Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue - PubMed

Affiliations

• PMID: 15073188
• DOI: 10.1074/jbc.M401167200

Free article

Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue

Anne Boucher et al. J Biol Chem. 2004.

Free article

Abstract

Hyperlipidemia appears to play an integral role in loss of glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. This impairment can be simulated in vitro by chronic culture of 832/13 insulinoma cells with high concentrations of free fatty acids, or by study of lipid-laden islets from Zucker diabetic fatty rats. Here we show that impaired GSIS is not a simple result of saturation of lipid storage pathways, as adenovirus-mediated overexpression of a cytosolically localized variant of malonyl-CoA decarboxylase in either cellular model results in dramatic lowering of cellular triglyceride stores but no improvement in GSIS. Instead, the glucose-induced increment in "pyruvate cycling" activity (pyruvate exchange with tricarboxylic acid cycle intermediates measured by (13)C NMR), previously shown to play an important role in GSIS, is completely ablated in concert with profound suppression of GSIS in lipid-cultured 832/13 cells, whereas glucose oxidation is unaffected. Moreover, GSIS is partially restored in both lipid-cultured 832/13 cells and islets from Zucker diabetic fatty rats by addition of a membrane permeant ester of a pyruvate cycling intermediate (dimethyl malate). We conclude that chronic exposure of islet beta-cells to fatty acids grossly alters a mitochondrial pathway of pyruvate metabolism that is important for normal GSIS.

Similar articles

• beta-Cell adaptation to insulin resistance. Increased pyruvate carboxylase and malate-pyruvate shuttle activity in islets of nondiabetic Zucker fatty rats.

  Liu YQ, Jetton TL, Leahy JL. Liu YQ, et al. J Biol Chem. 2002 Oct 18;277(42):39163-8. doi: 10.1074/jbc.M207157200. Epub 2002 Jul 29. J Biol Chem. 2002. PMID: 12147706

• The dicarboxylate carrier plays a role in mitochondrial malate transport and in the regulation of glucose-stimulated insulin secretion from rat pancreatic beta cells.

  Huypens P, Pillai R, Sheinin T, Schaefer S, Huang M, Odegaard ML, Ronnebaum SM, Wettig SD, Joseph JW. Huypens P, et al. Diabetologia. 2011 Jan;54(1):135-45. doi: 10.1007/s00125-010-1923-5. Epub 2010 Oct 15. Diabetologia. 2011. PMID: 20949348

• Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion.

  Heart E, Cline GW, Collis LP, Pongratz RL, Gray JP, Smith PJ. Heart E, et al. Am J Physiol Endocrinol Metab. 2009 Jun;296(6):E1354-62. doi: 10.1152/ajpendo.90836.2008. Epub 2009 Mar 17. Am J Physiol Endocrinol Metab. 2009. PMID: 19293334 Free PMC article.

• Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications.

  Unger RH. Unger RH. Diabetes. 1995 Aug;44(8):863-70. doi: 10.2337/diab.44.8.863. Diabetes. 1995. PMID: 7621989 Review.

• Metabolic coupling factors in pancreatic beta-cell signal transduction.

  Newgard CB, McGarry JD. Newgard CB, et al. Annu Rev Biochem. 1995;64:689-719. doi: 10.1146/annurev.bi.64.070195.003353. Annu Rev Biochem. 1995. PMID: 7574498 Review.

Cited by

• Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism.

  Ronnebaum SM, Joseph JW, Ilkayeva O, Burgess SC, Lu D, Becker TC, Sherry AD, Newgard CB. Ronnebaum SM, et al. J Biol Chem. 2008 May 23;283(21):14248-56. doi: 10.1074/jbc.M800119200. Epub 2008 Apr 1. J Biol Chem. 2008. PMID: 18381287 Free PMC article.

• Malic enzyme tracers reveal hypoxia-induced switch in adipocyte NADPH pathway usage.

  Liu L, Shah S, Fan J, Park JO, Wellen KE, Rabinowitz JD. Liu L, et al. Nat Chem Biol. 2016 May;12(5):345-52. doi: 10.1038/nchembio.2047. Epub 2016 Mar 21. Nat Chem Biol. 2016. PMID: 26999781 Free PMC article.

• Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes.

  Rivera Nieves AM, Wauford BM, Fu A. Rivera Nieves AM, et al. Front Mol Biosci. 2024 Feb 9;11:1354199. doi: 10.3389/fmolb.2024.1354199. eCollection 2024. Front Mol Biosci. 2024. PMID: 38404962 Free PMC article. Review.

• What Have Metabolomics Approaches Taught Us About Type 2 Diabetes?

  Gonzalez-Franquesa A, Burkart AM, Isganaitis E, Patti ME. Gonzalez-Franquesa A, et al. Curr Diab Rep. 2016 Aug;16(8):74. doi: 10.1007/s11892-016-0763-1. Curr Diab Rep. 2016. PMID: 27319324 Free PMC article. Review.

• Metabolomics applied to the pancreatic islet.

  Gooding JR, Jensen MV, Newgard CB. Gooding JR, et al. Arch Biochem Biophys. 2016 Jan 1;589:120-30. doi: 10.1016/j.abb.2015.06.013. Epub 2015 Jun 25. Arch Biochem Biophys. 2016. PMID: 26116790 Free PMC article. Review.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Other Literature Sources

  • The Lens - Patent Citations Database

• Medical

  • MedlinePlus Health Information