27.09.2018

CMCB Green seminar with Prof. Philip Newsholme, Curtin University Perth

11:00 - 12:00 Uhr
CRTD, ground floor, auditorium left
Prof. Philip Newsholme,
Curtin University Perth, Curtin Health Innovation Research Institute, Faculty of Health Sciences, School of Pharmacy and Biomedical Sciences

"The importance of metabolic reprogramming to cell function"

Abstract:

"Glucagon-like-peptide-1 (GLP-1) promotes insulin secretion from pancreatic β-cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. GLP-1-induced insulin secretion requires glucose metabolism, therefore GLP-1 receptor (GLP-1R) signalling may impact glucose uptake and utilization in β-cells. By determination of changes to various metabolic parameters after short and long exposure of clonal BRIN-BD11 β-cells and rodent islets to the GLP-1R agonist Exendin-4 (50 nM), we found that prolonged stimulation of the GLP-1R (18 hours) promoted metabolic reprogramming of β-cells. We determined up-regulation of glycolytic enzyme expression, increased rates of glucose uptake and consumption, as well as augmented ATP content, insulin secretion and glycolytic flux. In our model, depletion of Hypoxia-Inducible Factor 1 alpha (HIF-1α) impaired the effects of Exendin-4 on glucose metabolism, while pharmacological inhibition of Phosphoinositide 3-kinase (PI3K) or mTOR completely abolished such effects. Considering the central role of glucose catabolism for stimulus-secretion coupling in β-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated β-cell glucose metabolism."


Five important publications:

1. Carlessi R, Chen Y, Rowlands J, Cruzat VF, Keane KN, Egan L, Mamotte C, Stokes R, Gunton JE, Bittencourt PIH, Newsholme P (2017) GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation. Sci Rep. 2017 Jun 1;7(1):2661. doi: 10.1038/s41598-017-02838-2.

A key paper describing the ‘metabolic reprogramming’ action of the GLP-1 receptor agonist exendin-4, an important therapeutic drug used for the treatment of type 2 diabetes

2. McEvoy, B, Sumayao R, Slattery C, McMorrow T and Newsholme P (2015) Cystine accumulation attenuates insulin release from the pancreatic beta cell due to elevated oxidative stress and decreased ATP levels. J. Physiol. 593(23):5167-82. doi: 10.1113/JP271237

The first study to describe at the molecular level the biochemical and physiological basis for pancreatic beta cell dysfunction and death (resulting in diabetes in the clinical setting) in the disease of cystinosis

3. Masters S.L, Dunne A., Subramanian S.L., Hull R.L., Tannahill G.M., Sharp F.A., Becker C., Franchi L., Yoshihara E., Chen Z., Mullooly N., Mielke L.A., Harris J., Coll R.C., Mills K.H.G., Hun Mok K., Newsholme P., Nuñez G., Yodoi J., Kahn S.E., Lavelle E.C. & O'Neill L.A.J. (2010) Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1b in type 2 diabetes. Nature Immunology. 11: 897-904

A widely cited paper describing the molecular basis for IAPP (islet amyloid polypeptide) driven IL-1b production from the macrophage associated NLRP3 inflammasome, and subsequent pancreatic islet dysfunction, reduction in insulin secretion and pathophysiology of type-2 diabetes.

4. Morgan D, Oliveira-Emilio HR,  Keane D,. Hirata AE, Santos da Rocha M, Bordin S, Curi R, Newsholme P  and Carpinelli AR (2007) Glucose, Palmitate  and Pro-Inflammatory Cytokines Modulate Expression and Activity of a Phagocyte-like NADPH Oxidase in Rat Pancreatic Islets and a Clonal Beta Cell Line.  Diabetologia. 50: 359-369

A key paper advancing the original observation of expression of NADPH oxidase in pancreatic islets and beta cells, describing the regulation of protein levels of this enzyme by, fatty acids and pro-inflammatory cytokines.

5. Brennan, L.,  Shine, A., Hewage, C., Malthouse, J.P.G., Brindle, K., McClenaghan, N., Flatt, P.R. and Newsholme, P. (2002) A NMR based demonstration of substantial oxidative L-alanine metabolism and L-alanine enhanced glucose metabolism in a clonal pancreatic beta-cell line – Metabolism of L-alanine is important to the regulation of insulin secretion. Diabetes. 51: 1714-1721

A key paper which described the metabolic basis for enhanced glucose metabolism and insulin secretion driven by some amino acids including  L-alanine, thus demonstrating the importance  of supply of both amino acids and glucose to beta cells, in vivo (related to dietary intake in vivo).

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Dana Krüger
Letzte Änderung: 11.09.2018