Fed and fasting

Insulin and glucagon

After a meal the pancreas releases insulin, which promotes fuel storage; between meals insulin falls, glucagon rises and stored fuel is released ¹.

Insulin signals through its tyrosine kinase receptor, insulin receptor substrates and AKT; in muscle, heart and adipose tissue this translocates GLUT4 glucose transporters to the plasma membrane ¹. In hepatocytes, AKT phosphorylates FOXO1 and excludes it from the nucleus, which lowers transcription of PCK1 and G6PC1 ². Glucagon raises hepatic cAMP; protein kinase A then inactivates glycogen synthase, activates glycogen phosphorylase through phosphorylase kinase and lowers fructose 2,6-bisphosphate, an inhibitor of fructose-1,6-bisphosphatase ². Insulin also suppresses adipose lipolysis ²¹; see insulin and glucagon.

Glycogen

The liver stores glucose as glycogen after a meal and releases it between meals ³.

Glucose 6-phosphate activates liver glycogen synthase allosterically, and glucose favours the inactivation of glycogen phosphorylase ². In eight healthy adults, liver glycogen fell overnight from 350 to 207 mmol/L and peaked at 316 mmol/L a mean 318 minutes after an 824-kcal liquid meal with 67.3% of its energy as glucose ³. After an overnight fast, ethanol lowered plasma glucose below 50 mg/100 ml in five of seven patients with previous alcohol hypoglycaemia, and glucagon did not raise it ⁴.

Gluconeogenesis

Between meals the liver, and in long fasts also the kidney, makes glucose from lactate, amino acids and glycerol ²⁵.

Pyruvate carboxylase, activated by acetyl-CoA, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase bypass the irreversible steps of glycolysis ¹.

Gluconeogenesis from pyruvateMitochondrial matrix, cytosol and endoplasmic reticulum of liver and kidney cortex

Pyruvate
Pyruvate carboxylase (PC), mitochondrialATP to ADP, HCO3−, BiotinAcetyl-CoA activates allosterically; two pyruvate enter per glucose
Oxaloacetate
Malate dehydrogenase 2 (MDH2), mitochondrialNADH to NAD+Malate then crosses the inner mitochondrial membrane
Malate
Malate dehydrogenase 1 (MDH1), cytosolicNAD+ to NADHSupplies the cytosolic NADH used by GAPDH
Oxaloacetate
Phosphoenolpyruvate carboxykinase 1 (PCK1), cytosolicGTP to GDPReleases CO2; PCK2 catalyses the same reaction in mitochondria
Phosphoenolpyruvate
Enolase 1 (ENO1)H2O
2-Phosphoglycerate
Phosphoglycerate mutase 1 (PGAM1)
3-Phosphoglycerate
Phosphoglycerate kinase 1 (PGK1)ATP to ADP
1,3-Bisphosphoglycerate
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)NADH to NAD+Releases phosphate
Glyceraldehyde 3-phosphate
Aldolase B (ALDOB)Dihydroxyacetone phosphateDHAP comes from a second triose by triose-phosphate isomerase (TPI1)
Fructose 1,6-bisphosphate
Fructose-1,6-bisphosphatase 1 (FBP1)H2OFructose 2,6-bisphosphateAMPReleases phosphate; glucagon lowers fructose 2,6-bisphosphate
Fructose 6-phosphate
Glucose-6-phosphate isomerase (GPI)
Glucose 6-phosphate
Glucose-6-phosphatase (G6PC1), endoplasmic reticulumH2OSLC37A4 moves the substrate into the ER lumen; releases phosphate
Glucose

β-Oxidation degrades even-chain fatty acids to acetyl-CoA ⁶, which contributes no net carbon to gluconeogenesis ². Pyruvate dehydrogenase is irreversible, and the citric acid cycle releases two CO2 for each acetyl-CoA, leaving no net oxaloacetate for glucose ¹. The glyoxylate cycle, which bypasses these decarboxylations in plants and bacteria, has not been demonstrated in mammals ¹⁷.

Ketone bodies

When insulin is low and fat breakdown high, the liver converts fatty acids into ketone bodies, a fuel for the brain, heart and skeletal muscle ⁸.

Malonyl-CoA, formed in the fed state, inhibits carnitine palmitoyltransferase 1, which mediates the entry of long-chain fatty acids into mitochondria ⁹⁸.

KetogenesisMitochondrial matrix of hepatocytes

Long-chain acyl-CoA
several stepsMalonyl-CoAEntry through the CPT1A carnitine shuttle, then β-oxidation
Acetyl-CoA
Acetyl-CoA acetyltransferase 1 (ACAT1)Acetyl-CoAMitochondrial thiolase; condenses two acetyl-CoA and releases CoA
Acetoacetyl-CoA
HMG-CoA synthase 2 (HMGCS2), mitochondrialAcetyl-CoA, H2OCommitted step; releases CoA; deficiency impairs ketogenesis in fasting
HMG-CoA
HMG-CoA lyase (HMGCL)Releases acetyl-CoA; acetoacetate decarboxylates spontaneously to acetone
Acetoacetate
3-Hydroxybutyrate dehydrogenase 1 (BDH1)NADH to NAD+Near equilibrium; the product ratio follows mitochondrial NADH/NAD+
D-3-Hydroxybutyrate

Hepatocytes lack succinyl-CoA:3-oxoacid CoA transferase, so the liver exports ketone bodies; other tissues activate acetoacetate with it, without ATP ⁸. Total ketone bodies rise from about 100–250 µM to about 1 mM after 24 hours of fasting and up to 20 mM in diabetic ketoacidosis ⁸.

Ketone body oxidationMitochondrial matrix of extrahepatic tissues

D-3-Hydroxybutyrate
3-Hydroxybutyrate dehydrogenase 1 (BDH1)NAD+ to NADH
Acetoacetate
Succinyl-CoA:3-oxoacid CoA transferase (OXCT1)Succinyl-CoA to succinateUses no ATP; absent from hepatocytes
Acetoacetyl-CoA
Acetyl-CoA acetyltransferase 1 (ACAT1), mitochondrialCoAYields two acetyl-CoA for the citric acid cycle
Acetyl-CoA

The course of a fast

As a fast lengthens, the body shifts from glycogen to new glucose and then to fat and ketone bodies, sparing muscle protein ⁷¹⁰.

Gluconeogenesis supplied 47% of glucose production after 14 hours of fasting, 67% after 22 hours and 93% after 42 hours ¹¹. In six healthy men fasting for 180 hours, plasma glucose levelled off by the third day and 3-hydroxybutyrate rose from 0.016 to 4.23 mmol/L ⁷. Their urinary nitrogen peaked on the fourth day, then declined ⁷. In three obese adults fasting for 38 to 41 days, 3-hydroxybutyrate and acetoacetate had replaced glucose as the brain’s main fuel ¹⁰. In obese adults after 5 to 6 weeks, the kidney made 45% of the glucose produced, which totalled about 86 g a day ⁵.

References

Independent research
Judge A, Dodd MS. Metabolism Essays in Biochemistry, 2020.
doi:10.1042/EBC20190041 PubMed 32830223
Funding and finding
Funding
Ayesha Judge is funded by a PhD studentship from Coventry University with additional funding and support from the University Alliance Doctoral Training Alliance. Michael Dodd is funded by Coventry University and the Centre for Sport, Exercise and Life Sciences.
Finding
Educational review. Insulin, released after eating, binds the insulin receptor, a tyrosine kinase that autophosphorylates and recruits insulin receptor substrate, leading to phosphorylation of AKT; in skeletal muscle, heart and adipose tissue insulin signalling translocates GLUT4 from internal vesicles to the plasma membrane; insulin inhibits hormone-sensitive lipase in adipose tissue; glucagon, released as blood glucose falls, acts mainly on the liver through a G-protein-coupled receptor that raises cAMP. Gluconeogenesis bypasses the irreversible steps of glycolysis with pyruvate carboxylase, activated by acetyl-CoA, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase. Because pyruvate dehydrogenase is irreversible and the carbon entering the citric acid cycle as acetyl-CoA is lost in its decarboxylation steps, fats cannot produce glucose at a net rate; the glyoxylate cycle, which bypasses these steps in plants, bacteria, fungi, algae and protozoa, is stated not to exist in animals.
Independent research
Petersen MC, Vatner DF, Shulman GI. Regulation of hepatic glucose metabolism in health and disease Nature Reviews Endocrinology, 2017.
doi:10.1038/nrendo.2017.80 PubMed 28731034
Funding and finding
Funding
M.C.P. acknowledges grant support from the US National Institutes of Health (NIH; grants F30 DK-104596 and T32 GM-007205). D.F.V. acknowledges grant support from the NIH (grant K23 DK-102874). G.I.S. acknowledges grant support from the NIH (grants R01 DK40936, R01 DK113984 and P30 DK045735).
Finding
Narrative review. Glucagon receptor (GCGR) activation raises cAMP and activates PKA, which inhibits L-type pyruvate kinase, phosphorylates PFK-2/FBPase-2 to favour its phosphatase activity and lower fructose 2,6-bisphosphate, an allosteric inhibitor of FBPase-1 (printed as fructose-2,6-bisphosphatase 1), phosphorylates and inactivates glycogen synthase, and activates phosphorylase kinase, which phosphorylates glycogen phosphorylase at Ser15; PKA also activates the CREB-CBP-CRTC2 complex for gluconeogenic gene transcription. FOXO proteins with PGC1-alpha raise PCK1 and G6PC expression and are excluded from the nucleus after AKT phosphorylation. Glucose enters hepatocytes by facilitated diffusion through GLUT2; glucose allosterically inhibits glycogen phosphorylase; glucose 6-phosphate is the key allosteric activator of GYS2. In overnight-fasted humans under somatostatin, hyperinsulinaemia was required to stimulate hepatic glycogen synthesis and hyperglycaemia to suppress glycogenolysis. Hepatic glucose production and storage are dysregulated in type 1 and type 2 diabetes mellitus, and this imbalance contributes to hyperglycaemia in the fasted and postprandial states. Metformin is used as first-line therapy for type 2 diabetes and acts primarily through the suppression of hepatic gluconeogenesis, by a molecular mechanism that remains under investigation. Several lines of evidence cast doubt on the necessity of AMPK: metformin continues to inhibit glucose production in Ampk-knockout primary mouse hepatocytes and improves glucose tolerance in Ampk-knockout mice to a similar extent as in wild-type mice. Inhibition of mitochondrial complex I is observed only at suprapharmacological, millimolar concentrations, in contrast to the clinically relevant plasma concentration range of 50 to 100 µM in patients who take 2 g of metformin daily. Metformin non-competitively inhibits mitochondrial glycerol-3-phosphate dehydrogenase in isolated hepatocytes with a clinically relevant Ki of about 50 µM, which predicts impaired gluconeogenesis only from the redox-dependent substrates lactate and glycerol and not from pyruvate, alanine or dihydroxyacetone phosphate; the importance of the glycerol-3-phosphate shuttle in gluconeogenesis in the human liver is unclear, so studies in humans are required.
Independent research
Taylor R, Magnusson I, Rothman DL, Cline GW, Caumo A, Cobelli C, et al. Direct assessment of liver glycogen storage by 13C nuclear magnetic resonance spectroscopy and regulation of glucose homeostasis after a mixed meal in normal subjects Journal of Clinical Investigation, 1996.
doi:10.1172/JCI118379 PubMed 8550823
Funding and finding
Participants
18
Funding
The work was funded by the Public Health Service (DK49230, DK45735, RR-03475, RR-00125), a grant from the American Diabetes Association (G. I. Shulman), and a grant from the Juvenile Diabetes Foundation (I. Magnusson). It was also partially supported by a grant from the Italian Ministero della Universita e della Ricerca Scientifica e Tecnologica and by grant 9300457PF40 from the Italian National Research Council. Roy Taylor was supported by Medical Research Council Grant G9012977SB.
In-kind support
Purified acetaminophen glucuronide used as a standard was the gift of McNeil Pharmaceuticals.
Finding
Liver glycogen fell overnight from 350 ± 18 mmol/L 4 h after the evening meal to 207 ± 22 mmol/L in the fasting state. After an 824-kcal liquid meal with 67.3% of energy as glucose, it peaked at 316 ± 19 mmol/L at 318 ± 31 min; net hepatic glycogen synthesis was 28.3 ± 3.7 g, about 19% of the meal carbohydrate. Plasma insulin rose from 4.1 to 73 mU/L at 30 min. Hepatic glucose output, 1.90 ± 0.04 mg/kg per min fasting, was completely suppressed within 30 min and regained the fasting rate between 300 and 460 min after the meal (mean 380 ± 28 min). Mean liver volume 1.44 L.
Independent research
Freinkel N, Singer DL, Arky RA, Bleicher SJ, Anderson JB, Silbert CK. Alcohol hypoglycemia. I. Carbohydrate metabolism of patients with clinical alcohol hypoglycemia and the experimental reproduction of the syndrome with pure ethanol Journal of Clinical Investigation, 1963.
doi:10.1172/JCI104797 PubMed 16695908
Funding and finding
Participants
9
Funding
This work was supported in part by research grant A-1571 and training grant 2 A-5060 from the National Institute of Arthritis and Metabolic Diseases, U. S. Public Health Service. One author was an Investigator of the Howard Hughes Medical Institute.
In-kind support
Abbott Laboratories donated initial samples of 131I-insulin; Eli Lilly supplied human, bovine and porcine insulins; Ciba Pharmaceutical Products provided Metopirone.
Finding
Pure ethanol given after an overnight fast significantly lowered plasma glucose in six of seven patients, to below 50 mg per 100 ml in five, at moderate blood alcohol concentrations. Glucagon did not raise blood glucose during alcohol hypoglycaemia, from which the authors inferred exhausted hepatic glycogen; after a 3-day fast, hypoglycaemia was more pronounced and acute.
Independent research
Owen OE, Felig P, Morgan AP, Wahren J, Cahill GF Jr. Liver and kidney metabolism during prolonged starvation Journal of Clinical Investigation, 1969.
doi:10.1172/JCI106016 PubMed 5773093
Funding and finding
Participants
11
Follow-up
35 to 41 days of fasting
Funding
This work was supported in part by grants from the U. S. Public Health Service, AM-05077, AM-09584, AM-09748, AM-02657, HE-05679, HE-08591, HE-11306, and FR-31, the Adler Foundation, Inc., Rye, N. Y., and the U. S. Army Medical Research and Development Command (DA-49-193-MO-2337).
Finding
Venous 3-hydroxybutyrate was 0.07 mmol/L on day 0, 1.21 on day 3, 4.30 on day 10, 5.10 on day 17 and 5.85 mmol/L on days 35 to 38; blood glucose 4.79, 3.63 and 3.70 mmol/L and serum insulin 37, 20 and 14 µU/ml on days 0, 3 and 35 to 38. Fatty acids and ketone bodies reached a plateau after 17 days. After 5 to 6 weeks, estimated glucose production was about 86 g/24 h, about 55% from liver and 45% from kidney; about half of the glucose formed came from recycled lactate and pyruvate; liver and kidney removed about 19 g glycerol per day; urinary nitrogen was 4.66 g/24 h, 42% as ammonia.
Textbook or database
UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.
doi:10.1093/nar/gkae1010 PubMed 39552041
Funding and finding
Funding
National Human Genome Research Institute [HG002273]; NIH Office of the Director [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; BBSRC [BB/T015608/1]; National Science Foundation Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; Swiss State Secretariat for Education, Research and Innovation; EMBL Australia.
Finding
Reviewed UniProtKB entries, release 2026_03, read through rest.uniprot.org. HMGCR (P04035): converts HMG-CoA to mevalonate, the rate-limiting step in the synthesis of cholesterol and other isoprenoids; ER membrane; main target of statins. FDFT1 (P37268): joins two farnesyl diphosphates through presqualene diphosphate with NADPH or NADH; first committed enzyme of sterol synthesis. SQLE (Q14534): oxidises squalene to (S)-2,3-epoxysqualene; considered a rate-limiting enzyme. FDPS (P14324): forms farnesyl diphosphate, precursor of sterols, dolichols and ubiquinones and substrate for protein farnesylation and geranylgeranylation. GGPS1 (O95749): forms geranylgeranyl diphosphate. PDSS1 (Q5T2R2) and PDSS2 (Q86YH6): extend farnesyl diphosphate with isopentenyl diphosphate to the decaprenyl side chain of ubiquinone-10; mitochondrion. COQ2 (Q96H96): prenylates 4-hydroxybenzoate with the polyprenyl chain; in humans the product is CoQ10, which transports electrons between respiratory chain complexes. DHDDS (Q86SQ9) and NUS1 (Q96E22): condense isopentenyl diphosphate onto farnesyl diphosphate to dehydrodolichyl diphosphate, mostly C95 and C100, precursor of dolichol phosphate, the sugar carrier for ER protein glycosylation. SRD5A3 (Q9H8P0): polyprenal reductase in the conversion of polyprenol to dolichol. FNTA (P49354), FNTB (P49356) and PGGT1B (P53609): transfer a farnesyl or geranylgeranyl group to the cysteine fourth from the C-terminus of proteins ending in Cys-aliphatic-aliphatic-X. LDLR (P01130): binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis; receptor-ligand complexes first cluster into clathrin-coated pits. PCSK9 (Q8NBP7): binds LDLR and promotes its degradation in intracellular acidic compartments by a non-proteolytic mechanism. NPC1L1 (Q9UHC9): critical for cholesterol uptake across the enterocyte plasma membrane; apical membrane. CYP7A1 (P22680): 7-alpha-hydroxylates cholesterol, a rate-limiting step of bile acid synthesis, with electrons from NADPH through cytochrome P450 reductase; ER membrane. FGF19 (O95750): suppresses bile acid synthesis by down-regulating CYP7A1; activity requires KLB and FGFR4. Gene-to-protein assignments of reviewed human entries: SREBF2 SREBP-2 (Q12772); SCAP (Q12770); INSIG1 (O15503); INSIG2 (Q9Y5U4); MBTPS1 site-1 protease (Q14703); MBTPS2 site-2 protease (O43462); LIPA lysosomal acid lipase (P38571); NPC1 (O15118); STAR (P49675); CYP11A1 cholesterol side-chain cleavage enzyme (P05108); CYP27B1 25-hydroxyvitamin D 1-alpha-hydroxylase (O15528); CYP27A1 sterol 27-hydroxylase (Q02318); CYP7B1 oxysterol 7-alpha-hydroxylase (O75881); NR1H4 farnesoid X receptor (Q96RI1); NR0B2 small heterodimer partner (Q15466); POR NADPH-cytochrome P450 reductase (P16435); APOA1 (P02647); ABCG1 (P45844); LIPG endothelial lipase (Q9Y5X9); DHCR24 (Q15392); DHCR7 (Q9UBM7).
Independent research
Cahill GF Jr, Herrera MG, Morgan AP, Soeldner JS, Steinke J, Levy PL, et al. Hormone-fuel interrelationships during fasting Journal of Clinical Investigation, 1966.
doi:10.1172/JCI105481 PubMed 5926444
Funding and finding
Participants
8
Follow-up
total fast of 180 hours
Funding
Supported in part by grants from the U. S. Public Health Service (AM-9584-01, AM-09748-01, 8 MOI-FR-31-05, TI-AM-5077-10, and 5-ROI-AMO-2657); the Adler Foundation, Inc., Rye, N. Y.; the John A. Hartford Foundation, New York, N. Y.; and U. S. Army Medical Research and Development Command (DA-49-193-MD-2337). G. F. Cahill Jr. was an Investigator of the Howard Hughes Medical Institute.
Finding
In the six healthy men, plasma glucose reached a plateau by the third day (84 ± 1 mg/100 ml after an overnight fast, 63 ± 1 mg/100 ml in the last sample); serum insulin fell from 15.2 to 8.3 µU/ml; 3-hydroxybutyrate rose from 0.016 to 4.23 mmol/L and acetoacetate from 0.013 to 1.09 mmol/L. In the two men followed throughout, 4 days were required for the non-protein respiratory quotient to fall to 0.70; on day 8, five of six oxidised no carbohydrate by calculation from nitrogen loss and respiratory quotient. Urinary nitrogen rose from the second or third day, peaked on the fourth day and then declined. Glycogen stores in man are given as about 200 g, and gluconeogenesis from fatty acid via glyoxylate as not demonstrated in mammalian systems.
Independent research
Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics Cell Metabolism, 2017.
doi:10.1016/j.cmet.2016.12.022 PubMed 28178565
Funding and finding
Funding
P.A.C. is supported in part by NIH DK091538.
Finding
Review. Total ketone bodies in healthy adults oscillate between about 100 and 250 µM, rise to about 1 mM after 24 h of fasting or prolonged exercise and reach as high as 20 mM in diabetic ketoacidosis; the human liver produces up to 300 g per day. HMGCS2 catalyses the fate-committing condensation of acetoacetyl-CoA and acetyl-CoA; HMGCL releases acetyl-CoA and acetoacetate; BDH1 interconverts acetoacetate and D-3-hydroxybutyrate in a near-equilibrium NAD+/NADH-coupled reaction; acetoacetate decarboxylates spontaneously to acetone; MCT1 and MCT2 (SLC16A1, SLC16A7) release ketone bodies from cells. SCOT (OXCT1) is expressed in all mammalian cells with mitochondria except hepatocytes and activates acetoacetate without ATP; mitochondrial thiolases (ACAA2, ACAT1, HADHA or HADHB) yield two acetyl-CoA. Heart, skeletal muscle and brain oxidise ketone bodies, including during adherence to low-carbohydrate diets. Acetyl-CoA allosterically activates pyruvate carboxylase; malonyl-CoA inhibits CPT1. Hmgcs2 transcription is stimulated by FOXA2, which insulin inhibits through PI3K and Akt, induced by glucagon-cAMP-p300 signalling and induced by PPAR-alpha and FGF21 in starvation; these shifts have not been linked mechanistically to HMGCS2 protein abundance or ketogenic rate. Loss-of-function HMGCS2 mutations cause bouts of hypoketotic hypoglycaemia.
Independent research
McGarry JD, Mannaerts GP, Foster DW. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis Journal of Clinical Investigation, 1977.
doi:10.1172/JCI108764 PubMed 874089
Funding and finding
Funding
This work was supported by U. S. Public Health Service grant AM-18573 and training grant CA 05200. J. D. McGarry held Research Career Development Award I-KO4-AM0763; G. P. Mannaerts held Fogarty International Fellowship I-FOS-TW223401.
Finding
Malonyl-CoA inhibited ketogenesis from oleic acid but not from octanoic acid; the site of inhibition appeared to be the carnitine acyltransferase I reaction. The effect was specific and easily reversible, and inhibitory concentrations were in the range reported by others in livers of fed rats. The authors proposed that malonyl-CoA is both precursor of fatty acid synthesis and suppressor of fatty acid oxidation.
Independent research
Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GF Jr. Brain metabolism during fasting Journal of Clinical Investigation, 1967.
doi:10.1172/JCI105650 PubMed 6061736
Funding and finding
Participants
3
Follow-up
cerebral catheterisation after 38 to 41 days of fasting
Funding
This study was supported in part by grants from the U. S. Public Health Service AM-09584-02, AM-09748-02, 8 MO1-FR-31-06, T1-AM-5077-11, 5-RO1-AM-02657-07, 1-T1-HE-05679-02, and HE-08591-02; the Adler Foundation, Inc., Rye, N. Y.; the U. S. Army Medical Research and Development Command (DA-49-193-MO-2337); the John A. Hartford Foundation, Inc., New York, N. Y.; and the Atomic Energy Commission. G. F. Cahill Jr. was an Investigator of the Howard Hughes Medical Institute.
Finding
After 38 to 41 days of fasting, mean arterial 3-hydroxybutyrate was 6.67 mmol/L, acetoacetate 1.17 mmol/L and glucose 4.49 mmol/L of whole blood. Calculated brain oxygen equivalents per litre of blood: 3-hydroxybutyrate 1.53 mmol, acetoacetate 0.24 mmol, glucose corrected for lactate and pyruvate release 0.87 mmol and alpha-amino nitrogen 0.42 mmol, total 3.06 mmol against a measured oxygen uptake of 2.96 mmol. Urinary nitrogen 3.3 to 3.9 g/24 h, mainly ammonia. The introduction gives glucose and glycogen stores of adult man as 150 to 300 g, glycerol as about 10% of triglyceride weight, and net gluconeogenesis from fatty acid carbon as not demonstrated in mammals.
Independent research
Landau BR, Wahren J, Chandramouli V, Schumann WC, Ekberg K, Kalhan SC. Contributions of gluconeogenesis to glucose production in the fasted state Journal of Clinical Investigation, 1996.
doi:10.1172/JCI118803 PubMed 8755648
Funding and finding
Participants
8
Follow-up
42 h of fasting
Funding
This study was supported by National Institutes of Health grants DK-14507 and P50 HD-11089 and grant 89-0418 from the Bank of Sweden Tercentenary Foundation.
Finding
Deuterated water method, ratio of 2H enrichment at carbon 5 to carbon 2 of blood glucose. Gluconeogenesis contributed 47 ± 4% of glucose production after 14 h, 67 ± 4% after 22 h and 93 ± 2% after 42 h of fasting (mean ± SE, corrected for glycogen branch points; the PubMed abstract prints 47 +/- 49% and 67 +/- 41%). Plasma glucose was 5.2 ± 0.1 mmol/L at 14 h and 4.3 ± 0.1 mmol/L at 42 h; blood 3-hydroxybutyrate was 76 ± 25 µmol/L at 14 h and 1127 ± 153 µmol/L at 42 h.
Independent research
Reichard GA Jr, Haff AC, Skutches CL, Paul P, Holroyde CP, Owen OE. Plasma acetone metabolism in the fasting human Journal of Clinical Investigation, 1979.
doi:10.1172/JCI109344 PubMed 438326
Funding and finding
Participants
15
Funding
This work was supported by National Institutes of Health Research grants AM-13527 and AM-16102; General Clinical Research Centers Branch grant 5 M01 RR 349; and Biomedical Research Support grant 5-S07-RR-05585-11.
Finding
Plasma acetone 0.19 to 1.68 mmol/L, turnover 20 to 77 µmol/m2 per min; breath and urine removed 2 to 30% of production. Radioactivity from [2-14C]acetone appeared in plasma glucose, lipids and proteins. If glucose synthesis from acetone occurs, it could account for 4.2%, 3.1% and 11.0% of glucose production in 3-day fasted nonobese, 3-day fasted obese and 21-day fasted obese subjects; the authors state that this calculation rests on the unproven assumption that net glucose synthesis from acetone can occur in humans. Conversion of acetoacetate to acetone could account for 37% of acetoacetate production in 21-day fasted subjects.

Updated 2026-10-21