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Insulin Secretion and the Glutamine-Glutamate-Alpha-Ketoglutarate Axis

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Glutamine in Clinical Nutrition

Part of the book series: Nutrition and Health ((NH))

Abstract

Protein-sensitive hypoglycemia in children with congenital hyperinsulinism (HI) highlights the important role of amino acids in regulation of insulin secretion. The studies of insulin secretion in three HI mouse models suggested that glutamine (Q)-glutamate (E)-alpha-ketoglutarate (αKG) axis played a key role in amino acid-stimulated insulin secretion. The mechanism of dysregulated insulin secretion in HI with a glutamate dehydrogenase (GDH) gain of function mutation is due to increased amino acid oxidation via this key axis. Loss of function mutation of Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) also cause HI, the study of SCHAD knockout mice indicated that SCHAD inhibits GDH via protein-protein interaction; HI due to SCHAD deficiency shares a similar mechanism with GDH gain of function. In contrast, loss of function mutations of ATP-dependent potassium channels are sensitive to glutamine but not to leucine-stimulated insulin secretion. 13C tracing studies in islets suggested that generation of glutamine via the reverse flux of Q-E-αKG axis during glucose oxidation is important to maintain insulin secretion stimulated by glucose. The key enzymes in the Q-E-αKG axis, including glutaminase, GDH and glutamine synthetase, serve as intracellular energy sensors to determine the sensitivity of amino acid stimulation of insulin secretion.

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Acknowledgment  

I gratefully acknowledge the important contributions to this work by colleagues including Charles A. Stanley, Michael J. Bennett, Diva D. De León (The Children’s Hospital of Philadelphia, Philadelphia, PA), Franz M. Matschinsky (Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA) and Thomas J. Smith (Donald Danforth Plant Science Center, St Louis, MO). These studies were supported in part by NIH grants, U01DK089529, DK53012, DK22122, and a pilot grant from the Institute of Diabetes, Obesity and Metabolism (University of Pennsylvania, DK19525). Additional support was provided by the Radioimmunoassay and Islet Cores of the Diabetes Research Center of the University of Pennsylvania, Perelman School of Medicine (DK19525).

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Authors and Affiliations

  1. Division of Endocrinology, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, 3615 Civic Center Blvd., Philadelphia, PA, 19104, USA

    Changhong Li M.D., Ph.D.

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  1. Changhong Li M.D., Ph.D.
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Correspondence to Changhong Li M.D., Ph.D. .

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Editors and Affiliations

  1. Department of Intensive Care, Barnet and Chase Farm Hospitals, London, United Kingdom

    Rajkumar Rajendram

  2. Department of Nutrition and Dietetics, Diabetes and Nutritional Sciences, School of Medicine, King’s College London, London, United Kingdom

    Victor R. Preedy

  3. Department of Biomedical Sciences, University of Westminster, London, United Kingdom

    Vinood B. Patel

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Li, C. (2015). Insulin Secretion and the Glutamine-Glutamate-Alpha-Ketoglutarate Axis. In: Rajendram, R., Preedy, V., Patel, V. (eds) Glutamine in Clinical Nutrition. Nutrition and Health. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1932-1_19

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  • DOI: https://doi.org/10.1007/978-1-4939-1932-1_19

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-1931-4

  • Online ISBN: 978-1-4939-1932-1

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