Silencing of Cytosolic or Mitochondrial Isoforms of Malic Enzyme Has No Effect on Glucose-stimulated Insulin Secretion from Rodent Islets

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2008 Aug 30

PMID 18755687

Citations 45

Authors

Sarah M Ronnebaum

Mette V Jensen

Hans E Hohmeier

Shawn C Burgess

Yun-Ping Zhou

Su Qian

Douglas MacNeil

Andrew Howard

Nancy Thornberry

Olga Ilkayeva

Danhong Lu

A Dean Sherry

Christopher B Newgard

Affiliations

Soon will be listed here.

Abstract

We have previously demonstrated a role for pyruvate cycling in glucose-stimulated insulin secretion (GSIS). Some of the possible pyruvate cycling pathways are completed by conversion of malate to pyruvate by malic enzyme. Using INS-1-derived 832/13 cells, it has recently been shown by other laboratories that NADP-dependent cytosolic malic enzyme (MEc), but not NAD-dependent mitochondrial malic enzyme (MEm), regulates GSIS. In the current study, we show that small interfering RNA-mediated suppression of either MEm or MEc results in decreased GSIS in both 832/13 cells and a new and more glucose- and incretin-responsive INS-1-derived cell line, 832/3. The effect of MEm to suppress GSIS in these cell lines was linked to a substantial decrease in cell growth, whereas MEc suppression resulted in decreased NADPH, shown previously to be correlated with GSIS. However, adenovirus-mediated delivery of small interfering RNAs specific to MEc and MEm to isolated rat islets, while leading to effective suppression of the targets transcripts, had no effect on GSIS. Furthermore, islets isolated from MEc-null MOD1(-/-) mice exhibit normal glucose- and potassium-stimulated insulin secretion. These results indicate that pyruvate-malate cycling does not control GSIS in primary rodent islets.

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References

Hohmeier H, Newgard C . Cell lines derived from pancreatic islets. Mol Cell Endocrinol. 2004; 228(1-2):121-8. DOI: 10.1016/j.mce.2004.04.017. View

Milburn Jr J, Hirose H, Lee Y, Nagasawa Y, Ogawa A, Ohneda M . Pancreatic beta-cells in obesity. Evidence for induction of functional, morphologic, and metabolic abnormalities by increased long chain fatty acids. J Biol Chem. 1995; 270(3):1295-9. DOI: 10.1074/jbc.270.3.1295. View

Herrero L, Rubi B, Sebastian D, Serra D, Asins G, Maechler P . Alteration of the malonyl-CoA/carnitine palmitoyltransferase I interaction in the beta-cell impairs glucose-induced insulin secretion. Diabetes. 2005; 54(2):462-71. DOI: 10.2337/diabetes.54.2.462. View

Gunawardana S, Liu Y, MacDonald M, Straub S, Sharp G . Anaplerotic input is sufficient to induce time-dependent potentiation of insulin release in rat pancreatic islets. Am J Physiol Endocrinol Metab. 2004; 287(5):E828-33. DOI: 10.1152/ajpendo.00381.2003. View

Ivarsson R, Quintens R, Dejonghe S, Tsukamoto K, In t Veld P, Renstrom E . Redox control of exocytosis: regulatory role of NADPH, thioredoxin, and glutaredoxin. Diabetes. 2005; 54(7):2132-42. DOI: 10.2337/diabetes.54.7.2132. View

Cobb R, Burkhart J, Dubins J, BARNETT L, Lewis S . Biochemical and molecular analysis of spontaneous and induced mutations at the mouse Mod-1 locus. Mutat Res. 1990; 234(1):1-7. DOI: 10.1016/0165-1161(90)90024-i. View

Lu D, Mulder H, Zhao P, Burgess S, Jensen M, Kamzolova S . 13C NMR isotopomer analysis reveals a connection between pyruvate cycling and glucose-stimulated insulin secretion (GSIS). Proc Natl Acad Sci U S A. 2002; 99(5):2708-13. PMC: 122412. DOI: 10.1073/pnas.052005699. View

Muoio D, Newgard C . Mechanisms of disease:Molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol. 2008; 9(3):193-205. DOI: 10.1038/nrm2327. View

Corkey B, Deeney J, Yaney G, Tornheim K, Prentki M . The role of long-chain fatty acyl-CoA esters in beta-cell signal transduction. J Nutr. 2000; 130(2S Suppl):299S-304S. DOI: 10.1093/jn/130.2.299S. View

10.

Lee C, Chasalow F, Lee S, Lewis S, Johnson F . A null mutation of cytoplasmic malic enzyme in mice. Mol Cell Biochem. 1980; 30(3):143-9. DOI: 10.1007/BF00230167. View

11.

Pongratz R, Kibbey R, Shulman G, Cline G . Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. J Biol Chem. 2006; 282(1):200-7. DOI: 10.1074/jbc.M602954200. View

12.

Ronnebaum S, Joseph J, Ilkayeva O, Burgess S, Lu D, Becker T . Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism. J Biol Chem. 2008; 283(21):14248-56. PMC: 2386941. DOI: 10.1074/jbc.M800119200. View

13.

Komatsu M, Yajima H, Yamada S, Kaneko T, Sato Y, Yamauchi K . Augmentation of Ca2+-stimulated insulin release by glucose and long-chain fatty acids in rat pancreatic islets: free fatty acids mimic ATP-sensitive K+ channel-independent insulinotropic action of glucose. Diabetes. 1999; 48(8):1543-9. DOI: 10.2337/diabetes.48.8.1543. View

14.

Joseph J, Jensen M, Ilkayeva O, Palmieri F, Alarcon C, Rhodes C . The mitochondrial citrate/isocitrate carrier plays a regulatory role in glucose-stimulated insulin secretion. J Biol Chem. 2006; 281(47):35624-32. DOI: 10.1074/jbc.M602606200. View

15.

Schuit F, de Vos A, Farfari S, Moens K, Pipeleers D, Brun T . Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells. J Biol Chem. 1997; 272(30):18572-9. DOI: 10.1074/jbc.272.30.18572. View

16.

Henquin J, Ravier M, Nenquin M, Jonas J, Gilon P . Hierarchy of the beta-cell signals controlling insulin secretion. Eur J Clin Invest. 2003; 33(9):742-50. DOI: 10.1046/j.1365-2362.2003.01207.x. View

17.

MacDonald M, Marshall L . Survey of normal appearing mouse strain which lacks malic enzyme and Nad+-linked glycerol phosphate dehydrogenase: normal pancreatic beta cell function, but abnormal metabolite pattern in skeletal muscle. Mol Cell Biochem. 2001; 220(1-2):117-25. DOI: 10.1023/a:1010821821921. View

18.

Hohmeier H, Mulder H, Chen G, Prentki M, Newgard C . Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. Diabetes. 2000; 49(3):424-30. DOI: 10.2337/diabetes.49.3.424. View

19.

Khan A, Ling Z, Landau B . Quantifying the carboxylation of pyruvate in pancreatic islets. J Biol Chem. 1996; 271(5):2539-42. DOI: 10.1074/jbc.271.5.2539. View

20.

Brown M, Wise L, Rubin C . The molecular basis for a cytosolic malic enzyme null mutation. Malic enzyme mRNA from MOD-1 null mice contains an internal in-frame duplication that extends the coding sequence by 522 nucleotides. J Biol Chem. 1988; 263(9):4494-9. View