Pyruvate cycling

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]

## References

1. ↑ "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. doi:10.1074/jbc.M511908200. PMID 16912049.
2. ↑ "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. doi:10.1016/S0021-9258(19)50365-9. PMID 1577728. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1577728.
3. ↑ "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. doi:10.1042/bj2890255. PMID 8380985.
4. ↑ "Chapter 24 Investigating the Roles of Mitochondrial and Cytosolic Malic Enzyme in Insulin Secretion". Mitochondrial Function, Part B: Mitochondrial Protein Kinases, Protein Phosphatases and Mitochondrial Diseases. Methods in Enzymology. 457. 2009. pp. 425–50. doi:10.1016/S0076-6879(09)05024-1. ISBN 978-0-12-374622-1.
5. ↑ "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. doi:10.1074/jbc.M707294200. PMID 17928289.
6. ↑ "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. doi:10.1074/jbc.M804665200. PMID 18755687.
7. ↑ "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. doi:10.1152/ajpendo.90836.2008. PMID 19293334.
8. ↑ "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. doi:10.1042/bj2370691. PMID 3800911.

## Further reading

*   * "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. doi:10.1152/ajpregu.90771.2008. PMID 19193946.
* "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. doi:10.1074/jbc.M709235200. PMID 18445600.
* "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. doi:10.1074/jbc.M800119200. PMID 18381287.
* "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. doi:10.1074/jbc.M706540200. PMID 18042547.
*   * "Role of excess glycogenolysis in fasting hyperglycemia among pre-diabetic and diabetic Zucker (fa/fa) rats". Diabetes 56 (3): 777–85. March 2007. doi:10.2337/db06-0717. PMID 17327448.
* "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. doi:10.1007/s00418-006-0263-5. PMID 17211624.
* "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. doi:10.1007/s00125-006-0263-y. PMID 16752176.
* "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. doi:10.1074/jbc.M604350200. PMID 16740637.
* "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. doi:10.1152/ajpendo.00365.2004. PMID 15562253.
* "Impaired tricarboxylic acid cycle activity in mouse livers lacking cytosolic phosphoenolpyruvate carboxykinase". The Journal of Biological Chemistry 279 (47): 48941–9. November 2004. doi:10.1074/jbc.M407120200. PMID 15347677.
* Thompson SN (August 2004). "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. doi:10.1016/j.bbagen.2004.05.002. PMID 15279893.
* "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. doi:10.1074/jbc.M401167200. PMID 15073188.
* "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. doi:10.1016/j.ab.2003.12.036. PMID 15051530.
* "Mechanisms by which liver-specific PEPCK knockout mice preserve euglycemia during starvation". Diabetes 52 (7): 1649–54. July 2003. doi:10.2337/diabetes.52.7.1649. PMID 12829628.
* "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. doi:10.1007/s00360-002-0322-8. PMID 12624653.
* "Stimulus/secretion coupling factors in glucose-stimulated insulin secretion: insights gained from a multidisciplinary approach". Diabetes 51 Suppl 3 (90003): S389–93. December 2002. doi:10.2337/diabetes.51.2007.S389. PMID 12475781.
* "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. doi:10.1016/S0304-4165(02)00208-8. PMID 12049794.
* "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. doi:10.1073/pnas.052005699. PMID 11880625.
* Thompson SN (February 2001). "Parasitism enhances the induction of glucogenesis by the insect, Manduca sexta L". The International Journal of Biochemistry & Cell Biology 33 (2): 163–73. doi:10.1016/S1357-2725(00)00079-0. PMID 11240373.
* Thompson SN (August 2000). "Pyruvate cycling and implications for regulation of gluconeogenesis in the insect, Manduca sexta L". Biochemical and Biophysical Research Communications 274 (3): 787–93. doi:10.1006/bbrc.2000.3238. PMID 10924355.
* "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. doi:10.1007/s001250050360. PMID 7556986.
* "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. doi:10.1016/0167-4889(94)90192-9. PMID 7981234.
*   * "Control of reversible intracellular transfer of reducing potential". Archives of Biochemistry and Biophysics 284 (1): 40–6. January 1991. doi:10.1016/0003-9861(91)90260-P. PMID 1824912.
*   * Rognstad R (August 1979). "Pyruvate cycling involving possible oxaloacetate decarboxylase activity". Biochimica et Biophysica Acta (BBA) - General Subjects 586 (2): 242–9. doi:10.1016/0304-4165(79)90096-5. PMID 476141.

## External links

* Muoio, Deborah M.; Newgard, Christopher B. (March 2008). "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 9 (3): 193–205. doi:10.1038/nrm2327. PMID 18200017. https://www.nature.com/nrm/journal/v9/n3/fig_tab/nrm2327_F2.html. from Muoio, Deborah M.; Newgard, Christopher B. (2008). "Mechanisms of disease: Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes". Nature Reviews Molecular Cell Biology 9 (3): 193–205. doi:10.1038/nrm2327. PMID 18200017.

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