Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-cd9895bd7-gxg78 Total loading time: 0 Render date: 2024-12-18T16:09:38.892Z Has data issue: false hasContentIssue false

8 - Nutrient regulation in brain development: glucose and alternate fuels

Published online by Cambridge University Press:  10 December 2009

Patti J. Thureen
By
Camille Fung  and
Sherin U. Devaskar
Edited by
William W. Hay
Patti J. Thureen
Affiliation:
University of Colorado at Denver and Health Sciences Center
Camille Fung
Affiliation:
Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA
Sherin U. Devaskar
Affiliation:
Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA
William W. Hay
Affiliation:
University of Colorado at Denver and Health Sciences Center
Get access

Summary

To maintain normal cerebral function and development, a sufficient amount of metabolizable substrate must be supplied to the brain at all times. Glucose is the primary energy substrate for the growing fetus, newborn and adult brain under physiologic conditions. As much as 90% of all the energy consumed by the fetus is estimated to be derived from glucose. Plasma glucose concentration of the fetus changes with that of the mother, i.e. a linear relationship exists between the glucose concentrations of the mother and the fetus. At birth with umbilical cord clamping, the maternal supply of oxygen and nutrients ceases abruptly, which sets into motion the initiation of neonatal glucose production triggered by a surge in various circulating hormones. Most normal term and preterm infants are able to mobilize glycogen, initiate gluconeogenesis, and thereby produce glucose at 4–6 mg kg−1 min−1 in the immediate postnatal period. When glucose deficiency occurs, other organic non-glucose substrates are utilized to sustain the normal energy balance of supply and demand. This chapter will address normal cerebral glucose metabolism focusing on the delivery of glucose by a family of facilitative glucose transporters, the role of alternate substrates when glucose availability is limited, cerebral adaptive responses to hypoglycemia, and finally hypoglycemia-induced brain cellular apoptosis and/or necrosis.

Difficulties in defining hypoglycemia

Abnormalities in glucose homeostasis continue to pose problems in the term and preterm newborn infant. The reported incidence of hypoglycemia varies depending on the definition of hypoglycemia and the test employed to measure glucose concentrations.

Type
Chapter
Information
Neonatal Nutrition and Metabolism , pp. 91 - 103
Publisher: Cambridge University Press
Print publication year: 2006

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Nehlig, A., Vasconcelos, Pereira A.Glucose and ketone body utilization by the brain of neonatal rats. Prog. Neurobiol. 1993;40:163–221.CrossRefGoogle ScholarPubMed
Nehlig, A.Respective roles of glucose and ketone bodies as substrates for cerebral energy metabolism in the suckling rat. Dev. Neurosci. 1996;18:426–33.CrossRefGoogle ScholarPubMed
Kalhan, S. C., Raghavan, C. V. Metabolism of glucose in the fetus and newborn. In Polin, R. A., Fox, W. W., eds. Fetal and Neonatal Physiology. 2nd edn. Philadelphia, PA: W. B. Saunders & Co.; 1998:543–58.Google Scholar
Rosenblatt, J., Wolfe, R. R.Calculation of substrate flux using stable isotopes. Am. J. Physiol. 1988;254:E526–31.Google ScholarPubMed
Kalhan, S., Peter-Wohl, S.Hypoglycemia: what is it for the neonate?Am. J. Perinatol. 2000;17:11–18.CrossRefGoogle ScholarPubMed
Sexson, W. R.Incidence of neonatal hypoglycemia: a matter of definition. J. Pediatr. 1984;105:149–50.CrossRefGoogle ScholarPubMed
Anderson, J. M., Milner, R. D. G., Strich, S. J.Pathological changes in the nervous system in severe neonatal hypoglycemia. Lancet 1966;13:372–5.CrossRefGoogle Scholar
Lucas, A., Morley, R., Cole, T. J.Adverse neurodevelopmental outcome of moderate neonatal hypoglycemia. Br. Med. J. 1988;297:1304–8.CrossRefGoogle Scholar
Duvanel, C. B., Fawer, C.-L., Cotting, J.et al.Long-term effects of neonatal hypoglycemia on brain growth and psychomotor development in small-for-gestational age preterm infants. J. Pediatr. 1999;134:492–8.CrossRefGoogle ScholarPubMed
Singh, M., Singhal, P. K., Paul, V. K.et al.Neurodevelopmental outcome of asymptomatic and symptomatic babies with neonatal hypoglycemia. Indian J. Med. Res. 1991;94:6–10.Google Scholar
Koivisto, M., Blanco-Sequeiros, M., Krause, U.Neonatal symptomatic and asymptomatic hypoglycaemia: a follow-up study in 151 children. Dev. Med. Child Neurol. 1972;14:603–14.CrossRefGoogle ScholarPubMed
Koh, T. T. H. G., Aynsley-Green, A., Tarbit, M., Eyr, J. A.Neural dysfunction during hypoglycaemia. Arch. Dis. Child. 1988;63:1353–8.CrossRefGoogle ScholarPubMed
Evans, M. L., Sherwin, R. S.Brain glucose metabolism and hypoglycaemia. Diabetes Nutrition Metab. 2002;15:294–6.Google ScholarPubMed
Messier, C.Glucose improvement of memory: a review. Eur. J. Pharmacol. 2004;490:33–57.CrossRefGoogle ScholarPubMed
Cremer, J. E.Substrate utilization and brain development. J. Cereb. Blood Flow Metab. 1982;2:394–407.CrossRefGoogle ScholarPubMed
Wood, S., Trayhurn, P.Glucose transporters (glucose transporters and SGLT): expanded families of sugar transport proteins. Br. J. Nutr. 2003;89:3–9.CrossRefGoogle ScholarPubMed
Vannucci, S. J.Developmental expression of glucose transporters1 and glucose transporters3 glucose transporters in rat brain. J. Neurochem. 1994;62:240–6.CrossRefGoogle Scholar
Sivitz, W. S., DeSautel, P. S., Pessin, J. E.Regulation of the glucose transporter in developing rat brain. Endocrinology 1989;124:1875–80.CrossRefGoogle ScholarPubMed
Devaskar, S. U., Zahm, D. S., Holtzclaw, L., Chundu, K., Wadzinski, B. E.Developmental regulation of the distribution of rat brain insulin-insensitive (Glut 1) glucose transporter. Endocrinology 1991;129:1530–40.CrossRefGoogle ScholarPubMed
Dick, A. P., Harik, S. I., Klip, A., Walker, D. M.Identification and characterization of the glucose transporter of the blood-brain barrier by cytochalasin B binding and immunological reactivity. Proc. Natl Acad. Sci. USA 1984;81:7233–7.CrossRefGoogle ScholarPubMed
Pardridge, W. M., Boado, R. J., Farrell, C. R.Brain-type glucose transporter (Glut-1) is selectively localized to the blood-brain barrier. J. Biol. Chem 1990;265:18035–40.Google ScholarPubMed
Maher, F., Vannucci, S. J., Simpson, I. A.Glucose transporter isoforms in brain: absence of glucose transporters3 from the blood-brain barrier. J. Cereb. Blood Flow Metab. 1993;13:342–5.CrossRefGoogle ScholarPubMed
Bhattacharyya, M. V., Brodsky, J. L.Characterization of the glucose transporter from rat brain synaptosomes. Biochem. Biophys. Res. Commun. 1988;155:685–91.CrossRefGoogle ScholarPubMed
Sadiq, F., Holtzclaw, L., Chundu, K., Muzzafer, A., Devaskar, S.The ontogeny of the brain glucose transporter. Endocrinology 1990;126:2417–24.CrossRefGoogle ScholarPubMed
Walker, P. S., Donovan, J. A., Ness, B. G.et al.Glucose dependent regulation of glucose transport activity, protein and mRNA in primary cultures of rat brain glial cells. J. Biol. Chem. 1988;263:15594–601.Google ScholarPubMed
Maher, F., Davies-Hill, T. M., Simpson, I. A.Expression of glucose transporters, glucose transporters 1 and glucose transporters 3, in cultured cerebellar neurons: evidence for neuron-specific expression of glucose transporters 3. Mol. Cell Neurosci. 1991;2:351–60.CrossRefGoogle Scholar
Fields, H. M., Rinaman, L., Devaskar, S. U.Distribution of glucose transporter isoform-3 and hexokinase I in the postnatal murine brain. Brain Res. 1999;846:260–4.CrossRefGoogle ScholarPubMed
Robertson, P. L., Dubois, M., Bowman, P. D.et al.Angiogenesis in developing rat brain: an in vivo and in vitro study. Brain Res. Dev. Brain Res. 1985;23:219–23.CrossRefGoogle Scholar
Yoshida, Y., Yamada, M., Wakabayashi, K.et al.Endothelial fenestrae in the rat fetal cerebrum. Brain Res. Dev. Brain Res. 1988;44:211–19.CrossRefGoogle ScholarPubMed
Mantych, G., Sotelo-Avila, C., Devaskar, S.The blood-brain barrier glucose transport system is conserved in the very low birth weight, preterm, and term newborn infants. J. Clin. Endocrinol. Metab. 1993;77:46–9.Google Scholar
Farrell, C. L., Pardridge, W. M.Blood-brain barrier glucose transporter is asymmetrically distributed in brain capillary endothelial luminal and abluminal membranes: an electron microscopic immunogold study. Proc. Natl Acad. Sci. USA 1991;88:5779–83.CrossRefGoogle Scholar
Vorbrodt, A. W., Dobrogowska, D. H., Meeker, H. C., Carp, R. L.Immunogold study of regional differences in the distribution of glucose transporter (glucose transporters 1) in mouse brain associated with physiological and accelerated aging and scrapie infection. J. Neurocytol. 1999;28:711–19.CrossRefGoogle ScholarPubMed
Bondy, C. A., Lee, W., Zhou, J.Ontogeny and cellular distribution of brain glucose transporter gene expression. Mol. Cell Neurosci. 1992;3:305–14.CrossRefGoogle ScholarPubMed
Devaskar, S. U., Rajakumar, P. A., Mink, R. B.et al.Effect of development and hypoxic-ischemia upon rabbit brain glucose transporter expression. Brain Res. 1999;823:113–28.CrossRefGoogle ScholarPubMed
Khan, J. Y., Rajakumar, R. A., McKnight, R. A., Devaskar, U. P., Devaskar, S. U. Developmental regulation of genes mediating brain glucose uptake. Am. J. Physiol. 1999;45:892–900.Google Scholar
Rajakumar, R. A., Thamotharan, S., Menon, R. K., Devaskar, S. U.Sp1 and Sp3 regulate transcriptional activity of facilitative glucose transporter isoform-3 gene in mammalian neuroblasts and trophoblasts. J. Biol. Chem 1998;273:27474–83.CrossRefGoogle ScholarPubMed
Rajakumar, R. A., Thamotharan, S., Menon, R. K., Devaskar, S. U.Trans-activators regulating neuronal glucose transporter isoform-3 gene expression in mammalian neurons. J. Biol. Chem. 2004;279:26768–79.CrossRefGoogle ScholarPubMed
Mantych, G., James, D. E., Chung, H. D., Devaskar, S. U.Cellular localization and characterization of Glut 3 glucose transporter isoform in human brain. Endocrinology 1992;131:1270– 8.CrossRefGoogle ScholarPubMed
Caryannopoulos, M., Chi, M. M.-Y., Cui, Y.et al.glucose transporters 8 is a glucose transporter responsible for insulin-stimulated glucose uptake in the blastocyst. PNAS, USA. 2000;97:7313–18.CrossRefGoogle Scholar
Sankar, R., Thamotharan, S., Shin, D., Moley, K. H., Devaskar, S.Insulin-responsive glucose transporters – glucose transporters 8 and glucose transporters 4 are expressed in the developing mammalian brain. Mol. Brain Res. 2002;107:157–65.CrossRefGoogle Scholar
Shin, B., McKnight, R. A., Devaskar, S. U.Glucose transporter – glucose transporters 8 translocation in neurons is not insulin responsive. Neurosci. Res. 2004;75:835–44.CrossRefGoogle Scholar
Duffy, T. E., Cavazutti, M., Cruz, L. F.et al.Local cerebral glucose metabolism in newborn dogs: effects of hypoxia and halothane anesthesia. Ann. Neurol. 1982;11:233–46.CrossRefGoogle ScholarPubMed
Sokoloff, L., Reivich, M., Kennedy, C.et al.The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J. Neurochem. 1977;28:897–916.CrossRefGoogle Scholar
Chugani, H. T., Phelps, M. E.Maturational changes in cerebral function in infants determined by 18FDG positron emission tomography. Science 1986;231:840–3.CrossRefGoogle ScholarPubMed
Vivo, D. C., Trifiletti, R. R., Jacobson, R. I.et al.Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N. Engl. J. Med. 1991;325:703–9.CrossRefGoogle ScholarPubMed
Pascual, J. M., Wang, D., Lecumberri, B.et al.glucose transporters 1 deficiency and other glucose transporter diseases. Eur. J. Endocrinol. 2004;150:627–33.CrossRefGoogle ScholarPubMed
Das, U. G., Schroeder, R. E., Hay, W. W. Jr.Devaskar, S. U.Time-dependent and tissue-specific effects of circulating glucose on fetal ovine glucose transporters. Am. J. Physiol. 1999;276:R809–17.Google ScholarPubMed
Anderson, M. S., Flowers-Ziegler, J., Das, U. G., Hay, W. W. Jr, Devaskar, S. U.Glucose transporter protein responses to selective hyperglycemia or hyperinsulinemia in fetal sheep. Am. J. Physiol. 2001;281:R1545–52.Google ScholarPubMed
Dombrowski, G. J., Swiatek, K. R., Chao, K. L.Lactate, 3-Hydroxybutyrate, and glucose as substrates for the early postnatal rat brain. Neurochem. Res 1989;14:667–75.CrossRefGoogle ScholarPubMed
Anday, E. K., Stanley, C. A., Baker, L.et al.Plasma ketones in newborn infants: absence of suckling ketosis. J. Pediatr. 1981;98:628–30.CrossRefGoogle ScholarPubMed
Stanley, C. A., Anday, E. K., Baker, L.et al.Metabolic fuel and hormone responses to fasting in newborn infants. Pediatrics 1979;64:613–19.Google ScholarPubMed
Clark, J. B., Bates, T. E., Cullingford, T.et al.Development of enzymes of energy metabolism in the neonatal mammalian brain. Dev. Neurosci. 1993;15:174–80.CrossRefGoogle ScholarPubMed
Pellerin, L., Pellegri, G., Martin, J. L.et al.Expression of monocarboxylate transporter mRNAs in mouse brain: support for a distinct role of lactate as an every substrate for the neonatal vs. adult brain. Proc. Natl Acad. Sci. USA 1998;95:3990–5.CrossRefGoogle Scholar
Hernandez, M. J., Vannucci, R. C., Salcedo, A.et al.Cerebral blood flow and metabolism during hypoglycemia in newborn dogs. J. Neurochem. 1980;35:622–8.CrossRefGoogle ScholarPubMed
Maran, A., Cranston, I., Lomas, J.et al.Protection by lactate of cerebral function during hypoglycemia. Lancet 1994;343:16–20.CrossRefGoogle Scholar
Kim, C. M., Goldstein, J. L., Brown, M. S.cDNA cloning of MEV, a mutant protein that facilitates cellular uptake of mevalonate, and identification of the point mutation responsible for its gain of function. J. Biol. Chem. 1992;267:23113–21.Google ScholarPubMed
Halestrap, A. P., Price, N. T.The proton-linked MCT family: structure, function and regulation. Biochem. J. 1999;343:281–99.CrossRefGoogle ScholarPubMed
Price, N. T., Jackson, V. N., Halestrap, A. P. Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past. Biochem. J. 1998;329:321–8.CrossRef
Leino, R. L., Gerhart, D. Z., Drewes, L. R.Monocarboxylate transporter (MCT1) abundance in brains of suckling and adult rats: a quantitative electron microscopic immunogold study. Dev. Brain Res. 1999;113:47–54.CrossRefGoogle ScholarPubMed
Dringen, R., Wiesinger, H., Hamprecht, B.Uptake of L-lactate by cultured rat brain neurons. Neurosci. Lett. 1993;163:5–7.CrossRefGoogle ScholarPubMed
Broer, S., Rahman, B., Pellegri, G.et al.Comparison of lactate transport in astroglial cells and monocarboxylate transporter 1 (MCT 1) expressing Xenopus laevis oocytes. Expression of two different monocarboxylate transporters in astroglial cells and neurons. J. Biol. Chem. 1997;272:30096–102.CrossRefGoogle Scholar
Tsacopoulos, M., Magistretti, P. J.Metabolic coupling between glia and neurons. J. Neurosci. 1996;16:877–85.CrossRefGoogle ScholarPubMed
Pellerin, L., Magistretti, P. J.Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl Acad. Sci. USA 1994;91:10625–9.CrossRefGoogle ScholarPubMed
Prichard, J., Rothman, D., Novotny, E.et al.Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation. Proc. Natl Acad. Sci. USA 1991;88:5829–31.CrossRefGoogle ScholarPubMed
Fellows, L. K., Boutelle, M. G., Fillenz, M.Physiological stimulation increases nonoxidative glucose metabolism in the brain of the freely moving rat. J. Neurochem. 1993;60:1258–63.CrossRefGoogle ScholarPubMed
Nelson, S. R., Schulz, D. W., Passonneau, J. V.et al.Control of glycogen levels in brain. J. Neurochem. 1968;15:1271–9.CrossRefGoogle ScholarPubMed
Siesjo, B. K.Brain Energy Metabolism. New York, NY: John Wiley & Sons; 1978:162–4.Google ScholarPubMed
Dringen, R., Gebhardt, R., Hamprecht, B.Glycogen in astrocytes: possible function as lactate supply for neighboring cells. Brain Res. 1993;623:208–14.CrossRefGoogle ScholarPubMed
Swanson, R. A., Choi, D. W.Glial glycogen stores affect neuronal survival during glucose deprivation in vitro. J. Cereb. Blood Flow Metab. 1993;13:162–9.CrossRefGoogle ScholarPubMed
Clarke, W. L., Santiago, J. V., Thomas, L.et al.Adrenergic mechanisms in recovery from hypoglycemia in man: adrenergic blockade. Am. J. Physiol. 1979;236:E147–52.Google ScholarPubMed
Garber, A. J., Cryer, P. E., Santiago, J. V.et al.The role of adrenergic mechanisms in the substrate and hormonal response to insulin-induced hypoglycemia in man. J. Clin. Invest. 1976;58:7–15.CrossRefGoogle ScholarPubMed
Schwartz, N. S., Clutter, W. E., Shah, S. D.et al.Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J. Clin. Invest. 1987;79:777–81.CrossRefGoogle Scholar
Mitrakou, A., Ryan, C., Veneman, T.et al.Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms and cerebral dysfunction. Am. J. Physiol. 1991;260:E67–74.Google ScholarPubMed
Oomura, Y., Kimura, K., Ooyama, H.et al.Reciprocal activities of the ventromedial and lateral hypothalamic area of cats. Science 1964;143:484–5.CrossRefGoogle ScholarPubMed
Levin, B. E.Glucosensing neurons: the metabolic sensors of the brain?Diabetes Nutrition Metab. 2002;15:274–81.Google Scholar
Devaskar, S. U.Neurohumoral regulation of body weight gain. Pediatr. Diabetes 2001;2:131–44.CrossRefGoogle ScholarPubMed
Trapp, S., Ashcroft, F. M.A metabolic sensor in action: news from the adenosine triphosphate-sensitive K+-channel. News Physiol. Sci. 1997;12:255–63.Google Scholar
Routh, V. H., McArdle, J. J., Levin, B. E.Phosphorylation modulates the activity of adenosine triphosphate-sensitive K+-channel in the ventromedial hypothalamic nucleus. Brain Res. 1997;778:107–19.CrossRefGoogle Scholar
Amoroso, S., Schmid-Antomarchi, H., Fosset, M.et al.Glucose, sulfonylureas, and neurotransmitter release: role of adenosine triphosphate-sensitive K+-channels. Science 1990;247:852–4.CrossRefGoogle Scholar
Vannucci, R. C., Nardis, E. E., Vannucci, S. J.et al.Cerebral carbohydrate and energy metabolism during hypoglycemia in newborn dogs. Am. J. Physiol. 1981;240:R192–9.Google ScholarPubMed
Mujsce, D. J., Christensen, M. A., Vannucci, R. C.Regional cerebral blood flow and glucose utilization during hypoglycemia in newborn dogs. Am. J. Physiol. 1989;256:H1659–66.Google ScholarPubMed
Turner, C. P., Blackburn, M. R. and Rivkees, S. A.A1 adenosine receptors mediate hypoglycemia-induced neuronal injury. J. Mol. Endocrinol. 2004;32:129–44.CrossRefGoogle ScholarPubMed
Hvidberg, A., Fanelli, C. G., Hershey, T.et al.Impact of recent antecedent hypoglycemia on hypoglycemic cognitive dysfunction in nondiabetic humans. Diabetes 1996;45:1030– 6.CrossRefGoogle ScholarPubMed
Fanelli, C. G., Paramore, D. S., Hershey, T.et al.Impact of nocturnal hypoglycemia on hypoglycemic cognitive dysfunction in type I diabetes. Diabetes. 1998;47:1920–7.CrossRefGoogle Scholar
Sakurai, T., Yang, B., Takata, T.et al.Synaptic adaptation to repeated hypoglycemia depends on the utilization of monocarboxylates in guinea pig hippocampal slices. Diabetes 2002;51:430–8.CrossRefGoogle ScholarPubMed
Amiel, S. A.Hypoglycemia in diabetes mellitus: protecting the brain. Diabetologia 1997;40 (Suppl. 2);S62–8.CrossRefGoogle Scholar
Jacob, R. J., Dziura, J., Blumberg, M.et al.Effects of recurrent hypoglycemia on brain stem function in diabetic BB rats. Diabetes 1999;48:141–5.CrossRefGoogle ScholarPubMed
Saikumar, P., Dong, Z., Mikhailov, V.et al.Apoptosis: definition, mechanisms, and relevance to disease. Am. J. Med. 1999;107:489–506.CrossRefGoogle ScholarPubMed
Moley, K. H., Mueckler, M. M.Glucose transport and apoptosis. Apoptosis 2000;5:99–105.CrossRefGoogle ScholarPubMed
Deckwerth, T. L., Johnson, E. M. Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor. J. Cell. Biol. 1993;123:1207–22.CrossRef
Blackburn, R. V., Spitz, D. R., Liu, X.et al.Metabolic oxidative stress activates signal transduction and gene expression during glucose deprivation in human tumor cells. Free Radic. Biol. Med. 1999;26:419–30.CrossRefGoogle ScholarPubMed
Lee, Y. J., Galoforo, S. S., Berns, C. M.et al.Glucose deprivation-induced cytotoxicity in drug resistant human breast carcinoma MCF-7/ADR cells: role of c-myc and bcl-2 in apoptotic cell death. J. Cell Sci. 1997;110:681–6.Google ScholarPubMed
Ouyang, Y. B., He, Q. P., Li, P. A.et al.Is neuronal injury caused by hypoglycemic coma of the necrotic or apoptotic type?Neurochem. Res. 2000;25:661–7.CrossRefGoogle ScholarPubMed
Auer, R. N., Siesjo, B. K.Biological differences between ischemia, hypoglycemia, and epilepsy. Ann. Neurol. 1988;24:699–707.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×