Glucose-regulated anaplerosis and cataplerosis in pancreatic beta-cells: possible implication of a pyruvate/citrate shuttle in insulin secretion - PubMed (original) (raw)

Glucose-regulated anaplerosis and cataplerosis in pancreatic beta-cells: possible implication of a pyruvate/citrate shuttle in insulin secretion

S Farfari et al. Diabetes. 2000 May.

Abstract

The hypothesis proposing that anaplerosis and cataplerosis play an important role in fuel signaling by providing mitochondrially derived coupling factors for stimulation of insulin secretion was tested. A rise in citrate coincided with the initiation of insulin secretion in response to glucose in INS-1 beta-cells. The dose dependence of glucose-stimulated insulin release correlated closely with those of the cellular contents of citrate, malate, and citrate-derived malonyl-CoA. The glucose-induced elevations in citrate, alpha-ketoglutarate, malonyl-CoA, and the 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium reduction state, an index of beta-cell metabolic activity, were unaffected by the Ca2+ chelator EGTA. Glucose induced a rise in both mitochondrial and cytosolic citrate and promoted efflux of citrate from the cells. The latter amounted to approximately 20% of glucose carbons entering the glycolytic pathway. Phenylacetic acid, a pyruvate carboxylase inhibitor, reduced the glucose-induced rise in citrate in INS-1 cells and insulin secretion in both INS-1 cells and rat islets. The results indicate the feasibility of a pyruvate/citrate shuttle in INS-1 beta-cells, allowing the regeneration of NAD+ in the cytosol and the formation of cytosolic acetyl-CoA, malonyl-CoA, and NADPH. The data suggest that anaplerosis and cataplerosis are early signaling events in beta-cell activation that do not require a rise in Ca2+. It is proposed that citrate is a signal of fuel abundance that contributes to beta-cell activation in both the mitochondrial and cytosolic compartments and that a major fate of anaplerotic glucose carbons is external citrate.

PubMed Disclaimer

Cited by

An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion.
McCommis KS, Hodges WT, Bricker DK, Wisidagama DR, Compan V, Remedi MS, Thummel CS, Finck BN. McCommis KS, et al. Mol Metab. 2016 Jul 7;5(8):602-614. doi: 10.1016/j.molmet.2016.06.016. eCollection 2016 Aug. Mol Metab. 2016. PMID: 27656398 Free PMC article.
Augmented mitochondrial energy metabolism is an early response to chronic glucose stress in human pancreatic beta cells.
Chareyron I, Christen S, Moco S, Valsesia A, Lassueur S, Dayon L, Wollheim CB, Santo Domingo J, Wiederkehr A. Chareyron I, et al. Diabetologia. 2020 Dec;63(12):2628-2640. doi: 10.1007/s00125-020-05275-5. Epub 2020 Sep 22. Diabetologia. 2020. PMID: 32960311 Free PMC article.
13C NMR isotopomer analysis reveals a connection between pyruvate cycling and glucose-stimulated insulin secretion (GSIS).
Lu D, Mulder H, Zhao P, Burgess SC, Jensen MV, Kamzolova S, Newgard CB, Sherry AD. Lu D, et al. Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2708-13. doi: 10.1073/pnas.052005699. Proc Natl Acad Sci U S A. 2002. PMID: 11880625 Free PMC article.
Obesity-dependent CDK1 signaling stimulates mitochondrial respiration at complex I in pancreatic β-cells.
Gregg T, Sdao SM, Dhillon RS, Rensvold JW, Lewandowski SL, Pagliarini DJ, Denu JM, Merrins MJ. Gregg T, et al. J Biol Chem. 2019 Mar 22;294(12):4656-4666. doi: 10.1074/jbc.RA118.006085. Epub 2019 Jan 30. J Biol Chem. 2019. PMID: 30700550 Free PMC article.
Roles of Pyruvate, NADH, and Mitochondrial Complex I in Redox Balance and Imbalance in β Cell Function and Dysfunction.
Luo X, Li R, Yan LJ. Luo X, et al. J Diabetes Res. 2015;2015:512618. doi: 10.1155/2015/512618. Epub 2015 Oct 19. J Diabetes Res. 2015. PMID: 26568959 Free PMC article. Review.

Glucose-regulated anaplerosis and cataplerosis in pancreatic beta-cells: possible implication of a pyruvate/citrate shuttle in insulin secretion - PubMed (original) (raw)