1932

Abstract

Gluconeogenesis is a critical biosynthetic process that helps maintain whole-body glucose homeostasis and becomes altered in certain medical diseases. We review gluconeogenic flux in various medical diseases, including common metabolic disorders, hormonal imbalances, specific inborn genetic errors, and cancer. We discuss how the altered gluconeogenic activity contributes to disease pathogenesis using data from experiments using isotopic tracer and spectroscopy methodologies. These in vitro, animal, and human studies provide insights into the changes in circulating levels of available gluconeogenesis substrates and the efficiency of converting those substrates to glucose by gluconeogenic organs. We highlight ongoing knowledge gaps, discuss emerging research areas, and suggest future investigations. A better understanding of altered gluconeogenesis flux may ultimately identify novel and targeted treatment strategies for such diseases.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-nutr-061121-091507
2023-08-21
2024-05-28
Loading full text...

Full text loading...

/deliver/fulltext/nutr/43/1/annurev-nutr-061121-091507.html?itemId=/content/journals/10.1146/annurev-nutr-061121-091507&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Abate N, Garg A, Peshock RM, Stray-Gundersen J, Grundy SM. 1995. Relationships of generalized and regional adiposity to insulin sensitivity in men. J. Clin. Investig. 96:88–98
    [Google Scholar]
  2. 2.
    Ahlborg G, Hagenfeldt L, Wahren J. 1976. Influence of lactate infusion on glucose and FFA metabolism in man. Scand. J. Clin. Lab. Investig. 36:193–201
    [Google Scholar]
  3. 3.
    Andronescu CI, Purcarea MR, Babes PA. 2018. Nonalcoholic fatty liver disease: epidemiology, pathogenesis and therapeutic implications. J. Med. Life 11:20–23
    [Google Scholar]
  4. 4.
    Arner P, Ryden M. 2015. Fatty acids, obesity and insulin resistance. Obes. Facts 8:147–55
    [Google Scholar]
  5. 5.
    Ashby-Thompson M, Ji Y, Wang J, Yu W, Thornton JC et al. 2020. High-resolution three-dimensional photonic scan-derived equations improve body surface area prediction in diverse populations. Obesity 28:4706–17
    [Google Scholar]
  6. 6.
    Bakshi I, Suryana E, Small L, Quek LE, Brandon AE et al. 2018. Fructose bisphosphatase 2 overexpression increases glucose uptake in skeletal muscle. J. Endocrinol. 237:101–11
    [Google Scholar]
  7. 7.
    Bangsbo J, Gollnick PD, Graham TE, Saltin B. 1991. Substrates for muscle glycogen synthesis in recovery from intense exercise in man. J. Physiol. 434:423–40
    [Google Scholar]
  8. 8.
    Banka S, Newman WG. 2013. A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations. Orphanet J. Rare Dis. 8:84
    [Google Scholar]
  9. 9.
    Basu R, Shah P, Basu A, Norby B, Dicke B et al. 2008. Comparison of the effects of pioglitazone and metformin on hepatic and extra-hepatic insulin action in people with type 2 diabetes. Diabetes 57:24–31
    [Google Scholar]
  10. 10.
    Bijarnia-Mahay S, Bhatia S, Arora V 1993. Fructose-1,6-bisphosphatase deficiency. GeneReviews MP Adam, DB Everman, GM Mirzaa, RA Pagon, SE Wallace et al. Seattle, WA: Univ. Washington
    [Google Scholar]
  11. 11.
    Bugianesi E, Moscatiello S, Ciaravella MF, Marchesini G. 2010. Insulin resistance in nonalcoholic fatty liver disease. Curr. Pharm. Des. 16:1941–51
    [Google Scholar]
  12. 12.
    Cappel DA, Deja S, Duarte JAG, Kucejova B, Inigo M et al. 2019. Pyruvate-carboxylase-mediated anaplerosis promotes antioxidant capacity by sustaining TCA cycle and redox metabolism in liver. Cell Metab. 29:1291–305.e8
    [Google Scholar]
  13. 13.
    Chao HW, Chao SW, Lin H, Ku HC, Cheng CF. 2019. Homeostasis of glucose and lipid in non-alcoholic fatty liver disease. Int. J. Mol. Sci. 20:298
    [Google Scholar]
  14. 14.
    Chen S, Akter S, Kuwahara K, Matsushita Y, Nakagawa T et al. 2019. Serum amino acid profiles and risk of type 2 diabetes among Japanese adults in the Hitachi Health Study. Sci. Rep. 9:7010
    [Google Scholar]
  15. 15.
    Chen Y, Hodin RA, Pandolfi C, Ruan DT, McKenzie TJ. 2014. Hypoglycemia after resection of pheochromocytoma. Surgery 156:1404–9
    [Google Scholar]
  16. 16.
    Cheng T, Sudderth J, Yang C, Mullen AR, Jin ES et al. 2011. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. PNAS 108:8674–79
    [Google Scholar]
  17. 17.
    Chevalier S, Burgess SC, Malloy CR, Gougeon R, Marliss EB, Morais JA. 2006. The greater contribution of gluconeogenesis to glucose production in obesity is related to increased whole-body protein catabolism. Diabetes 55:675–81
    [Google Scholar]
  18. 18.
    Chiefari E, Mirabelli M, La Vignera S, Tanyolac S, Foti DP et al. 2021. Insulin resistance and cancer: in search for a causal link. Int. J. Mol. Sci. 22:11137
    [Google Scholar]
  19. 19.
    Christiansen JJ, Djurhuus CB, Gravholt CH, Iversen P, Christiansen JS et al. 2007. Effects of cortisol on carbohydrate, lipid, and protein metabolism: studies of acute cortisol withdrawal in adrenocortical failure. J. Clin. Endocrinol. Metab. 92:3553–59
    [Google Scholar]
  20. 20.
    Chung ST, Chacko SK, Sunehag AL, Haymond MW. 2015. Measurements of gluconeogenesis and glycogenolysis: a methodological review. Diabetes 64:3996–4010
    [Google Scholar]
  21. 21.
    Cohen JL, Vinik A, Faller J, Fox IH. 1985. Hyperuricemia in glycogen storage disease type I. Contributions by hypoglycemia and hyperglucagonemia to increased urate production. J. Clin. Investig. 75:251–57
    [Google Scholar]
  22. 22.
    Crawford SO, Hoogeveen RC, Brancati FL, Astor BC, Ballantyne CM et al. 2010. Association of blood lactate with type 2 diabetes: the Atherosclerosis Risk in Communities Carotid MRI Study. Int. J. Epidemiol. 39:1647–55
    [Google Scholar]
  23. 23.
    Cusi K, Consoli A, DeFronzo RA. 1996. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 81:4059–67
    [Google Scholar]
  24. 24.
    Davidson SM, Papagiannakopoulos T, Olenchock BA, Heyman JE, Keibler MA et al. 2016. Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer. Cell Metab. 23:517–28
    [Google Scholar]
  25. 25.
    De Leo S, Lee SY, Braverman LE. 2016. Hyperthyroidism. Lancet 388:906–18
    [Google Scholar]
  26. 26.
    DeBerardinis RJ, Cheng T. 2010. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29:313–24
    [Google Scholar]
  27. 27.
    Defronzo RA. 2009. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58:773–95
    [Google Scholar]
  28. 28.
    Diamanti-Kandarakis E, Dunaif A. 2012. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr. Rev. 33:981–1030
    [Google Scholar]
  29. 29.
    Diamond MP, Rollings RC, Steiner KE, Williams PE, Lacy WW, Cherrington AD. 1988. Effect of alanine concentration independent of changes in insulin and glucagon on alanine and glucose homeostasis in the conscious dog. Metabolism 37:28–33
    [Google Scholar]
  30. 30.
    Dimitriadis GD, Leighton B, Parry-Billings M, West D, Newsholme EA. 1989. Effects of hypothyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat. Biochem. J. 257:369–73
    [Google Scholar]
  31. 31.
    Droppelmann CA, Saez DE, Asenjo JL, Yanez AJ, Garcia-Rocha M et al. 2015. A new level of regulation in gluconeogenesis: Metabolic state modulates the intracellular localization of aldolase B and its interaction with liver fructose-1,6-bisphosphatase. Biochem. J. 472:225–37
    [Google Scholar]
  32. 32.
    Dunn WB, Erban A, Weber RJM, Creek DJ, Brown M et al. 2013. Mass appeal: metabolite identification in mass spectrometry-focused untargeted metabolomics. Metabolomics 9:44–66
    [Google Scholar]
  33. 33.
    Ekberg K, Landau BR, Wajngot A, Chandramouli V, Efendic S et al. 1999. Contributions by kidney and liver to glucose production in the postabsorptive state and after 60 h of fasting. Diabetes 48:292–98
    [Google Scholar]
  34. 34.
    Emwas AH, Szczepski K, Al-Younis I, Lachowicz JI, Jaremko M. 2022. Fluxomics—new metabolomics approaches to monitor metabolic pathways. Front. Pharmacol. 13:805782
    [Google Scholar]
  35. 35.
    Faubert B, Li KY, Cai L, Hensley CT, Kim J et al. 2017. Lactate metabolism in human lung tumors. Cell 171:358–71.e9
    [Google Scholar]
  36. 36.
    Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. 2016. Trends in obesity among adults in the United States, 2005 to 2014. JAMA 315:2284–91
    [Google Scholar]
  37. 37.
    Fletcher JA, Deja S, Satapati S, Fu X, Burgess SC, Browning JD. 2019. Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver. JCI Insight 5:e127737
    [Google Scholar]
  38. 38.
    Fletcher JW, Djulbegovic B, Soares HP, Siegel BA, Lowe VJ et al. 2008. Recommendations on the use of 18F-FDG PET in oncology. J. Nucl. Med. 49:480–508
    [Google Scholar]
  39. 39.
    Fontaine E. 2018. Metformin-induced mitochondrial complex I inhibition: facts, uncertainties, and consequences. Front. Endocrinol. 9:753
    [Google Scholar]
  40. 40.
    Foster MT, Pagliassotti MJ. 2012. Metabolic alterations following visceral fat removal and expansion: beyond anatomic location. Adipocyte 1:192–99
    [Google Scholar]
  41. 41.
    Froissart R, Piraud M, Boudjemline AM, Vianey-Saban C, Petit F et al. 2011. Glucose-6-phosphatase deficiency. Orphanet J. Rare Dis. 6:27
    [Google Scholar]
  42. 42.
    Fujiwara T, Cherrington AD, Neal DN, McGuinness OP. 1996. Role of cortisol in the metabolic response to stress hormone infusion in the conscious dog. Metabolism 45:571–78
    [Google Scholar]
  43. 43.
    Gastaldelli A, Baldi S, Pettiti M, Toschi E, Camastra S et al. 2000. Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study. Diabetes 49:1367–73
    [Google Scholar]
  44. 44.
    Gastaldelli A, Miyazaki Y, Pettiti M, Buzzigoli E, Mahankali S et al. 2004. Separate contribution of diabetes, total fat mass, and fat topography to glucose production, gluconeogenesis, and glycogenolysis. J. Clin. Endocrinol. Metab. 89:3914–21
    [Google Scholar]
  45. 45.
    Gastaldelli A, Miyazaki Y, Pettiti M, Matsuda M, Mahankali S et al. 2002. Metabolic effects of visceral fat accumulation in type 2 diabetes. J. Clin. Endocrinol. Metab. 87:5098–103
    [Google Scholar]
  46. 46.
    Gastaldelli A, Toschi E, Pettiti M, Frascerra S, Quinones-Galvan A et al. 2001. Effect of physiological hyperinsulinemia on gluconeogenesis in nondiabetic subjects and in type 2 diabetic patients. Diabetes 50:1807–12
    [Google Scholar]
  47. 47.
    Ghanaat F, Tayek JA. 2005. Growth hormone administration increases glucose production by preventing the expected decrease in glycogenolysis seen with fasting in healthy volunteers. Metabolism 54:604–9
    [Google Scholar]
  48. 48.
    Gormsen LC, Sondergaard E, Christensen NL, Brosen K, Jessen N, Nielsen S. 2019. Metformin increases endogenous glucose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes. Diabetologia 62:1251–56
    [Google Scholar]
  49. 49.
    Grasmann G, Mondal A, Leithner K. 2021. Flexibility and adaptation of cancer cells in a heterogenous metabolic microenvironment. Int. J. Mol. Sci. 22:1476
    [Google Scholar]
  50. 50.
    Grasmann G, Smolle E, Olschewski H, Leithner K. 2019. Gluconeogenesis in cancer cells—repurposing of a starvation-induced metabolic pathway?. Biochim. Biophys. Acta Rev. Cancer 1872:24–36
    [Google Scholar]
  51. 51.
    Gurung P, Zubair M, Jialal I. 2022. Plasma glucose. StatPearls Treasure Island, FL: StatPearls Publishing https://www.ncbi.nlm.nih.gov/books/NBK541081/
    [Google Scholar]
  52. 52.
    Haedersdal S, Lund A, Knop FK, Vilsboll T. 2018. The role of glucagon in the pathophysiology and treatment of type 2 diabetes. Mayo Clin. Proc. 93:217–39
    [Google Scholar]
  53. 53.
    Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: the next generation. Cell 144:646–74
    [Google Scholar]
  54. 54.
    Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E et al. 2016. Metabolic heterogeneity in human lung tumors. Cell 164:681–94
    [Google Scholar]
  55. 55.
    Herzig S, Long F, Jhala US, Hedrick S, Quinn R et al. 2001. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413:179–83
    [Google Scholar]
  56. 56.
    Hibuse T, Maeda N, Nagasawa A, Funahashi T. 2006. Aquaporins and glycerol metabolism. Biochim. Biophys. Acta Biomembr. 1758:1004–11
    [Google Scholar]
  57. 57.
    Holecek M. 2022. Serine metabolism in health and disease and as a conditionally essential amino acid. Nutrients 14:1987
    [Google Scholar]
  58. 58.
    Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW et al. 2002. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J. Clin. Endocrinol. Metab. 87:489–99
    [Google Scholar]
  59. 59.
    Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S et al. 2007. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56:901–11
    [Google Scholar]
  60. 60.
    Hoybye C, Chandramouli V, Efendic S, Hulting AL, Landau BR et al. 2008. Contribution of gluconeogenesis and glycogenolysis to hepatic glucose production in acromegaly before and after pituitary microsurgery. Horm. Metab. Res. 40:498–501
    [Google Scholar]
  61. 61.
    Huidekoper HH, Visser G, Ackermans MT, Sauerwein HP, Wijburg FA. 2010. A potential role for muscle in glucose homeostasis: in vivo kinetic studies in glycogen storage disease type 1a and fructose-1,6-bisphosphatase deficiency. J. Inherit Metab. Dis. 33:25–31
    [Google Scholar]
  62. 62.
    Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V et al. 2000. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49:2063–69
    [Google Scholar]
  63. 63.
    Hyotylainen T, Jerby L, Petaja EM, Mattila I, Jantti S et al. 2016. Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease. Nat. Commun. 7:8994
    [Google Scholar]
  64. 64.
    Iwasaki Y, Takayasu S, Nishiyama M, Tsugita M, Taguchi T et al. 2008. Is the metabolic syndrome an intracellular Cushing state? Effects of multiple humoral factors on the transcriptional activity of the hepatic glucocorticoid-activating enzyme (11β-hydroxysteroid dehydrogenase type 1) gene. Mol. Cell. Endocrinol. 285:10–18
    [Google Scholar]
  65. 65.
    Jahoor F, Peters EJ, Wolfe RR. 1990. The relationship between gluconeogenic substrate supply and glucose production in humans. Am. J. Physiol. 258:E288–96
    [Google Scholar]
  66. 66.
    Jenssen T, Nurjhan N, Consoli A, Gerich JE. 1990. Failure of substrate-induced gluconeogenesis to increase overall glucose appearance in normal humans. Demonstration of hepatic autoregulation without a change in plasma glucose concentration. J. Clin. Investig. 86:489–97
    [Google Scholar]
  67. 67.
    Jomain-Baum M, Hanson RW. 1975. Regulation of hepatic gluconeogenesis in the guinea pig by fatty acids and ammonia. J. Biol. Chem. 250:8978–85
    [Google Scholar]
  68. 68.
    Kalemba KM, Wang Y, Xu H, Chiles E, McMillin SM et al. 2019. Glycerol induces G6pc in primary mouse hepatocytes and is the preferred substrate for gluconeogenesis both in vitro and in vivo. J. Biol. Chem. 294:18017–28
    [Google Scholar]
  69. 69.
    Kaloyianni M, Freedland RA. 1990. Contribution of several amino acids and lactate to gluconeogenesis in hepatocytes isolated from rats fed various diets. J. Nutr. 120:116–22
    [Google Scholar]
  70. 70.
    Kaplan W, Sunehag AL, Dao H, Haymond MW. 2008. Short-term effects of recombinant human growth hormone and feeding on gluconeogenesis in humans. Metabolism 57:725–32
    [Google Scholar]
  71. 71.
    Khan MW, Biswas D, Ghosh M, Mandloi S, Chakrabarti S, Chakrabarti P. 2015. mTORC2 controls cancer cell survival by modulating gluconeogenesis. Cell Death Discov. 1:15016
    [Google Scholar]
  72. 72.
    Khani S, Tayek JA. 2001. Cortisol increases gluconeogenesis in humans: its role in the metabolic syndrome. Clin. Sci. 101:739–47
    [Google Scholar]
  73. 73.
    Kim SH, Park MJ. 2017. Effects of growth hormone on glucose metabolism and insulin resistance in human. Ann. Pediatr. Endocrinol. Metab. 22:145–52
    [Google Scholar]
  74. 74.
    Kim YD, Li T, Ahn SW, Kim DK, Lee JM et al. 2012. Orphan nuclear receptor small heterodimer partner negatively regulates growth hormone-mediated induction of hepatic gluconeogenesis through inhibition of signal transducer and activator of transcription 5 (STAT5) transactivation. J. Biol. Chem. 287:37098–108
    [Google Scholar]
  75. 75.
    Kraus-Friedmann N. 1984. Hormonal regulation of hepatic gluconeogenesis. Physiol. Rev. 64:170–259
    [Google Scholar]
  76. 76.
    Kreisman SH, Ah Mew N, Arsenault M, Nessim SJ, Halter JB et al. 2000. Epinephrine infusion during moderate intensity exercise increases glucose production and uptake. Am. J. Physiol. Endocrinol. Metab. 278:E949–57
    [Google Scholar]
  77. 77.
    Kreisman SH, Ah Mew N, Halter JB, Vranic M, Marliss EB 2001. Norepinephrine infusion during moderate-intensity exercise increases glucose production and uptake. J. Clin. Endocrinol. Metab. 86:2118–24
    [Google Scholar]
  78. 78.
    Laakso M, Kuusisto J. 2014. Insulin resistance and hyperglycaemia in cardiovascular disease development. Nat. Rev. Endocrinol. 10:293–302
    [Google Scholar]
  79. 79.
    LaMoia TE, Butrico GM, Kalpage HA, Goedeke L, Hubbard BT et al. 2022. Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis. PNAS 119:e2122287119
    [Google Scholar]
  80. 80.
    Landau BR, Wahren J, Chandramouli V, Schumann WC, Ekberg K, Kalhan SC. 1996. Contributions of gluconeogenesis to glucose production in the fasted state. J. Clin. Investig. 98:378–85
    [Google Scholar]
  81. 81.
    Lanthier N, Molendi-Coste O, Horsmans Y, van Rooijen N, Cani PD, Leclercq IA. 2010. Kupffer cell activation is a causal factor for hepatic insulin resistance. Am. J. Physiol. Gastrointest. Liver Physiol. 298:G107–16
    [Google Scholar]
  82. 82.
    Lehninger AL, Nelson DL, Cox MM. 2005. Lehninger Principles of Biochemistry New York: W.H. Freeman
  83. 83.
    Leithner K, Hrzenjak A, Trotzmuller M, Moustafa T, Kofeler HC et al. 2015. PCK2 activation mediates an adaptive response to glucose depletion in lung cancer. Oncogene 34:1044–50
    [Google Scholar]
  84. 84.
    Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK et al. 2014. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 99:1915–42
    [Google Scholar]
  85. 85.
    Li B, Qiu B, Lee DS, Walton ZE, Ochocki JD et al. 2014. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513:251–55
    [Google Scholar]
  86. 86.
    Li X, Monks B, Ge Q, Birnbaum MJ. 2007. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1α transcription coactivator. Nature 447:1012–16
    [Google Scholar]
  87. 87.
    Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K et al. 2008. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456:269–73
    [Google Scholar]
  88. 88.
    Lovejoy J, Newby FD, Gebhart SS, DiGirolamo M. 1992. Insulin resistance in obesity is associated with elevated basal lactate levels and diminished lactate appearance following intravenous glucose and insulin. Metabolism 41:22–27
    [Google Scholar]
  89. 89.
    Ma R, Zhang W, Tang K, Zhang H, Zhang Y et al. 2013. Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma. Nat. Commun. 4:2508
    [Google Scholar]
  90. 90.
    Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT et al. 2014. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510:542–46
    [Google Scholar]
  91. 91.
    Magnusson I, Rothman DL, Katz LD, Shulman RG, Shulman GI. 1992. Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J. Clin. Investig. 90:1323–27
    [Google Scholar]
  92. 92.
    Mahendran Y, Cederberg H, Vangipurapu J, Kangas AJ, Soininen P et al. 2013. Glycerol and fatty acids in serum predict the development of hyperglycemia and type 2 diabetes in Finnish men. Diabetes Care 36:3732–38
    [Google Scholar]
  93. 93.
    Marin-Valencia I, Roe CR, Pascual JM. 2010. Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Mol. Genet. Metab. 101:9–17
    [Google Scholar]
  94. 94.
    Martin JD, Fukumura D, Duda DG, Boucher Y, Jain RK. 2016. Reengineering the tumor microenvironment to alleviate hypoxia and overcome cancer heterogeneity. Cold Spring Harb. Perspect. Med. 6:a027094
    [Google Scholar]
  95. 95.
    Mauras N, O'Brien KO, Welch S, Rini A, Helgeson K et al. 2000. Insulin-like growth factor I and growth hormone (GH) treatment in GH-deficient humans: differential effects on protein, glucose, lipid, and calcium metabolism. J. Clin. Endocrinol. Metab. 85:1686–94
    [Google Scholar]
  96. 96.
    McCulloch AJ, Nosadini R, Pernet A, Piniewska M, Cook DB et al. 1983. Glucose turnover and indices of recycling in thyrotoxicosis and primary thyroid failure. Clin. Sci. 64:41–47
    [Google Scholar]
  97. 97.
    McGuinness OP, Shau V, Benson EM, Lewis M, Snowden RT et al. 1997. Role of epinephrine and norepinephrine in the metabolic response to stress hormone infusion in the conscious dog. Am. J. Physiol. 273:E674–81
    [Google Scholar]
  98. 98.
    Mesmar B, Poola-Kella S, Malek R. 2017. The physiology behind diabetes mellitus in patients with pheochromocytoma: a review of the literature. Endocr. Pract. 23:999–1005
    [Google Scholar]
  99. 99.
    Mihaylova MM, Vasquez DS, Ravnskjaer K, Denechaud PD, Yu RT et al. 2011. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145:607–21
    [Google Scholar]
  100. 100.
    Mithieux G, Gautier-Stein A. 2014. Intestinal glucose metabolism revisited. Diabetes Res. Clin. Pract. 105:295–301
    [Google Scholar]
  101. 101.
    Mithieux G, Rajas F, Gautier-Stein A. 2004. A novel role for glucose 6-phosphatase in the small intestine in the control of glucose homeostasis. J. Biol. Chem. 279:44231–34
    [Google Scholar]
  102. 102.
    Mitrou P, Raptis SA, Dimitriadis G. 2010. Insulin action in hyperthyroidism: a focus on muscle and adipose tissue. Endocr. Rev. 31:663–79
    [Google Scholar]
  103. 103.
    Moore MC, Coate KC, Winnick JJ, An Z, Cherrington AD. 2012. Regulation of hepatic glucose uptake and storage in vivo. Adv. Nutr. 3:286–94
    [Google Scholar]
  104. 104.
    Morigny P, Houssier M, Mouisel E, Langin D. 2016. Adipocyte lipolysis and insulin resistance. Biochimie 125:259–66
    [Google Scholar]
  105. 105.
    Muller C, Assimacopoulos-Jeannet F, Mosimann F, Schneiter P, Riou JP et al. 1997. Endogenous glucose production, gluconeogenesis and liver glycogen concentration in obese non-diabetic patients. Diabetologia 40:463–68
    [Google Scholar]
  106. 106.
    Mutel E, Gautier-Stein A, Abdul-Wahed A, Amigo-Correig M, Zitoun C et al. 2011. Control of blood glucose in the absence of hepatic glucose production during prolonged fasting in mice: induction of renal and intestinal gluconeogenesis by glucagon. Diabetes 60:3121–31
    [Google Scholar]
  107. 107.
    Nielsen MF, Caumo A, Chandramouli V, Schumann WC, Cobelli C et al. 2004. Impaired basal glucose effectiveness but unaltered fasting glucose release and gluconeogenesis during short-term hypercortisolemia in healthy subjects. Am. J. Physiol. Endocrinol. Metab. 286:E102–10
    [Google Scholar]
  108. 108.
    Opherk C, Tronche F, Kellendonk C, Kohlmuller D, Schulze A et al. 2004. Inactivation of the glucocorticoid receptor in hepatocytes leads to fasting hypoglycemia and ameliorates hyperglycemia in streptozotocin-induced diabetes mellitus. Mol. Endocrinol. 18:1346–53
    [Google Scholar]
  109. 109.
    Perez G, Ungaro B, Covelli A, Morrone G, Lombardi G et al. 1980. Altered glucoregulatory response to physiological infusions of epinephrine and glucagon in hyperthyroidism. J. Clin. Endocrinol. Metab. 51:972–77
    [Google Scholar]
  110. 110.
    Petersen MC, Shulman GI. 2018. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98:2133–223
    [Google Scholar]
  111. 111.
    Petersen MC, Vatner DF, Shulman GI. 2017. Regulation of hepatic glucose metabolism in health and disease. Nat. Rev. Endocrinol. 13:572–87
    [Google Scholar]
  112. 112.
    Petrova IO, Smirnikhina SA. 2022. Studies on glycogen storage disease type 1a animal models: a brief perspective. Transgenic Res. 31:593–606
    [Google Scholar]
  113. 113.
    Pfeiffer T, Schuster S, Bonhoeffer S. 2001. Cooperation and competition in the evolution of ATP-producing pathways. Science 292:504–7
    [Google Scholar]
  114. 114.
    Rafacho A, Goncalves-Neto LM, Santos-Silva JC, Alonso-Magdalena P, Merino B et al. 2014. Pancreatic alpha-cell dysfunction contributes to the disruption of glucose homeostasis and compensatory insulin hypersecretion in glucocorticoid-treated rats. PLOS ONE 9:e93531
    [Google Scholar]
  115. 115.
    Rahim M, Hasenour CM, Bednarski TK, Hughey CC, Wasserman DH, Young JD. 2021. Multitissue 2H/13C flux analysis reveals reciprocal upregulation of renal gluconeogenesis in hepatic PEPCK-C-knockout mice. JCI Insight 6:e149278
    [Google Scholar]
  116. 116.
    Raza M, Arif F, Giyanwani PR, Azizullah S, Kumari S. 2017. Dietary therapy for Von Gierke's disease: a case report. Cureus 9:e1548
    [Google Scholar]
  117. 117.
    Resmini E, Minuto F, Colao A, Ferone D. 2009. Secondary diabetes associated with principal endocrinopathies: the impact of new treatment modalities. Acta Diabetol. 46:85–95
    [Google Scholar]
  118. 118.
    Rosenstock J, Banarer S, Fonseca VA, Inzucchi SE, Sun W et al. 2010. The 11-β-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy. Diabetes Care 33:1516–22
    [Google Scholar]
  119. 119.
    Rui L. 2014. Energy metabolism in the liver. Compr. Physiol. 4:177–97
    [Google Scholar]
  120. 120.
    Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F et al. 2013. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the task force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur. Heart J. 34:3035–87
    [Google Scholar]
  121. 121.
    Rytka JM, Wueest S, Schoenle EJ, Konrad D 2011. The portal theory supported by venous drainage-selective fat transplantation. Diabetes 60:56–63
    [Google Scholar]
  122. 122.
    Sakharova AA, Horowitz JF, Surya S, Goldenberg N, Harber MP et al. 2008. Role of growth hormone in regulating lipolysis, proteolysis, and hepatic glucose production during fasting. J. Clin. Endocrinol. Metab. 93:2755–59
    [Google Scholar]
  123. 123.
    Saklayen MG. 2018. The global epidemic of the metabolic syndrome. Curr. Hypertens. Rep. 20:12
    [Google Scholar]
  124. 124.
    Saltiel AR, Kahn CR. 2001. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806
    [Google Scholar]
  125. 125.
    Sandler MP, Robinson RP, Rabin D, Lacy WW, Abumrad NN. 1983. The effect of thyroid hormones on gluconeogenesis and forearm metabolism in man. J. Clin. Endocrinol. Metab. 56:479–85
    [Google Scholar]
  126. 126.
    Schwarz JM, Mulligan K, Lee J, Lo JC, Wen M et al. 2002. Effects of recombinant human growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation. J. Clin. Endocrinol. Metab. 87:942–45
    [Google Scholar]
  127. 127.
    Shah A, Wang Y, Wondisford FE. 2022. Differential metabolism of glycerol based on oral versus intravenous administration in humans. Metabolites 12:890
    [Google Scholar]
  128. 128.
    Shah AM, Wondisford FE. 2020. Tracking the carbons supplying gluconeogenesis. J. Biol. Chem. 295:14419–29
    [Google Scholar]
  129. 129.
    Sharma R, Tiwari S. 2021. Renal gluconeogenesis in insulin resistance: a culprit for hyperglycemia in diabetes. World J. Diabetes 12:556–68
    [Google Scholar]
  130. 130.
    She P, Burgess SC, Shiota M, Flakoll P, Donahue EP et al. 2003. Mechanisms by which liver-specific PEPCK knockout mice preserve euglycemia during starvation. Diabetes 52:1649–54
    [Google Scholar]
  131. 131.
    Shieh JJ, Pan CJ, Mansfield BC, Chou JY. 2003. A glucose-6-phosphate hydrolase, widely expressed outside the liver, can explain age-dependent resolution of hypoglycemia in glycogen storage disease type Ia. J. Biol. Chem. 278:47098–103
    [Google Scholar]
  132. 132.
    Shieh JJ, Pan CJ, Mansfield BC, Chou JY. 2004. A potential new role for muscle in blood glucose homeostasis. J. Biol. Chem. 279:26215–19
    [Google Scholar]
  133. 133.
    Shiratori R, Furuichi K, Yamaguchi M, Miyazaki N, Aoki H et al. 2019. Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner. Sci. Rep. 9:18699
    [Google Scholar]
  134. 134.
    Stark R, Guebre-Egziabher F, Zhao X, Feriod C, Dong J et al. 2014. A role for mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) in the regulation of hepatic gluconeogenesis. J. Biol. Chem. 289:7257–63
    [Google Scholar]
  135. 135.
    Stumvoll M, Chintalapudi U, Perriello G, Welle S, Gutierrez O, Gerich J. 1995. Uptake and release of glucose by the human kidney. Postabsorptive rates and responses to epinephrine. J. Clin. Investig. 96:2528–33
    [Google Scholar]
  136. 136.
    Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. 1995. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N. Engl. J. Med. 333:550–54
    [Google Scholar]
  137. 137.
    Suh JH, Sieglaff DH, Zhang A, Xia X, Cvoro A et al. 2013. SIRT1 is a direct coactivator of thyroid hormone receptor β1 with gene-specific actions. PLOS ONE 8:e70097
    [Google Scholar]
  138. 138.
    Sunny NE, Parks EJ, Browning JD, Burgess SC. 2011. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 14:804–10
    [Google Scholar]
  139. 139.
    Taguchi Y, Tasaki Y, Terakado K, Kobayashi K, Machida T, Kobayashi T. 2010. Impaired insulin secretion from the pancreatic islets of hypothyroidal growth-retarded mice. J. Endocrinol. 206:195–204
    [Google Scholar]
  140. 140.
    Thorens B. 2015. GLUT2, glucose sensing and glucose homeostasis. Diabetologia 58:221–32
    [Google Scholar]
  141. 141.
    Tran C. 2017. Inborn errors of fructose metabolism. What can we learn from them?. Nutrients 9:356
    [Google Scholar]
  142. 142.
    US Dep. Health Hum. Serv 2020. National diabetes statistics report, 2020 Rep. Cent. Dis. Control Prev. Atlanta, GA:
  143. 143.
    van den Berghe G 1996. Disorders of gluconeogenesis. J. Inherit. Metab. Dis. 19:470–77
    [Google Scholar]
  144. 144.
    van Poelje PD, Potter SC, Erion MD. 2011. Fructose-1, 6-bisphosphatase inhibitors for reducing excessive endogenous glucose production in type 2 diabetes. Handbook of Experimental Pharmacology, Vol. 203 Diabetes—Perspectives in Drug Therapy M Schwanstecher 279–301. Berlin/Heidelberg: Springer
    [Google Scholar]
  145. 145.
    Wang B, Hsu SH, Frankel W, Ghoshal K, Jacob ST. 2012. Stat3-mediated activation of microRNA-23a suppresses gluconeogenesis in hepatocellular carcinoma by down-regulating glucose-6-phosphatase and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha. Hepatology 56:186–97
    [Google Scholar]
  146. 146.
    Wang D, De Vivo D 1993. Pyruvate carboxylase deficiency. GeneReviews MP Adam, DB Everman, GM Mirzaa, RA Pagon, SE Wallace et al. Seattle, WA: Univ. Washington
    [Google Scholar]
  147. 147.
    Westergaard N, Madsen P. 2001. Glucose-6-phosphatase inhibitors for the treatment of type 2 diabetes. Expert Opin. Ther. Pat. 11:1429–41
    [Google Scholar]
  148. 148.
    Williamson JR, Browning ET, Scholz R. 1969. Control mechanisms of gluconeogenesis and ketogenesis. I. Effects of oleate on gluconeogenesis in perfused rat liver. J. Biol. Chem. 244:4607–16
    [Google Scholar]
  149. 149.
    Winnick JJ, Ramnanan CJ, Saraswathi V, Roop J, Scott M et al. 2013. Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis. Am. J. Physiol. Endocrinol. Metab. 304:E747–56
    [Google Scholar]
  150. 150.
    Wishart DS, Feunang YD, Marcu A, Guo AC, Liang K et al. 2018. HMDB 4.0: the human metabolome database for 2018. Nucleic Acids Res. 46:D608–17
    [Google Scholar]
  151. 151.
    Woerle HJ, Szoke E, Meyer C, Dostou JM, Wittlin SD et al. 2006. Mechanisms for abnormal postprandial glucose metabolism in type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 290:E67–77
    [Google Scholar]
  152. 152.
    Wondmkun YT. 2020. Obesity, insulin resistance, and type 2 diabetes: associations and therapeutic implications. Diabetes Metab. Syndr. Obes. 13:3611–16
    [Google Scholar]
  153. 153.
    Wu Z, Jiao P, Huang X, Feng B, Feng Y et al. 2010. MAPK phosphatase-3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice. J. Clin. Investig. 120:3901–11
    [Google Scholar]
  154. 154.
    Ximenes HM, Lortz S, Jorns A, Lenzen S. 2007. Triiodothyronine (T3)-mediated toxicity and induction of apoptosis in insulin-producing INS-1 cells. Life Sci. 80:2045–50
    [Google Scholar]
  155. 155.
    Yi SW, Park S, Lee YH, Balkau B, Yi JJ. 2018. Fasting glucose and all-cause mortality by age in diabetes: a prospective cohort study. Diabetes Care 41:623–26
    [Google Scholar]
  156. 156.
    Yip J, Geng X, Shen J, Ding Y. 2016. Cerebral gluconeogenesis and diseases. Front. Pharmacol. 7:521
    [Google Scholar]
  157. 157.
    Yu S, Meng S, Xiang M, Ma H. 2021. Phosphoenolpyruvate carboxykinase in cell metabolism: roles and mechanisms beyond gluconeogenesis. Mol. Metab. 53:101257
    [Google Scholar]
  158. 158.
    Zhang X, Yang S, Chen J, Su Z. 2018. Unraveling the regulation of hepatic gluconeogenesis. Front. Endocrinol. 9:802
    [Google Scholar]
  159. 159.
    Zhou XY, Shibusawa N, Naik K, Porras D, Temple K et al. 2004. Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein. Nat. Med. 10:633–37
    [Google Scholar]
/content/journals/10.1146/annurev-nutr-061121-091507
Loading
/content/journals/10.1146/annurev-nutr-061121-091507
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error