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Effect of Hyperketonemia and Hyperlacticacidemia on Symptoms, Cognitive Dysfunction, and Counterregulatory Hormone Responses During Hypoglycemia in Normal Humans
Abstract
The brain usually depends almost exclusively on glucose for its energy requirements. During hypoglycemia associated with prolonged fasting or strenuous exercise, circulating ketone-body and lactate levels increase severalfold; in both situations, certain signs and symptoms of hypoglycemia are diminished. Therefore, to test the hypothesis that hyperketonemia or hyperlacticacidemia of the magnitude seen during certain clinical situations can substitute for glucose as an energy source for the brain and alter physiological responses to hypoglycemia, we assessed autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive function during standardized insulin-induced hypoglycemia in normal volunteers with and without infusion of (β-hydroxybutyrate (BOHB) or lactate designed to reproduce circulating levels of these substrates seen during prolonged fasting and strenuous exercise. Compared with paired control experiments, infusion of BOHB and lactate increased the glycemic threshold (required greater hypoglycemia for initiation) and reduced the magnitude of autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive dysfunction (all P < 0.05). The hypoglycemic threshold for autonomic symptoms increased from 3.8 ± 0.1 to 3.1 ± 0.2 mmoM during BOHB infusion and from 3.7 ± 0.1 to 2.8 ± 0 . 1 mmol<1 during lactate infusion, and the threshold for neuroglycopenic symptoms increased from 2.8 ± 0.1 to 2.4 ± 0.1 and 2.3 ± 0.1 mmol/1, respectively. The magnitude for autonomic symptoms decreased from 12 ± 2 and 11 ± 1 to 6 ± 2 and 4 ± 1 during BOHB and lactate infusion, respectively. Neuroglycopenic symptoms decreased from 11 ± 2 to 3 ± 1 during both series of experiments. Infusion of BOHB and lactate-reduced responses for all counterregulatory hormones, the reduction being the greatest for epinephrine (∼57 and 73%, during BOHB and lactate infusion, respectively) and least for cortisol (7sim;28 and 29%, respectively). These results indicate that under certain clinical conditions, BOHB and lactate may substitute for glucose as a fuel for the brain and alter physiological responses to hypoglycemia.
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“Although the brain has an obligate requirement for glucose, it also can use plasma ketones and lactate as energy sources if the concentrations of these substances are sufficiently elevated.14”
From Recommendations from the Pediatric Endocrine Society for evaluation and management of persistent hypoglycemia in neonates, infants, and children (2015) · cites this paper as [14]
In the citing paper
“The consumption of caffeine in either the fed or fasted state appears to influence the appearance of caffeine in the circulation 62”
From Half-time strategies to enhance second-half performance in team-sports players: A review and recommendations (2015) · cites this paper as [62]
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“Under insulin clamp conditions, thresholds for counter-regulatory hormone responses, hypoglycemic symptoms, and cognitive dysfunction are all reduced to lower glucose concentrations by infusions of either -HOB or lactate (46).”
BackgroundThornton, P. S., Stanley, C. A., De Leon, D. D., Harris, D., Haymond, M. W., Hussain, K., Levitsky, L. L., Murad, M. H., Rozance, P. J., Simmons, R. A., et al. (2015) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2015.03.057 · Cited by 625
“Although the brain has an obligate requirement for glucose, it also can use plasma ketones and lactate as energy sources if the concentrations of these substances are sufficiently elevated.(14) However, in hypoketotic conditions, such as hyperinsulinism or fatty acid oxidation disorders, ketones and lactate are not av…”
BackgroundBrain fuel metabolism, aging, and Alzheimer’s disease
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“More-over, during hypoglycemia, cognitive function is improved when lactate is infused in a similar manner to hyperketonemia (King et al , 1998, 1997; Maran et al , 1994; Veneman et al , 1994).”
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“This results in an excess of acetyl-CoA, and in turn the rapid production of ketones (10), an energy source for the brain (3,5,7).”
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BackgroundSandoval, 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 135
“It has been previously shown that prior peripheral infusion of lactate or -hydroxybutyrate in humans (39) and intracerebroventricular infusion of lactate in rats (40) significantly reduced counterregulatory responses to hypoglycemia.”
BackgroundIncreased Brain Monocarboxylic Acid Transport and Utilization in Type 1 Diabetes
Mason, G. F., Petersen, K. F., Lebon, V., Rothman, D. L., & Shulman, G. I. (2006) · Diabetes · doi:10.2337/diabetes.55.04.06.db05-1325 · Cited by 130
“Several studies (27,28,31,32) of insulin-induced hypoglycemia make lactate in particular a prime candidate.”
Local Lactate Perfusion of the Ventromedial Hypothalamus Suppresses Hypoglycemic Counterregulation
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Central mechanisms of glucose sensing and counterregulation in defense of hypoglycemia
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“In humans, insulin-induced hypoglycemia with infusion of βhydroxybutyrate improved cognitive functioning in healthy subjects (Veneman et al., 1994) and hyperketonemiaameliorated cognition in memory-impaired subjects as well (Krikorian et al., 2012; Henderson and Poirier, 2011; Henderson et al.,…”
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“Different interesting works have emphasized a role of lactate in the brain as a protective substrate not only in animal studies [4,21–23], but also in humans [10,13].”
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“Ketones also prevent symptoms of experimental hypoglycemia in adults, including anxiety, fainting, hunger, irritability, and tremor (1, 39).”
BackgroundExercise hypoglycemia in nondiabetic subjects.
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“2007), and lactate also appears to play a role in memory formation (Veneman et al. 1994; Berthet et al. 2009; Suzuki et al. 2011).”
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“Ethanol administration may also increase circulating acetate levels, which by itself may modulate the counterregulatory response to hypoglycemia (27).”
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“Such findings stimulated the first investigations in humans that demonstrated that infusion of exogenous lactate or ketones could partially attenuate the counterregulatory response associated with insulin-induced hypoglycemia and help prevent cerebral dysfunction in type 1 diabetes, presumably through increased lactat…”
BackgroundKetones: potential to achieve brain energy rescue and sustain cognitive health during ageing
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“Other authors have proposed the production of alternative brain fuels; however, neither the nature nor the existence of a second adaptive mechanism is clear [42, 43 ].”
BackgroundWiegers, E. C., Rooijackers, H. M. M., Tack, C. J., Heerschap, A., de Galan, B. E., & van der Graaf, M. (2016) · Diabetes · doi:10.2337/db16-0068 · Cited by 43
“Administration of lactate during hypoglycemia impairs hypoglycemic symptoms, attenuates counterregulatory hormone responses, and preserves cognitive function, mirroring the changes seen in subjects with IAH (11,12).”
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“Therefore, in contrast to the role of other non-glucose substrates such as lactate (19) and ketones (20) amino acids limit their effect only to cognitive function.”
BackgroundResultInfluentialEffects of β-hydroxybutyrate on cognition in patients with type 2 diabetes
Jensen, N. J., Nilsson, M., Ingerslev, J. S., Olsen, D. A., Fenger, M., Svart, M. V., Møller, N., Zander, M., Miskowiak, K. W., & Rungby, J. (2019) · European Journal of Endocrinology · doi:10.1530/eje-19-0710 · Cited by 40
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“An increase in brain lactate oxidation during hypoglycemia has been suggested to preserve brain metabolism (10,12).”
BackgroundResultPatients with type 1 diabetes exhibit altered cerebral metabolism during hypoglycemia
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“Indeed, intravenous administration of both lactate and b-hydroxybutyrate during hypoglycemia has been shown to decrease symptoms, cognitive dysfunction, and hormonal counterregulation in healthy subjects (42).”
BackgroundFrom 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 37
Schultes, B., Schmid, S. M., Wilms, B., Jauch‐Chara, K., Oltmanns, K. M., & Hallschmid, M. (2012) · Appetite · doi:10.1016/j.appet.2012.01.022 · Cited by 31
Evans, M. L., Matyka, K. A., Lomas, J., Pernet, A., CRANSTON, I. C., Macdonald, I. A., & Amiel, S. A. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.8.4937 · Cited by 30
“Finally, previous studies in which BOB has been shown to have an effect have shown an equivalent alteration of thresholds for neurohumoral responses and cognitive dysfunction (6, 7).”
BackgroundMethodResultInfluentialGlucose Homeostasis – Mechanism and Defects
Szablewski, L. (2011) · InTech eBooks · doi:10.5772/22905 · Cited by 34
Cognitive Impairment in Patients with Type 1 (Insulin-Dependent) Diabetes Mellitus
Weinger, K., & Jacobson, A. M. (1998) · CNS Drugs · doi:10.2165/00023210-199809030-00006 · Cited by 28
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
“This is in contrast to wholebody ketone infusions, which have previously been shown to suppress the counterregulatory responses to insulininduced hypoglycemia (16).”
BackgroundResultInfluentialWiegers, E. C., Rooijackers, H. M. M., Tack, C. J., Groenewoud, H., Heerschap, A., de Galan, B. E., & van der Graaf, M. (2017) · Diabetes · doi:10.2337/db17-0794 · Cited by 28
“This concept is supported by the finding that intravenous administration of lactate has brain glucose–sparing effects under euglycemic conditions (7), suppresses counterregulatory hormone and symptom responses to hypoglycemia, and preserves cognitive function (8,9).”
BackgroundThe role of hepatic portal glucose sensing in modulating responses to hypoglycaemia in man
Smith, D., Pernet, A., Reid, H., Bingham, E., Rosenthal, J., Macdonald, I. A., Umpleby, A. M., & Amiel, S. A. (2002) · Diabetologia · doi:10.1007/s00125-002-0909-3 · Cited by 27
“sponse to experimental hypoglycaemia when non-glucose metabolic fuels are available to replace the glucose [6, 7].”
BackgroundDoes Insulin Therapy for Type 1 Diabetes Mellitus Protect Against Alzheimer's Disease?
Rdzak, G. M., & Abdelghany, O. (2014) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.1494 · Cited by 25
Wiegers, E. C., Rooijackers, H. M. M., Tack, C. J., Philips, B. W. J., Heerschap, A., van der Graaf, M., & de Galan, B. E. (2018) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x18775884 · Cited by 25
Using positron emission tomography to study human ketone body metabolism: A review
Bouteldja, N., Andersen, L. T., Møller, N., & Gormsen, L. C. (2014) · Metabolism · doi:10.1016/j.metabol.2014.08.001 · Cited by 24
The Prevention and Correction of Hypoglycemia
Cryer, P. E. (2001) · Comprehensive Physiology · doi:10.1002/cphy.cp070235 · Cited by 23
Self-citationA Systematic Review of Intravenous β-Hydroxybutyrate Use in Humans – A Promising Future Therapy?
White, H. T., Heffernan, A. J., Worrall, S., Grunsfeld, A., & Thomas, M. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.740374 · Cited by 26
Rise of ketone bodies with psychosocial stress in normal weight men
Kubera, B., Hubold, C., Wischnath, H., Zug, S., & Peters, A. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.03.008 · Cited by 25
Evans, M. L., Hopkins, D., Macdonald, I. A., & Amiel, S. A. (2004) · Diabetic Medicine · doi:10.1111/j.1464-5491.2004.01174.x · Cited by 22
Porcellati, F., Pampanelli, S., Rossetti, P., Cordoni, C., Marzotti, S., Scionti, L., Bolli, G. B., & Fanelli, C. G. (2003) · Diabetes · doi:10.2337/diabetes.52.11.2774 · Cited by 23
“Although -hydroxybutyrate, amino acids, and lactate might have, at least in part, served as fuel for the brain (38), in the present studies responses of counterregulatory hormones glucagon and adrenaline were potentiated, and those of symptoms were not reduced with the exception of hunger (discussed previously).”
BackgroundKojima, K., Ishikawa, H., Watanabe, S., Nosaka, N., & Mutoh, T. (2023) · Nutrients · doi:10.3390/nu15143275 · Cited by 24
“In studies that administered MCFAs to type 1 diabetes patients to induce cognitive impairment by forcibly lowering blood glucose levels and intravenously administered ketone bodies to healthy individuals to induce cognitive impairment using the same method, a significant reduction in cognitive impairment was observed…”
MethodHerbel, G., & Boyle, P. J. (2000) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(05)70161-4 · Cited by 20
Hypoglycaemia in diabetes mellitus - protecting the brain
Amiel, S. A. (1997) · Diabetologia · doi:10.1007/s001250051404 · Cited by 21
“These studies provide an explanation for the clinical presentation of ketotic hypoglycaemic states in childhood [32]; however, except in the special circumstances of inborn errors of metabolism, ketones are unlikely to provide a useful therapeutic manoeuvre for protecting cerebral function during hypoglycaemia in phar…”
BackgroundLactate infusion as therapeutical intervention: a scoping review
van Gemert, L. A., de Galan, B. E., Wevers, R. A., ter Heine, R., & Willemsen, M. A. A. P. (2022) · European Journal of Pediatrics · doi:10.1007/s00431-022-04446-3 · Cited by 19
“Several studies showed that lactate administration suppresses the counterregulatory hormone and symptom responses to hypoglycemia [19, 20, 23, 25], whereas a fall in brain lactate concentration during hypoglycemia among people with type 1 diabetes and impaired awareness of hypoglycemia also suggests lactate consumptio…”
BackgroundTreatment and Prevention of Hypoglycemia and its Unawareness in Type 1 Diabetes Mellitus
Bolli, G. B. (2003) · Reviews in Endocrine and Metabolic Disorders · doi:10.1023/a:1027397911746 · Cited by 21
“In fact, although in theory the brain can oxidize ketones [5] and lactate [6], this occurs in humans only under experimental hypoglycemia conditions where supraphysiological concentrations of these substrates are produced in plasma by means of exogenous infusion.”
Background
Metadata
- Authors
- Veneman, T., Mitrakou, A., Mokan, M., Cryer, P., & Gerich, J.
- Affiliations
- General Clinical Research Center Pittsburgh, Pennsylvania
- University of Pittsburgh (US)
- University of Rochester Medicine (US)
- ORCID
- Mitrakou, Asimina
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1994-11-01
- Volume
- 43
- Issue
- 11
- Pages
- 1311-1317
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2158679643
- Cited by
- 163
- References
- 0
- Citations by year
- 2026: 3 · 2025: 6 · 2023: 5 · 2022: 5 · 2021: 7 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 7 · 2015: 6 · 2014: 6 · 2013: 8 · 2012: 5
- FWCI
- 1.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Center for Research Resources (RR-00044, M01RR000056, M01RR000044, 5 MO1 RR 00056, RR.00036)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Physiology (medical) › Diet and metabolism studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Keywords
- hyperketonemia, hypoglycemia, beta-hydroxybutyrate, lactate, brain glucose metabolism, counterregulatory hormones, epinephrine, cortisol, autonomic symptoms, neuroglycopenic symptoms, cognitive impairment, insulin-induced hypoglycemia, ketone bodies, prolonged fasting, physical activity, glycemic thresholds
- MeSH terms
- Adult, Blood Glucose, Cognition, Female, Hormones, Humans, Hydroxybutyrates, Hypoglycemia, Infusions, Intravenous, Insulin, Ketone Bodies, Lactates, Male, Reference Values, Lactic Acid, 3-Hydroxybutyric Acid
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