P. MacDonald

Dr Patrick E MacDonald



Office: 6-126 Li Ka Shing Centre  (☎) 780.492.8063
Lab: 6-040 Li Ka Shing Centre  (☎) 780.492.9475

BSc (Hons), University of Western Ontario, Physiology, 1998
PhD, University of Toronto, Physiology, 2003

WebSite: http://www.bcell.org

Research: Function and dysfunction of pancreatic endocrine cells in human health and diabetes

Research Interests / Laboratory Techniques

Our main interests lie in understanding the mechanisms that control hormone release from the endocrine pancreatic islets of Langerhans, and how this is disrupted in diabetes. We study the control of both insulin and glucagon secretion, with a particular interest in elucidating the metabolic and receptor-mediated signaling mechanisms that control key ion channels and exocytotic processes responsible for secretion. We have a major interest in asking these questions, not only in standard experimental models such as cell lines and rodent islets, but also in pancreatic islets isolated from human donors. As such, we run a human research islet program, aimed at understanding the mechanisms that control human insulin (and glucagon) secretion in health and disease.

Current projects include studies of the voltage-dependent K+ channel (Kv2.1) as a regulator of insulin and glucagon release; the regulation of insulin granule dynamics by PI3 kinases in an isoform-specific manner; the role of post-translational SUMOylation in insulin exocytosis and ion channel function; and interactions between metabolic stress and inflammatory cytokines in islet secretory dysfunction and apoptosis.

Selected Recent Publications / Recent Funding

Gordon HM, Majithia N, MacDonald PE, Fox JE, Sharma PR, Byrne FL, Hoehn KL, Evans-Molina C, Langman L, Brayman KL and Nunemaker CS. (2017) STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation. Endocrine [Epub ahead of print]. PMID: 28405880.

Ferdaoussi M, Fu J, Dai X, Manning Fox JE, Suzuki K, Smith N, Plummer G and MacDonald PE. (2017) SUMOylation and calcium control syntaxin-1A and secretagogin sequestration by tomosyn to regulate insulin exocytosis in human ß cells. Sci Rep 7(1):248. PMID: 28325894.

Yan-Do R and MacDonald PE. (2017) Impaired "glycine"-mia in type 2 diabetes and potential mechanisms contributing to glucose homeostasis. Endocrinology [Epub ahead of print]. PMID: 28323968.

Chakravarthy H, Gu X, Enge M, Dai X, Wang Y, Damond N, Downie C, Liu K, Wang J, Xing Y, Chera S, Thorel F, Quake S, Oberholzer J, MacDonald PE, Herrera PL and Kim SK. (2017) Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx. Cell Metab 25(3):622-634. PMID: 28215845.

Carrat GR, Hu M, Nguyen-Tu MS, Chabosseau P, Gaulton KJ, van de Bunt M, Siddiq A, Falchi M, Thurner M, Canouil M, Pattou F, Leclerc I, Pullen TJ, Cane MC, Prabhala P, Greenwald W, Schulte A, Marchetti P, Ibberson M, MacDonald PE, Manning Fox JE, Gloyn AL, Froguel P, Solimena M, McCarthy MI and Rutter GA. (2017) Decreased STARD10 Expression Is Associated with Defective Insulin Secretion in Humans and Mice. Am J Hum Genet 100(2):238-256. PMID: 28132686.

Ferdaoussi M and MacDonald PE. (2017) Toward Connecting Metabolism to the Exocytotic Site. Trends Cell Biol 27(3):163-171. PMID: 27932063.

Hamza SM, Sung MM, Gao F, Soltys CM, Smith NP, MacDonald PE, Light PE and Dyck JR. (2017)Chronic insulin infusion induces reversible glucose intolerance in lean rats yet ameliorates glucose intolerance in obese rats. Biochim Biophys Acta 1861(2):313-322. PMID: 27871838.

Hajmrle C, Smith N, Spigelman AF, Dai X, Senior L, Bautista A, Ferdaoussi M and MacDonald PE. (2016) Interleukin-1 signaling contributes to acute islet compensation. JCI Insight 1(4):e86055. PMID: 27699257.

Koppe L, Nyam E, Vivot K, Manning Fox JE, Dai XQ, Nguyen BN, Trudel D, Attané C, Moullé VS, MacDonald PE, Ghislain J and Poitout V. (2016) Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease. J Clin Invest 126(9):3598-612. PMID: 27525435.

Kolic J, Manning Fox JE, Chepurny OG, Spigelman AF, Ferdaoussi M, Schwede F, Holz GG and MacDonald PE. (2016) PI3 kinases p110α and PI3K-C2β negatively regulate cAMP via PDE3/8 to control insulin secretion in mouse and human islets. Mol Metab 5(7):459-71. PMID: 27408772.

Yan-Do R, Duong E, Manning Fox JE, Dai X, Suzuki K, Khan S, Bautista A, Ferdaoussi M, Lyon J, Wu X, Cheley S, MacDonald PE and Braun M. (2016) A Glycine-Insulin Autocrine Feedback Loop Enhances Insulin Secretion From Human β-Cells and Is Impaired in Type 2 Diabetes. Diabetes 65(8):2311-21. PMID: 27207556.

Lyon J, Manning Fox JE, Spigelman AF, Kim R, Smith N, O'Gorman D, Kin T, Shapiro AM, Rajotte RV and MacDonald PE. (2016) Research-Focused Isolation of Human Islets From Donors With and Without Diabetes at the Alberta Diabetes Institute IsletCore. Endocrinology 157(2):560-9. PMID: 26653569.

Campbell JE, Ussher JR, Mulvihill EE, Kolic J, Baggio LL, Cao X, Liu Y, Lamont BJ, Morii T, Streutker CJ, Tamarina N, Philipson LH, Wrana JL, MacDonald PE and Drucker DJ. (2016) TCF1 links GIPR signaling to the control of beta cell function and survival. Nat Med 22(1):84-90. PMID: 26642437.

van de Bunt M, Manning Fox JE, Dai X, Barrett A, Grey C, Li L, Bennett AJ, Johnson PR, Rajotte RV, Gaulton KJ, Dermitzakis ET, MacDonald PE, McCarthy MI and Gloyn AL. (2015) Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors. PLoS Genet 11(12):e1005694. PMID: 26624892.

Gala-Lopez BL, Pepper AR, Pawlick RL, O'Gorman D, Kin T, Bruni A, Abualhassan N, Bral M, Bautista A, Manning Fox JE, Young LG, MacDonald PE and Shapiro AM. (2016) Antiaging Glycopeptide Protects Human Islets Against Tacrolimus-Related Injury and Facilitates Engraftment in Mice. Diabetes 65(2):451-62. PMID: 26581595.

Gooding JR, Jensen MV, Dai X, Wenner BR, Lu D, Arumugam R, Ferdaoussi M, MacDonald PE and Newgard CB. (2015) Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism. Cell Rep 13(1):157-67. PMID: 26411681.

Schwede F, Chepurny OG, Kaufholz M, Bertinetti D, Leech CA, Cabrera O, Zhu Y, Mei F, Cheng X, Manning Fox JE, MacDonald PE, Genieser HG, Herberg FW and Holz GG. (2015) Rp-cAMPS Prodrugs Reveal the cAMP Dependence of First-Phase Glucose-Stimulated Insulin Secretion. Mol Endocrinol 29(7):988-1005. PMID: 26061564.

Manning Fox JE, Lyon J, Dai XQ, Wright RC, Hayward J, van de Bunt M, Kin T, Shapiro AM, McCarthy MI, Gloyn AL, Ungrin MD, Lakey JR, Kneteman NM, Warnock GL, Korbutt GS, Rajotte RV and MacDonald PE. (2015) Human islet function following 20 years of cryogenic biobanking. Diabetologia 58(7):1503-12. PMID: 25930156.

Kushner JA, MacDonald PE and Atkinson MA. (2014) Stem cells to insulin secreting cells: two steps forward and now a time to pause?. Cell Stem Cell 15(5):535-6. PMID: 25517460.

Kolic J, Spigelman AF, Smith AM, Manning Fox JE and MacDonald PE. (2014) Insulin Secretion Induced by Glucose-dependent Insulinotropic Polypeptide Requires Phosphatidylinositol 3-Kinase γ in Rodent and Human β-Cells. J Biol Chem. 289(46):32109-20. PMID: 25288806.

MacDonald PE. (2014) Controlling insulin secretion: an exciting TASK. Endocrinology. 155(10):3729-31. PMID: 25238133.

Khan S, Yan-Do R, Duong E, Wu X, Bautista A, Cheley S, MacDonald PE, and Braun M. (2014) Autocrine activation of P2Y1 receptors couples Ca (2+) influx to Ca (2+) release in human pancreatic beta cells. Diabetologia. 57(12):2535-45. PMID: 25208758.

Hajmrle C, Ferdaoussi M, Plummer G, Spigelman AF, Lai K, Fox JE and MacDonald PE. (2014) SUMOylation protects against IL-1beta-induced apoptosis in INS-1 832/13 and human islets. Am J Physiol Endocrinol Metab. 2014 Aug 19. [Epub ahead of print]. PMID: 25139051.

Dai XQ, Spigelman AF, Khan S, Braun M, Manning Fox JE and MacDonald PE. (2014) SUMO1 enhances cAMP-dependent exocytosis and glucagon secretion from pancreatic alpha-cells. J Physiol. 592(Pt 17):3715-3726. PMID: 24907310.

Patterson JN, Cousteils K, Lou JW, Manning Fox JE, Macdonald PE, Joseph JW. (2014) Mitochondrial metabolism of pyruvate is essential for regulating glucose-stimulated insulin secretion. J Biol Chem. 289(19):13335-46. PMID: 24675076.

Gutierrez-Aguilar R, Kim DH, Casimir M, Dai XQ, Pfluger PT, Park J, Haller A, Donelan E, Park J, D'Alessio D, Woods SC, MacDonald PE, Seeley RJ. (2014) The role of the transcription factor ETV5 in insulin exocytosis. Diabetologia. 57(2):383-91. PMID: 24190582.