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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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Loucks, A. B., & Thuma, J. R. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-020369 · Cited by 760
“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
Cunnane, S. C., Nugent, S., Roy, M., Courchesne‐Loyer, A., Croteau, É., Tremblay, S., Castellano, A., Pifferi, F., Bocti, C., Paquet, N., et al. (2010) · Nutrition · doi:10.1016/j.nut.2010.07.021 · Cited by 633
Blood lactate is an important energy source for the human brain.
van Hall, G., Stømstad, M., Rasmussen, P., Jans, Ø., Zaar, M., Gam, C., Quistorff, B., Secher, N. H., & Nielsen, H. B. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2009.35 · Cited by 522
“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).”
BackgroundEffects of β-hydroxybutyrate on cognition in memory-impaired adults
Reger, M. A., Henderson, S. T., Hale, C. M., Cholerton, B., Baker, L. D., Watson, G. S., Hyde, K., Chapman, D., & Craft, S. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(03)00087-3 · Cited by 510
“In humans, ketone infusion delays and reduces hormonal responses to acute hypoglycemia [1] and improves cognitive functioning [18].”
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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