Diabetes Metab J.  2011 Oct;35(5):458-465. 10.4093/dmj.2011.35.5.458.

Fuel-Stimulated Insulin Secretion Depends upon Mitochondria Activation and the Integration of Mitochondrial and Cytosolic Substrate Cycles

• Cline GW

• KMID: 1857500
• DOI: http://doi.org/10.4093/dmj.2011.35.5.458

Abstract

The pancreatic islet beta-cell is uniquely specialized to couple its metabolism and rates of insulin secretion with the levels of circulating nutrient fuels, with the mitochondrial playing a central regulatory role in this process. In the beta-cell, mitochondrial activation generates an integrated signal reflecting rates of oxidativephosphorylation, Kreb's cycle flux, and anaplerosis that ultimately determines the rate of insulin exocytosis. Mitochondrial activation can be regulated by proton leak and mediated by UCP2, and by alkalinization to utilize the pH gradient to drive substrate and ion transport. Converging lines of evidence support the hypothesis that substrate cycles driven by rates of Kreb's cycle flux and by anaplerosis play an integral role in coupling responsive changes in mitochondrial metabolism with insulin secretion. The components and mechanisms that account for the integrated signal of ATP production, substrate cycling, the regulation of cellular redox state, and the production of other secondary signaling intermediates are operative in both rodent and human islet beta-cells.

Keyword

Islet beta-cells; Glucose-stimulated insulin secretion; Mitochondrial metabolism; Anaplerosis; Substrate cycling

MeSH Terms

Adenosine Triphosphate
Cytosol
Exocytosis
Humans
Insulin
Ion Transport
Islets of Langerhans
Mitochondria
Oxidation-Reduction
Proton-Motive Force
Protons
Rodentia
Substrate Cycling
Adenosine Triphosphate
Insulin
Protons

Figure

• 

  Fig. 1 Pyruvate (PYR) and Phospho-enol-pyruvate (PEP) cycles are hypothesized to play a role in coupling anaplerosis through pyruvate carboxylase (PC), and by the rate of the Krebs cycle determined by pyruvate dehydrogenase (PDH). (A) Pyruvate cycling is dependent upon anaplerosis to carboxylate pyruvate to oxaloacetate (OAA) by PC, and thereby generate excess malate and citrate. Export of either transfers reducing equivalents from mitochondrial NADH to cytosolic NADPH by the action of malic enzyme (ME) [19]. Alternatively, citrate can be converted to isocitrate and shunted back toα ketoglutarate (αKG) by the activity of isocitrate dehydrogenase (ICD) and reduction of NADP+ to NADPH [24,25]. (B) PEP cycling is dependent upon the synthesis of GTP by the activity of the GTP isoform of succinyl-CoA-synthetase (SCS-GTP) [32]. The GTP synthesized by the activity of SCS-GTP is then used to drive the synthesis of PEP by the activity of the mitochondrial isoform of Phospho-enol-pyruvate carboxykinase (PEPCK-M) [33]. Mitochondrial PEP is exported to the cytosolic PEP pool to enhance glucose-stimulated insulin secretion by an undetermined mechanism.

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