute one of the main obstacles to optimum treatment of type 1 diabetes (1).”
Background
Utility of continuous glucose monitoring following gastrectomy
Kubota, T., Shoda, K., Ushigome, E., Kosuga, T., Konishi, H., Shiozaki, A., Kudo, M., Arita, T., Murayama, Y., Morimura, R., et al. (2020) · Gastric Cancer · doi:10.1007/s10120-019-01036-5 · Cited by 37 · see citing works
“This results in a weakening of the autonomic response, termed ‘hypoglycemia-associated autonomic failure’, which further contributes to the development of hypoglycemia unawareness [17, 18].”
Background
Impaired glucagon response to sympathetic nerve stimulation in the BB diabetic rat: effect of early sympathetic islet neuropathy
Mundinger, T. O., Mei, Q., Figlewicz, D. P., Lernmark, Å., & Taborsky, G. J. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00136.2003 · Cited by 36 · see citing works
“Third, the brain’s sensitivity to hypoglycemia, and thus the magnitude of sympathetic outflow from the brain, can be impaired by repetitive iatrogenic hypoglycemia, a phenomenon termed hypoglycemia-associated autonomic failure (8, 9, 23).”
Background
Effects of Gastric Bypass Surgery on the Brain: Simultaneous Assessment of Glucose Uptake, Blood Flow, Neural Activity, and Cognitive Function During Normo- and Hypoglycemia
Almby, K. E., Lundqvist, M., Abrahamsson, N., Kvernby, S., Fahlström, M., Pereira, M. J., Gingnell, M., Karlsson, F. A., Fanni, G., Sundbom, M., et al. (2021) · Diabetes · doi:10.2337/db20-1172 · Cited by 35 · see citing works
“attenuation of symptoms and some counterregulatory hormonal responses during hypoglycemia compared with patients with normal hypoglycemic awareness (6).”
Background
Neuroendocrine abnormalities in fibromyalgia
Adler, G. K., Manfredsdottir, V. F., & Creskoff, K. W. (2002) · Current Pain and Headache Reports · doi:10.1007/s11916-002-0050-5 · Cited by 51 · see citing works
From Bedside to Bench and Back Again: Research Issues in Animal Models of Human Disease
Tkacs, N. C., & Thompson, H. J. (2006) · Biological Research For Nursing · doi:10.1177/1099800406289717 · Cited by 33 · see citing works
“Recurrent hypoglycemia is associated with progressive blunting of autonomic responses to hypoglycemia, particularly manifested as a deficient epinephrine secretory response to hypoglycemia, giving rise to the phenomenon of HAAF (Cryer, 2001).”
BackgroundResult
Prevention of hypoglycemia-induced neuronal death by minocycline
Won, S. J., Kim, J. H., Yoo, B. H., Sohn, M., Kauppinen, T. M., Park, M.-S., Kwon, H., Liu, J., & Suh, S. W. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-225 · Cited by 32 · see citing works
“; licensee BioMed Central Lt Commons Attribution License (http://creativec reproduction in any medium, provided the or and coma, and resulting in sudden death [7].”
Background
Hypoglycemia-Induced Changes in the Electroencephalogram
Blaabjerg, L., & Juhl, C. B. (2016) · Journal of Diabetes Science and Technology · doi:10.1177/1932296816659744 · Cited by 31 · see citing works
Psychometric analysis of the Spanish and Catalan versions of a questionnaire for hypoglycemia awareness
Jansà, M., Quirós, C., Giménez, M., Vidal, M., Galindo, M., & Conget, I. (2015) · Medicina Clínica (English Edition) · doi:10.1016/j.medcle.2015.12.012 · Cited by 30 · see citing works
Devices for continuous monitoring of glucose: update in technology
Gómez, A. M., Carrillo, D. C. H., & Múñoz, Ó. (2017) · Medical Devices Evidence and Research · doi:10.2147/mder.s110121 · Cited by 29 · see citing works
“…cortisol, fail as beta cell function is lost, and this phenomenon has been associated with increased episodes of unawareness hypoglycemia (UH) 29,30 ; this phenomenon usually appears between 5 and 10 years after diagnosis and increases in 25 times the risk of severe hypoglycemia, and of these…”
Habituation of insulin-induced hypoglycemic transcription activation of lateral hypothalamic orexin-A-containing neurons to recurring exposure
Paranjape, S., Vavaiya, K. V., Kale, A. Y., & Briski, K. P. (2006) · Regulatory Peptides · doi:10.1016/j.regpep.2006.02.002 · Cited by 29 · see citing works
Recurrent Hypoglycemia Exacerbates Cerebral Ischemic Damage in Diabetic Rats via Enhanced Post-Ischemic Mitochondrial Dysfunction
Shukla, V., Fuchs, P., Liu, A., Cohan, C. H., Dong, C., Wright, C. B., Pérez‐Pinzón, M. A., & Dave, K. R. (2018) · Translational Stroke Research · doi:10.1007/s12975-018-0622-2 · Cited by 28 · see citing works
“sequently increasing the risk of hypoglycemic brain injury [19, 25, 31, 32, 62].”
Background
Altered glycemia and brain—update and potential relevance to the aging brain
McCall, A. L. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.08.009 · Cited by 28 · see citing works
Metabolic Sensors Mediate Hypoglycemic Detection at the Portal Vein
Matveyenko, A. V., & Donovan, C. M. (2006) · Diabetes · doi:10.2337/db05-1665 · Cited by 27 · see citing works
“Because the defect in the sympathoadrenal response for type 1 diabetic patients is specific to hypoglycemia (6) and is often associated with hypoglycemic unawareness (1), impaired glucose sensing has been implicated as a cause.”
Background
Autonomic disturbances in diabetes: Assessment and anaesthetic implications
Moningi, S., Nikhar, S. A., & Ramachandran, G. (2018) · Indian Journal of Anaesthesia · doi:10.4103/ija.ija_224_18 · Cited by 26 · see citing works
“Most of them are asymptomatic due to AN.”
BackgroundInfluential
Inactivation of the DMH selectively inhibits the ACTH and corticosterone responses to hypoglycemia
Evans, S. B., Wilkinson, C. W., Gronbeck, P., Bennett, J. L., Zavosh, A., Taborsky, G. J., & Figlewicz, D. P. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00328.2003 · Cited by 26 · see citing works
Current perspectives on neonatal hypoglycemia, its management, and cerebral injury risk
Hussain, K., Chandran, S., Rajadurai, V. S., & Alim, A. (2015) · Research and Reports in Neonatology · doi:10.2147/rrn.s55353 · Cited by 25 · see citing works
“Moreover, recurrent episodes of insulininduced hypoglycemia have been shown to blunt or completely prevent the secretion of counter-regulatory hormones, termed as “hypoglycaemia-associated autonomic failure”.(89,90)”
A Potential Important Role of Skeletal Muscle in Human Counterregulation of Hypoglycemia
Meyer, C., Saar, P., Soydan, N., Eckhard, M., Bretzel, R. G., Gerich, J. E., & Linn, T. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0225 · Cited by 24 · see citing works
Pyruvate Administration Reduces Recurrent/Moderate Hypoglycemia-Induced Cortical Neuron Death in Diabetic Rats
Choi, B. Y., Kim, J. H., Kim, H. J., Yoo, J. H., Song, H. K., Sohn, M., Won, S. J., & Suh, S. W. (2013) · PLoS ONE · doi:10.1371/journal.pone.0081523 · Cited by 23 · see citing works
Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglycemia
Matveyenko, A. V., Bohland, M., Saberi, M., & Donovan, C. M. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00283.2007 · Cited by 22 · see citing works
“Inappropriately low epinephrine and glucagon responses to hypoglycemia have been identified as the critical pathophysiological events in T1DM, because in the absence of glucagon secretion, epinephrine constitutes a primary defense against hypoglycemia (6, 8).”
Background
Hypoglycaemia and its management in primary care setting
Ibrahim, M., Baker, J., Cahn, A., Eckel, R. H., El Sayed, N. A., Fischl, A. H., Gaede, P., Leslie, R. D., Pieralice, S., Tuccinardi, D., et al. (2020) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.3332 · Cited by 21 · see citing works
“arising a vicious cycle where hypoglycaemic events lead to more episodes of hypoglycaemia, which describes the concept of hypoglycaemia-associated autonomic failure (HAAF).(20) This mechanism causes a higher recurrence of severe iatrogenic hypoglycaemia.”
Background
Nicotinic Induction of Preproenkephalin and Tyrosine Hydroxylase Gene Expression in Butyrate-Differentiated Rat PC12 Cells: A Model for Adaptation to Gut-Derived Environmental Signals
Nankova, B. B., Chua, J., Mishra, R., Kobasiuk, C. D., & Gamma, E. F. L. (2003) · Pediatric Research · doi:10.1203/00006450-200301000-00019 · Cited by 22 · see citing works
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 · see citing works
2. Hypoglycemia Detection
Routh, V. H., Donovan, C. M., & Ritter, S. (2012) · Translational endocrinology & metabolism · doi:10.1210/team.9781936704200.ch2 · Cited by 19 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
“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 16 · see citing works
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 15 · see citing works
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 · see citing works
“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 · see citing works
Glycemia-Induced miRNA Changes: A Review
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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 · see citing works
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“23”
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“…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
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Background
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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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