Journal Article


Pierre Maechler
Blanca Rubi
Lorraine Brennan
Philip Newsholme



humans physiology amino acids diabetes mellitus secretion islets of langerhans signal transduction calcium insulin mitochondria glucose metabolism

New insights into amino acid metabolism, beta-cell function and diabetes. (2004)

Abstract Specific amino acids are now known to acutely and chronically regulate insulin secretion from pancreatic beta-cells in vivo and in vitro. Understanding the molecular mechanisms by which amino acids regulate insulin secretion may identify novel targets for future diabetes therapies. Mitochondrial metabolism is crucial for the coupling of amino acid and glucose recognition to the exocytosis of the insulin granules. This is illustrated by in vitro and in vivo observations discussed in the present review. Mitochondria generate ATP, which is the main coupling factor in insulin secretion; however, the subsequent Ca2+ signal in the cytosol is necessary, but not sufficient, for full development of sustained insulin secretion. Hence mitochondria generate ATP and other coupling factors serving as fuel sensors for the control of the exocytotic process. Numerous studies have sought to identify the factors that mediate the amplifying pathway over the Ca2+ signal in nutrient-stimulated insulin secretion. Predominantly, these factors are nucleotides (GTP, ATP, cAMP and NADPH), although metabolites have also been proposed, such as long-chain acyl-CoA derivatives and the key amino acid glutamate. This scenario highlights further the importance of the key enzymes or transporters, glutamate dehydrogenase, the aspartate and alanine aminotransferases and the malate/aspartate shuttle, in the control of insulin secretion. Therefore amino acids may play a direct or indirect (via generation of putative messengers of mitochondrial origin) role in insulin secretion.
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Full list of authors on original publication

Pierre Maechler, Blanca Rubi, Lorraine Brennan, Philip Newsholme

Experts in our system

Lorraine Brennan
University College Dublin
Total Publications: 166
Philip Newsholme
University College Dublin
Total Publications: 51