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.
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?
The brain can use plasma ketones and lactate as energy sources if their concentrations are sufficiently elevated.
“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]
The consumption of caffeine in either the fed or fasted state appears to influence the appearance of caffeine in the circulation.
“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]
Cited by
Sorted by citations
Loucks, A. B., & Thuma, J. R. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-020369 · Cited by 760 · see citing works
“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 · see citing works
“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 607 · see citing works
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 · see citing works
“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 · see citing works
“In humans, ketone infusion delays and reduces hormonal responses to acute hypoglycemia [1] and improves cognitive functioning [18].”
BackgroundThe selfish brain: Competition for energy resources
Peters, A., Schweiger, U., Pellerin, L., Hubold, C., Oltmanns, K. M., Conrad, M., Schultes, B., Born, J., & Fehm, H. L. (2004) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2004.03.002 · Cited by 489 · see citing works
Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases
Jensen, N. J., Wodschow, H. Z., Nilsson, M., & Rungby, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228767 · Cited by 450 · see citing works
“, greater hypoglycemia was required for initiation) [59,60].”
BackgroundMechanisms of hypoglycemia-associated autonomic failure in diabetes
Cryer, P. E. (2013) · New England Journal of Medicine · doi:10.1056/nejmra1215228 · Cited by 433 · see citing works
Self-citationLactate kinetics in human tissues at rest and during exercise
van Hall, G. (2010) · Acta Physiologica · doi:10.1111/j.1748-1716.2010.02122.x · Cited by 346 · see citing works
Lactic Acid: No Longer an Inert and End-Product of Glycolysis
Sun, S., Li, H., Chen, J., & Qian, Q. (2017) · Physiology · doi:10.1152/physiol.00016.2017 · Cited by 319 · see citing works
“In line with these observations, cognitive function can be improved in the setting of hypoglycemia by lactate infusion (77, 78, 100, 137).”
BackgroundLactate: A Preferred Fuel for Human Brain Metabolism in Vivo
Smith, D., Pernet, A., Hallett, W. A., Bingham, E., Marsden, P. K., & Amiel, S. A. (2003) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/01.wcb.0000063991.19746.11 · Cited by 282 · see citing works
“…acute hypoglycemia, when elevated either by exercise (Coyle et al., 1986; Felig et al., 1982) or by infusion (King et al., 1998; Maran et al., 1994; Veneman et al., 1994) in human studies, attests to the ability of the lactate to cross the blood–brain barrier in humans and replace glucose as a…”
BackgroundInfluentialLactate as a Metabolite and a Regulator in the Central Nervous System
Proia, P., Liegro, C. M. D., Schiera, G., Fricano, A., & Liegro, I. D. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17091450 · Cited by 280 · see citing works
Cunnane, S. C., Courchesne‐Loyer, A., St‐Pierre, V., Vandenberghe, C., Pierotti, T., Fortier, M., Croteau, E., & Castellano, C. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12999 · Cited by 250 · see citing works
Abi‐Saab, W., Maggs, D. G., Jones, T. W., Jacob, R. J., Srihari, V. H., Thompson, J. L., Kerr, D. E., Leone, P., Krystal, J. H., Spencer, D. D., et al. (2002) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200203000-00004 · Cited by 219 · see citing works
“…lactate is an effective alternate fuel for the central nervous system in human subjects under experimental hypoglycemic conditions, where exogenous lactate infusion has been shown to offset the effects of hypoglycemic neuroglycopenia (Maran et al., 1994; Veneman et al., 1994; King et al., 1997).”
BackgroundResultLactic Acidosis Induced by Metformin
Lalau, J. (2010) · Drug Safety · doi:10.2165/11536790-000000000-00000 · Cited by 221 · see citing works
Cunnane, S. C., Courchesne‐Loyer, A., Vandenberghe, C., St‐Pierre, V., Fortier, M., Hennebelle, M., Croteau, É., Bocti, C., Fülöp, T., & Castellano, C. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00053 · Cited by 224 · 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
Herbel, G., & Boyle, P. J. (2000) · Cited by 199 · see citing works
Dalsgaard, M. K., Quistorff, B., Danielsen, E. R., Selmer, C., Vogelsang, T. W., & Secher, N. H. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.055053 · Cited by 191 · see citing works
“Lactate appears to be a substrate for the brain as reflected by an increased cerebral uptake during cardiopulmonary resuscitation (Rivers et al. 1991), with acute hypoglycaemia in insulin-dependent diabetes mellitus (Avogaro et al. 1990), and in healthy hypoglycaemic subjects (Veneman et al. 1994).”
BackgroundOmega-3 fatty acids, energy substrates, and brain function during aging
Freemantle, E., Vandal, M., Tremblay‐Mercier, J., Tremblay, S., Blachère, J.-C., Bégin, M. E., Brenna, J. T., Windust, A. J., & Cunnane, S. C. (2006) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2006.05.011 · Cited by 172 · see citing works
Neuroendocrine responses to hypoglycemia
Tesfaye, N., & Seaquist, E. R. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05820.x · Cited by 164 · see citing works
Page, K. A., Williamson, A., Yu, N., McNay, E. C., Dzuira, J. D., McCrimmon, R. J., & Sherwin, R. S. (2009) · Diabetes · doi:10.2337/db08-1557 · Cited by 159 · see citing works
“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).”
BackgroundGalassetti, P. R., Tate, D. B., Neill, R. A., Morrey, S., Wasserman, D. H., & Davis, S. N. (2003) · Diabetes · doi:10.2337/diabetes.52.7.1761 · Cited by 146 · see citing works
“The mechanisms responsible for acute counterregulatory failure during repeated hypoglycemia, however, are also speculative and could include prior hypercortisolemia (40), alterations in cerebral glucose extraction (41), and elevations of circulating levels of lactate (42) and ketone bodies (42) during the subsequent s…”
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 134 · see citing works
“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 · see citing works
“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
Borg, M. A., Tamborlane, W. V., Shulman, G. I., & Sherwin, R. S. (2003) · Diabetes · doi:10.2337/diabetes.52.3.663 · Cited by 122 · see citing works
“Specifically, both in vivo and in vitro studies suggest that lactate is readily utilized as a substrate for neurons when glucose is deficient (19,20,25,26).”
Central mechanisms of glucose sensing and counterregulation in defense of hypoglycemia
Stanley, S., Moheet, A., & Seaquist, E. R. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00226 · Cited by 112 · see citing works
Brain glucose and acetoacetate metabolism: a comparison of young and older adults
Nugent, S., Tremblay, S., Chen, K. W., Ayutyanont, N., Roontiva, A., Castellano, C., Fortier, M., Roy, M., Courchesne‐Loyer, A., Bocti, C., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.11.027 · Cited by 113 · see citing works
“Normal brain function can be maintained by ketone infusion during acute, controlled experimental plasma glucose depletion (Amiel et al., 1991; Page and Williamson, 1971; Veneman et al., 1994).”
BackgroundRussell, M., West, D. J., Harper, L. D., Cook, C. J., & Kilduff, L. P. (2015) · Sports Medicine · doi:10.1007/s40279-014-0297-0 · Cited by 111 · see citing works
Effects of antecedent prolonged exercise on subsequent counterregulatory responses to hypoglycemia
Galassetti, P. R., Mann, S. L., Tate, D. B., Neill, R. A., da Costa, F. A. A., Wasserman, D. H., & Davis, S. N. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.280.6.e908 · Cited by 108 · see citing works
Bouzier‐Sore, A., Thiaudière, E., Biran, M., Rouland, R., Canioni, P., & Merle, M. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0750480.x · Cited by 105 · see citing works
“In fact, protection by lactate of cerebral function during hypoglycemia has been demonstrated (Maran et al., 1994; Veneman et al., 1994; King et al., 1997).”
BackgroundMaran, A., Lomas, J., Macdonald, I. A., & Amiel, S. A. (1995) · Diabetologia · doi:10.1007/bf00400601 · Cited by 102 · see citing works
“Onset of both can be delayed during hypoglycaemia by provision of physiological levels of non-glucose substrates for metabolism [30-32], and animal studies localise the site of initiation of counterregulatory responses to the brain [11, 12].”
BackgroundNybo, L., Møller, K., Pedersen, B. K., Nielsen, B., & Secher, N. H. (2003) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2003.01175.x · Cited by 101 · see citing works
Davis, S. N., Mann, S., Galassetti, P., Neill, R. A., Tate, D., Ertl, A. C., & Costa, F. (2000) · Diabetes · doi:10.2337/diabetes.49.11.1897 · Cited by 100 · see citing works
PHYSIOLOGY OF GLUCOSE COUNTERREGULATION TO HYPOGLYCEMIA
Bolli, G. B., & Fanelli, C. G. (1999) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(05)70083-9 · Cited by 99 · see citing works
St‐Pierre, V., Vandenberghe, C., Lowry, C.-M., Fortier, M., Castellano, C., Wagner, J. R., & Cunnane, S. C. (2019) · Frontiers in Nutrition · doi:10.3389/fnut.2019.00046 · Cited by 100 · see citing works
Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia
Herzog, R. I., Jiang, L., Hermán, P., Zhao, C., Sanganahalli, B. G., Mason, G. F., Hyder, F., Rothman, D. L., Sherwin, R. S., & Behar, K. L. (2013) · Journal of Clinical Investigation · doi:10.1172/jci65105 · Cited by 99 · see citing works
McNay, E. C., & Sherwin, R. S. (2004) · Diabetes · doi:10.2337/diabetes.53.2.418 · Cited by 98 · see citing works
Izumi, Y., Ishii, K., Katsuki, H., Benz, A. M., & Zorumski, C. F. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1009 · Cited by 95 · see citing works
Cognitive and Neural Hippocampal Effects of Long-Term Moderate Recurrent Hypoglycemia
McNay, E. C., Williamson, A., McCrimmon, R. J., & Sherwin, R. S. (2006) · Diabetes · doi:10.2337/diabetes.55.04.06.db05-1314 · Cited by 95 · see citing works
Ota, M., Matsuo, J., Ishida, I., Hattori, K., Teraishi, T., Tonouchi, H., Ashida, K., Takahashi, T., & Kunugi, H. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4414-7 · Cited by 92 · see citing works
“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.,…”
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
“, lactate and ketone bodies) can be used acutely by the brain as fuel during hypoglycemia and downregulate neuroendocrine responses (19, 34).”
BackgroundLactate: A key metabolite in the intercellular metabolic interplay.
Leverve, X. M., & Mustafa, I. (2002) · Critical Care · doi:10.1186/cc1509 · Cited by 85 · see citing works
“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].”
BackgroundImpact of Hypoglycemia on Brain Metabolism During Diabetes
Rehni, A. K., & Dave, K. R. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1044-6 · Cited by 80 · see citing works
Influence of Exercise on Skill Proficiency in Soccer
Russell, M., & Kingsley, M. (2011) · Sports Medicine · doi:10.2165/11589130-000000000-00000 · Cited by 78 · see citing works
Galassetti, P. R., Tate, D. B., Neill, R. A., Richardson, A., Leu, S., & Davis, S. N. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00244.2005 · Cited by 77 · see citing works
Sandoval, D. A., Guy, D. L. A., Richardson, M. A., Ertl, A. C., & Davis, S. N. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00283.2005 · Cited by 71 · see citing works
Maran, A., Crepaldi, C., Trupiani, S., Lucca, T., Jori, E., Macdonald, I. A., Tiengo, A., Avogaro, A., & Prato, S. D. (2000) · Diabetologia · doi:10.1007/s001250051371 · Cited by 70 · see citing works
“This result has been confirmed [6, 7] with similar results in diabetic patients [8].”
BackgroundMethodResultInfluentialMeasurement of β‐hydroxybutyrate in acute hyperketonemia in human brain
Pan, J. W., Telang, F., Lee, J. H., et al. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00575.x · Cited by 69 · see citing works
“After baseline MR data were acquired, acute hyperketonemia was induced using a variant of the protocol described by Veneman et al. (1994).”
MethodDavis, S. N., Shavers, C., & Costa, F. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.6.6641 · Cited by 69 · see citing works
Energy metabolism in critically ill patients: lactate is a major oxidizable substrate
Leverve, X. M. (1999) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/00075197-199903000-00013 · Cited by 66 · see citing works
King, P., Kong, M., Parkin, H., Macdonald, I. A., Barber, C., & Tattersall, R. B. (1998) · Clinical Science · doi:10.1042/cs0940157 · Cited by 67 · see citing works
Carbohydrate restriction for diabetes: rediscovering centuries-old wisdom
Lennerz, B. S., Koutnik, A. P., Azova, S., Wolfsdorf, J. I., & Ludwig, D. S. (2021) · Journal of Clinical Investigation · doi:10.1172/jci142246 · Cited by 69 · see citing works
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
Rooijackers, H. M. M., Wiegers, E. C., Tack, C. J., van der Graaf, M., & de Galan, B. E. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2079-8 · Cited by 62 · see citing works
PET study of11C-acetoacetate kinetics in rat brain during dietary treatments affecting ketosis
Bentourkia, M., Tremblay, S., Pifferi, F., et al. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90644.2008 · Cited by 60 · see citing works
“Ketones also prevent symptoms of experimental hypoglycemia in adults, including anxiety, fainting, hunger, irritability, and tremor (1, 39).”
BackgroundExercise hypoglycemia in nondiabetic subjects.
Brun, J. ‐., Dumortier, M., Fédou, C., & Mercier, J. G. (2001) · PubMed · Cited by 58 · see citing works
CNS sensing and regulation of peripheral glucose levels
Levin, B. E., Dunn-Meynell, A. A., & Routh, V. H. (2002) · International review of neurobiology · doi:10.1016/s0074-7742(02)51007-2 · Cited by 54 · see citing works
Jacobson, L., Ansari, T., & McGuinness, O. P. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00383.2005 · Cited by 51 · see citing works
Elhomsy, G. C., Eranki, V., Albert, S. G., Fesler, M. J., Parker, S. M., Michael, A., & Griffing, G. T. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-2327 · Cited by 51 · see citing works
Effect of exercise on mouse liver and brain bioenergetic infrastructures
Lezi, E., Lu, J., Burns, J. M., & Swerdlow, R. H. (2012) · Experimental Physiology · doi:10.1113/expphysiol.2012.066688 · Cited by 49 · see citing works
“2007), and lactate also appears to play a role in memory formation (Veneman et al. 1994; Berthet et al. 2009; Suzuki et al. 2011).”
BackgroundKalantar‐Zadeh, K., Uppot, R. N., & Lewandrowski, K. B. (2013) · New England Journal of Medicine · doi:10.1056/nejmcpc1208154 · Cited by 48 · see citing works
Kishore, P., Gabriely, I., Cui, M., Vito, J. D., Gajavelli, S., Hwang, J.-H., & Shamoon, H. (2006) · Diabetes · doi:10.2337/diabetes.55.03.06.db05-0849 · Cited by 48 · see citing works
“Ethanol administration may also increase circulating acetate levels, which by itself may modulate the counterregulatory response to hypoglycemia (27).”
BackgroundTaher, M., Leen, W. G., Wevers, R. A., & Willemsen, M. A. A. P. (2015) · European Journal of Paediatric Neurology · doi:10.1016/j.ejpn.2015.09.008 · Cited by 46 · see citing works
Lubow, J. M., Pinon, I., Avogaro, A., Cobelli, C., Treeson, D. M., Mandeville, K. A., TOFFOLO, G. M., & Boyle, P. J. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00049.2005 · Cited by 45 · see citing works
“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
Myette‐Côté, É., Soto-Mota, A., & Cunnane, S. C. (2021) · British Journal Of Nutrition · doi:10.1017/s0007114521003883 · Cited by 43 · see citing works
Prevention and Correction of Hypoglycemia
Cryer, P. E. (2003) · Humana Press eBooks · doi:10.1007/978-1-59259-310-1_7 · Cited by 42 · see citing works
Self-citationCentral nervous system involvement in diabetes mellitus
Selvarajah, D., & Tesfaye, S. H. (2006) · Current Diabetes Reports · doi:10.1007/s11892-006-0075-y · Cited by 41 · see citing works
“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 42 · see citing works
“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).”
BackgroundRossetti, P., Porcellati, F., Ricci, N. B., Candeloro, P., Cioli, P., Nair, K. S., Santeusanio, F., Bolli, G. B., & Fanelli, C. G. (2008) · Diabetes · doi:10.2337/db08-0276 · Cited by 39 · see citing works
“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 · see citing works
Juby, A. G., Blackburn, T. E., & Mager, D. R. (2022) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12259 · Cited by 42 · see citing works
Fattor, J. A., Miller, B. F., Jacobs, K. A., & Brooks, G. A. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00117.2004 · Cited by 40 · see citing works
Rooijackers, H. M. M., Wiegers, E. C., van der Graaf, M., Thijssen, D. H. J., Kessels, R. P. C., Tack, C. J., & de Galan, B. E. (2017) · Diabetes · doi:10.2337/db16-1535 · Cited by 39 · see citing works
“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
van de Ven, K. C. C., Tack, C. J., Heerschap, A., van der Graaf, M., & de Galan, B. E. (2013) · Journal of Clinical Investigation · doi:10.1172/jci62742 · Cited by 39 · see citing works
Ashton, J. S., Roberts, J. W., Wakefield, C. J., Page, R. M., MacLaren, D. P. M., Marwood, S., & Malone, J. J. (2020) · Physiology & Behavior · doi:10.1016/j.physbeh.2020.113252 · Cited by 37 · see citing works
Davis, S. N., & Tate, D. B. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.5.7495 · Cited by 41 · see citing works
Inouye, K., Shum, K. K., Chan, O. T. M., Mathoo, J., Matthews, S. G., & Vranić, M. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00480.2001 · Cited by 36 · see citing works
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
“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 33 · see citing works
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 · see citing works
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 · see citing works
“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 32 · see citing works
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 · 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
“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 · see citing works
“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 · see citing works
“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 · see citing works
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 24 · see citing works
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 · see citing works
The Prevention and Correction of Hypoglycemia
Cryer, P. E. (2001) · Comprehensive Physiology · doi:10.1002/cphy.cp070235 · Cited by 23 · see citing works
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 24 · see citing works
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 23 · see citing works
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 · see citing works
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 22 · see citing works
“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 · see citing works
“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 · see citing works
Hypoglycaemia in diabetes mellitus - protecting the brain
Amiel, S. A. (1997) · Diabetologia · doi:10.1007/s001250051404 · Cited by 21 · see citing works
“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 · see citing works
“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 20 · see citing works
“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
- 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 › Diet and metabolism studies
- Health Sciences › Medicine › Surgery › 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
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
