Effect of Antecedent Hypoglycemia on Cognitive Function and on Glycemie Thresholds for Counterregulatory Hormone Secretion in Healthy Humans
Abstract
OBJECTIVE: To determine whether reduced hormonal, symptomatic, and/or cognitive responses to hypoglycemia are caused by an increase in the plasma glucose concentration required to stimulate these counterregulatory parameters after antecedent hypoglycemia. RESEARCH DESIGN AND METHODS: We studied nine healthy volunteers during stepped hypoglycemia clamps (plasma glucose targets from 80 to 50 mg/dl in 10 mg/dl steps) on two separate days. The study was preceded either by a 2-h period of hypoglycemia (plasma glucose 58 +/- 2 mg/dl) or a 2-h period of euglycemia (plasma glucose 94 +/- 2 mg/dl) for 90 min. RESULTS: The plasma glucose that triggered secretion of plasma norepinephrine (NE) was lower after antecedent hypoglycemia (control = 74 +/- 2 and experimental = 67 +/- 2 mg/dl, respectively, P < 0.005). In contrast, a relatively higher plasma glucose stimulated secretion of other counterregulatory hormones after antecedent hypoglycemia: growth hormone (GH) (65 +/- 2 to 72 +/- 2 mg/dl, P < 0.01); glucagon (63 +/- 2 to 70 +/- 2 mg/dl, P < 0.01); and epinephrine (EPI) (68 +/- 2 to 76 +/- 2 mg/dl, P < 0.01) when comparing control days with experimental days. Hypoglycemic symptoms were first observed at a plasma glucose plateau of 59 +/- 2 mg/dl. Motor function reflected by Digit Symbol Substitution deteriorated equally whether there had been antecedent hypoglycemia or euglycemia. Logical (immediate) memory deteriorated in the control study at a plasma glucose of 54 +/- 2 mg/dl but remained unchanged at equivalent hypoglycemia in the experimental study (P < 0.03). CONCLUSIONS: Our conclusions are as follows: 1) symptoms of moderate hypoglycemia occur at plasma glucose levels averaging approximately 5-15 mg/dl lower than the plasma glucose concentrations required to trigger counterregulatory hormone release; 2) after acute antecedent hypoglycemia, glucagon, EPI, and GH secretion occur at higher plasma glucose concentrations and NE is released at lower plasma glucose concentrations; and 3) there may be CNS adaptation to prior hypoglycemia reflected in preservation of logical memory function at plasma glucose levels of approximately 50 mg/dl. These findings suggest that thresholds for hormone secretion and for changes in cognitive function can be altered very acutely by foregoing hypoglycemia in healthy humans.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A total of 25 studies (40%) provided data to either calculate or extract the glycaemic threshold for symptom responses to hypoglycaemia.
“A total of 25 studies (40%) provided data to either calculate or extract the glycaemic threshold for symptom responses to hypoglycaemia [6, 13, 16–18, 20, 23, 24, 26, 29, 31, 33–37, 46, 51–53, 56, 57, 58, 63, 68].”
From Glycaemic thresholds for counterregulatory hormone and symptom responses to hypoglycaemia in people with and without type 1 diabetes: a systematic review (2022) · cites this paper as [23]
A longer euglycemic period between hypoglycemic episodes is required to elicit HAAF.
“This is not surprising, given the short interval between the 2 episodes of hypoglycemia, and is consistent with prior observation that a longer euglycemic period between hypoglycemic episodes is required to elicit HAAF (20, 24, 25).”
From Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure (2020) · cites this paper as [20]
Cited by
Sorted by citations
Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes
Geddes, J., Schopman, J. E., Zammitt, N. N., & Frier, B. M. (2008) · Diabetic Medicine · doi:10.1111/j.1464-5491.2008.02413.x · Cited by 387 · see citing works
Symptoms of hypoglycaemia in people with diabetes
McAulay, V., Deary, I. J., & Frier, B. M. (2001) · Diabetic Medicine · doi:10.1046/j.1464-5491.2001.00620.x · Cited by 264 · see citing works
Hypoglycaemia and cognitive function
Warren, R. E., & Frier, B. M. (2004) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2004.00421.x · Cited by 219 · see citing works
Impact of rapid weight loss on cognitive function in collegiate wrestlers
Choma, C., Sforzo, G. A., & Keller, B. A. (1998) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-199805000-00016 · Cited by 138 · see citing works
Draelos, M. T., Jacobson, A. M., Weinger, K., Widom, B., Ryan, C. M., Finkelstein, D. M., & Simonson, D. C. (1995) · The American Journal of Medicine · doi:10.1016/s0002-9343(99)80397-0 · Cited by 117 · see citing works
Strachan, M. W., Deary, I. J., Ewing, F. M., & Frier, B. M. (2000) · Diabetes Care · doi:10.2337/diacare.23.3.305 · Cited by 113 · see citing works
Visual information processing during controlled hypoglycaemia in humans
McCrimmon, R. J., Deary, I. J., Huntly, B. J. P., MacLeod, K. J., & Frier, B. M. (1996) · Brain · doi:10.1093/brain/119.4.1277 · Cited by 93 · see citing works
“This has been demonstrated and quantified in studies using a variety of neuropsychological (Holmes et al., 1983, 1984, 1986: Pramming et al., 1986; Heller et al., 1987; Hoffman et al., 1989; Stevens et al., 1989; Blackman et al., 1990; Widom and Simonson 1990; Mitrakou et al., 1991; Cox et al., 1993a; Gonder-Frederick…”
Davis, S. N., Shavers, C., & Costa, F. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.5.e1054 · Cited by 86 · see citing works
“The experimental methodology used to measure glycemic thresholds has differed in previous studies (4, 7, 27, 29, 32).”
MethodResultModulation of Hunger by Plasma Glucose and Metformin
Schultes, B., Oltmanns, K. M., Kern, W., Fehm, H. L., Jan Born, A., & Peters, A. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-021450 · Cited by 81 · see citing works
Effects of Glycemic Control on Protective Responses Against Hypoglycemia in Type 2 Diabetes
Korzon-Burakowska, A., Hopkins, D., Matyka, K., Lomas, J., Pernet, A., Macdonald, I., & Amiel, S. (1998) · Diabetes Care · doi:10.2337/diacare.21.2.283 · Cited by 71 · see citing works
“It has been shown that the magnitude of such responses is influenced by previous hypoglycemic experience, and that even one or two episodes of hypoglycemia can blunt subsequent responses for several days (1-7).”
BackgroundAdaptation of cognitive function to hypoglycemia in healthy men.
Fruehwald‐Schultes, B., Jan Born, A., Kern, W., Peters, A., & Fehm, H. L. (2000) · Diabetes Care · doi:10.2337/diacare.23.8.1059 · Cited by 68 · see citing works
Delayed Recovery of Cognitive Function Following Hypoglycemia in Adults With Type 1 Diabetes
Zammitt, N. N., Warren, R. E., Deary, I. J., & Frier, B. M. (2008) · Diabetes · doi:10.2337/db07-0695 · Cited by 61 · see citing works
“5 [22-43] years) compared to the NHA group (29 [19-44] years; p<0.”
BackgroundWagner, V. M., Grabert, M., & Holl, R. W. (2004) · European Journal of Pediatrics · doi:10.1007/s00431-004-1560-4 · Cited by 60 · see citing works
“unawareness and defective counter regulation [7, 9,23].”
Hypoglycemia in diabetes: common, often unrecognized.
Gabriely, I., & Shamoon, H. (2004) · Cleveland Clinic Journal of Medicine · doi:10.3949/ccjm.71.4.335 · Cited by 58 · see citing works
Self-citationHormones and Cognition: Current Concepts and Issues in Neuropsychology
Erlanger, D. M., Kutner, K. C., & Jacobs, A. R. (1999) · Neuropsychology Review · doi:10.1023/a:1021634622577 · Cited by 48 · see citing works
Vele, S., Milman, S., Shamoon, H., & Gabriely, I. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1723 · Cited by 47 · see citing works
“The methods for measurement of plasma insulin, C-peptide, glucagon, cortisol, and their intra- and interassay variations have been previously reported (13).”
MethodSelf-citationBeck, R. W., Bergenstal, R. M., Riddlesworth, T. D., & Kollman, C. (2019) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2018.0362 · Cited by 42 · 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
“The methods for measurement of plasma insulin, C-peptide, glucagon, cortisol, and their intra- and interassay variations have been previously reported (17).”
Self-citationVerhulst, C. E. M., Fabricius, T. W., Teerenstra, S., Kristensen, P. L., Tack, C. J., McCrimmon, R. J., Heller, S., Evans, M. L., Amiel, S. A., Pedersen-Bjergaard, U., et al. (2022) · Diabetologia · doi:10.1007/s00125-022-05749-8 · Cited by 34 · see citing works
Principles of Rapid Weight Loss in Female Sambo Athletes
Todorović, N., Ranisavljev, M., Tapavički, B., et al. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph182111356 · Cited by 31 · see citing works
“These explanations include the systematic effects of dehydration, hyperglycemia, and affective changes to memory and cognitive perception [11,24,25].”
BackgroundShift of glycaemic thresholds for cognitive function in hypoglycaemia unawareness in humans
Fanelli, C. G., Pampanelli, S., Porcellati, F., & Bolli, G. B. (1998) · Diabetologia · doi:10.1007/s001250050974 · Cited by 31 · see citing works
“In contrast, a single episode of hypoglycaemia lasting 56 h, was induced in non-diabetic subjects in the study by Boyle et al. [9], whereas other studies induced only one episode of hypoglycaemia for only 2 h [8, 17 ].”
BackgroundMANAGEMENT OF HYPOGLYCEMIA AND DIABETIC KETOACIDOSIS IN PREGNANCY
Whiteman, V. E., Homko, C. J., & Reece, E. A. (1996) · Obstetrics and Gynecology Clinics of North America · doi:10.1016/s0889-8545(05)70246-1 · Cited by 30 · see citing works
Differential adaptation of neurocognitive brain functions to recurrent hypoglycemia in healthy men
Schultes, B., Kern, W., Oltmanns, K. M., Peters, A., Gais, S., Fehm, H. L., & Jan Born, A. (2004) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2004.06.007 · Cited by 26 · see citing works
“Several studies reported on recovered cognitive functions during recurrent hypoglycemia in comparison with performance during antecedent hypoglycemia (Veneman et al., 1993; Mellman et al., 1994; Ovalle et al., 1998; Fanelli et al., 1998; Fruehwald-Schultes et al., 2000) others, however, failed (Lingenfelser et al.”
ResultThe role of glycemia in insulin resistance in youth with type 1 and type 2 diabetes
Chan, C. L., Pyle, L. L., Morehead, R., Baumgartner, A., Cree‐Green, M., & Nadeau, K. J. (2016) · Pediatric Diabetes · doi:10.1111/pedi.12422 · Cited by 25 · see citing works
Opioid receptor activation impairs hypoglycemic Counterregulation in humans
Carey, M., Gospin, R., Goyal, A., Tomuta, N., Sandu, O., Mbanya, A., Lontchi-Yimagou, E., Hulkower, R., Shamoon, H., Gabriely, I., et al. (2017) · Diabetes · doi:10.2337/db16-1478 · Cited by 23 · see citing works
“Measurements of plasma insulin, C-peptide, glucagon, and cortisol concentrations were measured by radioimmunoassay in the Diabetes Research Center Hormone Assay Core, as previously reported (19).”
Self-citationImpaired Awareness of Hypoglycaemia
Frier, B. M. (2007) · Hypoglycaemia in Clinical Diabetes · doi:10.1002/9780470516270.ch7 · Cited by 22 · see citing works
Beck, R. W., & Bergenstal, R. M. (2021) · Diabetes Spectrum · doi:10.2337/ds20-0090 · Cited by 21 · see citing works
Plasma Glucose Alone Does Not Predict Neurologic Dysfunction in Hypoglycemic Nondiabetic Subjects
Osorio, I., Arafah, B., Mayor, L. C., & Tröster, A. I. (1999) · Annals of Emergency Medicine · doi:10.1016/s0196-0644(99)70365-3 · Cited by 21 · see citing works
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-citationOpioid Receptor Blockade Prevents Exercise-Associated Autonomic Failure in Humans
Milman, S., Leu, J. P., Shamoon, H., Vele, S., & Gabriely, I. (2012) · Diabetes · doi:10.2337/db11-1622 · Cited by 17 · see citing works
“The methods for measurement of plasma insulin, C-peptide, glucagon, cortisol, and their intra- and interassay variations have been previously reported (20).”
MethodSelf-citationMilman, S., Leu, J. P., Shamoon, H., Vele, S., & Gabriely, I. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1391 · Cited by 17 · see citing works
Self-citationHypoglycemia Induced by Insulin as a Triggering Factor of Cognitive Deficit in Diabetic Children
Vilela, V. R., Marques, A. D. C. R., Schamber, C. R., & Bazotte, R. B. (2014) · The Scientific World JOURNAL · doi:10.1155/2014/616534 · Cited by 17 · see citing works
“This phenomenon, also present in children [6, 7], which may be detected from the moment of the second episode of hypoglycemia [8, 9], has mechanisms which are not yet completely understood [10] and may disappear as adjustments in treatment to avoid the occurrence of new episodes of hypoglycemia [11, 12].”
BackgroundIn-Season Physiological and Biochemical Status of Reforestation Workers
Roberts, D. (2002) · Journal of Occupational and Environmental Medicine · doi:10.1097/00043764-200206000-00019 · Cited by 12 · see citing works
“0 mmol/L.(15) The expected correlation between cortisol levels and blood glucose levels was observed in the current study (r 0.”
BackgroundKaffel, N., Chakroun, E., Dammak, M., Mnif, M. F., Smaoui, M., Charfi, N., Bayrouti, I., & Abid, M. (2007) · Annales d Endocrinologie · doi:10.1016/j.ando.2007.02.007 · Cited by 10 · see citing works
Roberts, D. (2013) · BioMed Research International · doi:10.1155/2013/121832 · Cited by 9 · see citing works
“Hindawi Publishing Corporation BioMed Research International Volume 2013, Article ID 121832, 12 pages http://dx.doi.org/10.1155/2013/121832”
InfluentialAwakening from Sleep and Hypoglycemia in Type 1 Diabetes Mellitus
Gabriely, I., & Shamoon, H. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040099 · Cited by 9 · see citing works
“As shown experimentally in people without diabetes, recurrent and/or recent episodes of hypoglycemia are associated with reduced sympathoadrenal (epinephrine and norepinephrine), symptomatic, and cognitive responses to subsequent hypoglycemia, impairing all of the defense mechanisms required for prevention and reversa…”
Self-citationImpaired Awareness of Hypoglycaemia
Frier, B. M. (2013) · Wiley eBooks · doi:10.1002/9781118695432.ch6 · Cited by 10 · see citing works
Aleksić, S., Lontchi‐Yimagou, E., Mitchell, W. G., Boyle, C., Matias, P., Manavalan, A. D., Goyal, A., Carey, M., Gabriely, I., & Hawkins, M. A. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae479 · Cited by 6 · see citing works
Effect of Near Physiologic Insulin Therapy on Hypoglycemia Counterregulation in Type-1 Diabetes
Bischof, M. G., Bernroider, E., Ludwig, C., Kurzemann, S., Kletter, K., Waldhäusl, W., & Roden, M. (2001) · Hormone Research in Paediatrics · doi:10.1159/000048111 · Cited by 5 · see citing works
Svensson, C. H., Fabricius, T. W., Verhulst, C. E. M., Tack, C. J., Kristensen, P. L., de Galan, B. E., & Pedersen‐Bjergaard, U. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.16587 · Cited by 4 · see citing works
“10 – 15 Instead, in the present analysis of people with type 1 diabetes, we used the advantage of CGM to capture exposure to antecedent hypoglycaemia experienced in real life up to 1 week before clamp participation.”
Galderisi, A., Kariyawasam, D., Stoupa, A., Quoc, A. N., Pinto, G., Viaud, M., Brabant, S., Beltrand, J., Polak, M., & Samara‐Boustani, D. (2023) · European Journal of Endocrinology · doi:10.1093/ejendo/lvad147 · Cited by 3 · see citing works
The effect of rapid weight loss on cognitive function in collegiate wrestlers
Choma, C. (1995) · Digital Collections - Ithaca College Library (Ithaca College) · Cited by 2 · see citing works
Insulin, glucagon, and oral hypoglycemic drugs
Krans, H. M. J. (1994) · Side effects of drugs annual · doi:10.1016/s0378-6080(05)80287-9 · Cited by 1 · see citing works
Ryan, C. M. (2002) · Elsevier eBooks · doi:10.1016/b978-012532104-4/50102-5
- Authors
- Mellman, M. J., Davis, M. R., Brisman, M., & Shamoon, H.
- Affiliations
- Albert Einstein College of Medicine (US)
- ORCID
- Shamoon, Harry
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 1994-03-01
- Volume
- 17
- Issue
- 3
- Pages
- 183-188
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- OpenAlex
- W2015448905
- Cited by
- 44
- References
- 0
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2014: 1 · 2013: 2 · 2012: 1
- FWCI
- 1.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes Care (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- National Institutes of Health (5r01dk036617-03)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-36617, DK20541)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- counterregulatory hormones, plasma glucose, norepinephrine, growth hormone, glucagon, epinephrine, hypoglycemic symptoms, cognitive function, memory, motor function, normoglycemia, healthy volunteers, hypoglycemia
- MeSH terms
- Insulin Secretion, Adult, Blood Glucose, Cognition, Epinephrine, Fatty Acids, Nonesterified, Female, Glucagon, Humans, Hypoglycemia, Insulin, Male, Memory, Norepinephrine, Reference Values, Glucose Clamp Technique
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.
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 ›
Are you an author, or do you see a problem with this page? Request a review
