Pyruvate cycling explained

Pyruvate cycling commonly refers to an intracellular loop of spatial movements and chemical transformations involving pyruvate. Spatial movements occur between mitochondria and cytosol and chemical transformations create various Krebs cycle intermediates. In all variants, pyruvate is imported into the mitochondrion for processing through part of the Krebs cycle. In addition to pyruvate, alpha-ketoglutarate may also be imported. At various points, the intermediate product is exported to the cytosol for additional transformations and then re-imported. Three specific pyruvate cycles are generally considered,^[1] each named for the principal molecule exported from the mitochondrion: malate, citrate, and isocitrate. Other variants may exist, such as dissipative or "futile" pyruvate cycles.^{[2] [3]}

This cycle is usually studied in relation to Glucose Stimulated Insulin Secretion (or GSIS) and there is thought to be a relationship between the insulin response and NADPH produced from this cycle^{[4] [5]} but the specifics are not clear and particular confusion exists about the role of malic enzymes.^{[6] [7]} It has been observed in various cell types including islet cells.

The pyruvate-malate cycle was described in liver and kidney preparations as early as 1971.^[8]

Further reading

• • Kley S, Hoenig M, Glushka J, etal . The impact of obesity, sex, and diet on hepatic glucose production in cats . American Journal of Physiology. Regulatory, Integrative and Comparative Physiology . 296 . 4 . R936–43 . April 2009 . 19193946 . 10.1152/ajpregu.90771.2008 . 2698604.
• Li C, Nissim I, Chen P, etal . Elimination of KATP Channels in Mouse Islets Results in Elevated U-13CGlucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt . The Journal of Biological Chemistry . 283 . 25 . 17238–49 . June 2008 . 18445600 . 2427330 . 10.1074/jbc.M709235200 . free .
• Ronnebaum SM, Joseph JW, Ilkayeva O, etal . Chronic Suppression of Acetyl-CoA Carboxylase 1 in β-Cells Impairs Insulin Secretion via Inhibition of Glucose Rather Than Lipid Metabolism . The Journal of Biological Chemistry . 283 . 21 . 14248–56 . May 2008 . 18381287 . 2386941 . 10.1074/jbc.M800119200 . free .
• Burgess SC, Iizuka K, Jeoung NH, etal . Carbohydrate-response element-binding protein deletion alters substrate utilization producing an energy-deficient liver . The Journal of Biological Chemistry . 283 . 3 . 1670–8 . January 2008 . 18042547 . 10.1074/jbc.M706540200 . free .
  • Jin ES, Park BH, Sherry AD, Malloy CR . Role of excess glycogenolysis in fasting hyperglycemia among pre-diabetic and diabetic Zucker (fa/fa) rats . Diabetes . 56 . 3 . 777–85 . March 2007 . 17327448 . 10.2337/db06-0717 . free .
• Rajas F, Jourdan-Pineau H, Stefanutti A, Mrad EA, Iynedjian PB, Mithieux G . Immunocytochemical localization of glucose 6-phosphatase and cytosolic phosphoenolpyruvate carboxykinase in gluconeogenic tissues reveals unsuspected metabolic zonation . Histochemistry and Cell Biology . 127 . 5 . 555–65 . May 2007 . 17211624 . 10.1007/s00418-006-0263-5 . 20621391 .
• Fransson U, Rosengren AH, Schuit FC, Renström E, Mulder H . Anaplerosis via pyruvate carboxylase is required for the fuel-induced rise in the ATP:ADP ratio in rat pancreatic islets . Diabetologia . 49 . 7 . 1578–86 . July 2006 . 16752176 . 10.1007/s00125-006-0263-y . free .
• Jensen MV, Joseph JW, Ilkayeva O, etal . Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion . The Journal of Biological Chemistry . 281 . 31 . 22342–51 . August 2006 . 16740637 . 10.1074/jbc.M604350200 . free .
• Jin ES, Burgess SC, Merritt ME, Sherry AD, Malloy CR . Differing mechanisms of hepatic glucose overproduction in triiodothyronine-treated rats vs. Zucker diabetic fatty rats by NMR analysis of plasma glucose . American Journal of Physiology. Endocrinology and Metabolism . 288 . 4 . E654–62 . April 2005 . 15562253 . 10.1152/ajpendo.00365.2004 . 5870945 .
• Burgess SC, Hausler N, Merritt M, etal . Impaired tricarboxylic acid cycle activity in mouse livers lacking cytosolic phosphoenolpyruvate carboxykinase . The Journal of Biological Chemistry . 279 . 47 . 48941–9 . November 2004 . 15347677 . 10.1074/jbc.M407120200 . free .
• Thompson SN . Dietary fat mediates hyperglycemia and the glucogenic response to increased protein consumption in an insect, Manduca sexta L . Biochimica et Biophysica Acta (BBA) - General Subjects . 1673 . 3 . 208–16 . August 2004 . 15279893 . 10.1016/j.bbagen.2004.05.002 .
• Boucher A, Lu D, Burgess SC, etal . Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue . The Journal of Biological Chemistry . 279 . 26 . 27263–71 . June 2004 . 15073188 . 10.1074/jbc.M401167200 . free .
• Jin ES, Jones JG, Merritt M, Burgess SC, Malloy CR, Sherry AD . Glucose production, gluconeogenesis, and hepatic tricarboxylic acid cycle fluxes measured by nuclear magnetic resonance analysis of a single glucose derivative . Analytical Biochemistry . 327 . 2 . 149–55 . April 2004 . 15051530 . 10.1016/j.ab.2003.12.036 . 10316/3869 . free .
• She P, Burgess SC, Shiota M, etal . Mechanisms by which liver-specific PEPCK knockout mice preserve euglycemia during starvation . Diabetes . 52 . 7 . 1649–54 . July 2003 . 12829628 . 10.2337/diabetes.52.7.1649.
• Thompson SN, Borchardt DB, Wang LW . Dietary nutrient levels regulate protein and carbohydrate intake, gluconeogenic/glycolytic flux and blood trehalose level in the insect Manduca sexta L . Journal of Comparative Physiology B . 173 . 2 . 149–63 . March 2003 . 12624653 . 10.1007/s00360-002-0322-8 . 21527819 .
• Newgard CB, Lu D, Jensen MV, etal . Stimulus/secretion coupling factors in glucose-stimulated insulin secretion: insights gained from a multidisciplinary approach . Diabetes . 51 Suppl 3 . 90003. S389–93 . December 2002 . 12475781 . 10.2337/diabetes.51.2007.S389. free .
• Thompson SN, Redak RA, Borchardt DB . The glucogenic response of a parasitized insect Manduca sexta L. is partially mediated by differential nutrient intake . Biochimica et Biophysica Acta (BBA) - General Subjects . 1571 . 2 . 138–50 . June 2002 . 12049794 . 10.1016/S0304-4165(02)00208-8.
• Lu D, Mulder H, Zhao P, etal . 13C NMR isotopomer analysis reveals a connection between pyruvate cycling and glucose-stimulated insulin secretion (GSIS) . Proceedings of the National Academy of Sciences of the United States of America . 99 . 5 . 2708–13 . March 2002 . 11880625 . 122412 . 10.1073/pnas.052005699 . free .
• Thompson SN . Parasitism enhances the induction of glucogenesis by the insect, Manduca sexta L . The International Journal of Biochemistry & Cell Biology . 33 . 2 . 163–73 . February 2001 . 11240373 . 10.1016/S1357-2725(00)00079-0.
• Thompson SN . Pyruvate cycling and implications for regulation of gluconeogenesis in the insect, Manduca sexta L . Biochemical and Biophysical Research Communications . 274 . 3 . 787–93 . August 2000 . 10924355 . 10.1006/bbrc.2000.3238 .
• Landau BR, Chandramouli V, Schumann WC, etal . Estimates of Krebs cycle activity and contributions of gluconeogenesis to hepatic glucose production in fasting healthy subjects and IDDM patients . Diabetologia . 38 . 7 . 831–8 . July 1995 . 7556986 . 10.1007/s001250050360 . free .
• Tosh D, Beresford G, Agius L . Glycogen synthesis from glucose by direct and indirect pathways in hepatocyte cultures from different nutritional states . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1224 . 2 . 205–12 . November 1994 . 7981234 . 10.1016/0167-4889(94)90192-9.
  • Kunz WS, Davis EJ . Control of reversible intracellular transfer of reducing potential . Archives of Biochemistry and Biophysics . 284 . 1 . 40–6 . January 1991 . 1824912 . 10.1016/0003-9861(91)90260-P.
  • Rognstad R . Pyruvate cycling involving possible oxaloacetate decarboxylase activity . Biochimica et Biophysica Acta (BBA) - General Subjects . 586 . 2 . 242–9 . August 1979 . 476141 . 10.1016/0304-4165(79)90096-5.

External links

• FIGURE 2: Biochemical mechanisms of glucose-stimulated insulin secretion, including roles of the pyruvate cycling pathways of the β-cell . Nature Reviews Molecular Cell Biology . March 2008 . 9 . 3 . 193–205 . 10.1038/nrm2327 . Muoio . Deborah M. . Newgard . Christopher B. . 18200017 . from 10.1038/nrm2327 . 18200017 . Mechanisms of disease: Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes . 2008 . Muoio . Deborah M. . Deborah Muoio. Newgard . Christopher B. . Nature Reviews Molecular Cell Biology . 9 . 3 . 193–205. 3335727 .

Notes and References

1. Ronnebaum SM, Ilkayeva O, Burgess SC, etal . A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion . The Journal of Biological Chemistry . 281 . 41 . 30593–602 . October 2006 . 16912049 . 10.1074/jbc.M511908200. free .
2. Gregory RB, Berry MN . Stimulation by thyroid hormone of coupled respiration and of respiration apparently not coupled to the synthesis of ATP in rat hepatocytes . The Journal of Biological Chemistry . 267 . 13 . 8903–8 . May 1992 . 10.1016/S0021-9258(19)50365-9 . 1577728 . free .
3. Agius L, Tosh D, Peak M . The contribution of pyruvate cycling to loss of 6-3Hglucose during conversion of glucose to glycogen in hepatocytes: effects of insulin, glucose and acinar origin of hepatocytes . The Biochemical Journal . 289 . Pt 1 . 255–62 . January 1993 . 8380985 . 1132158 . 10.1042/bj2890255.
4. Book: Pongratz RL, Kibbey RG, Cline GW . Mitochondrial Function, Part B: Mitochondrial Protein Kinases, Protein Phosphatases and Mitochondrial Diseases . Chapter 24 Investigating the Roles of Mitochondrial and Cytosolic Malic Enzyme in Insulin Secretion . 457 . 425–50 . 2009 . 19426882 . 10.1016/S0076-6879(09)05024-1 . Methods in Enzymology . 978-0-12-374622-1. 4422111 .
5. Guay C, Madiraju SR, Aumais A, Joly E, Prentki M . A role for ATP-citrate lyase, malic enzyme, and pyruvate/citrate cycling in glucose-induced insulin secretion . The Journal of Biological Chemistry . 282 . 49 . 35657–65 . December 2007 . 17928289 . 10.1074/jbc.M707294200 . free .
6. Ronnebaum SM, Jensen MV, Hohmeier HE, etal . Silencing of Cytosolic or Mitochondrial Isoforms of Malic Enzyme Has No Effect on Glucose-stimulated Insulin Secretion from Rodent Islets . The Journal of Biological Chemistry . 283 . 43 . 28909–17 . October 2008 . 18755687 . 2570884 . 10.1074/jbc.M804665200 . free .
7. Heart E, Cline GW, Collis LP, Pongratz RL, Gray JP, Smith PJ . Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion . American Journal of Physiology. Endocrinology and Metabolism . 296 . 6 . E1354–62 . June 2009 . 19293334 . 10.1152/ajpendo.90836.2008 . 2692397.
8. Scaduto RC, Davis EJ . The involvement of pyruvate cycling in the metabolism of aspartate and glycerate by the perfused rat kidney . The Biochemical Journal . 237 . 3 . 691–8 . August 1986 . 3800911 . 1147046 . 10.1042/bj2370691.