Pharmacology

Patrick E MacDonald

Dr Patrick E MacDonald

Professor

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

Teaching: PMCOL450/550

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 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 islet function in health and disease.

Techniques used in the laboratory range from biochemical and molecular techniques to assess hormone secretion and signalling, to patch-clamp electrophysiology and fixed or live-cell imaging approaches that include confocal and TIRF microscopy. Recently we have developed an interest in combining these techniques with single-cell approaches to interrogate gene expression in order to study the function and dysfunction of islet cell sub-populations.

Selected Recent Publications

Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells.
Thomsen SK, Raimondo A, Hastoy B, Sengupta S, Dai XQ, Bautista A, Censin J, Payne AJ, Umapathysivam MM, Spigelman AF, Barrett A, Groves CJ, Beer NL, Manning Fox JE, McCarthy MI, Clark A, Mahajan A, Rorsman P, MacDonald PE, Gloyn AL.
Nat Genet. 2018 Aug;50(8):1122-1131. doi: 10.1038/s41588-018-0173-1. Epub 2018 Jul 27.
PMID: 30054598

Cystic fibrosis-related diabetes is caused by islet loss and inflammation.
Hart NJ, Aramandla R, Poffenberger G, Fayolle C, Thames AH, Bautista A, Spigelman AF, Babon JAB, DeNicola ME, Dadi PK, Bush WS, Balamurugan AN, Brissova M, Dai C, Prasad N, Bottino R, Jacobson DA, Drumm ML, Kent SC, MacDonald PE, Powers AC.
JCI Insight. 2018 Apr 19;3(8). pii: 98240. doi: 10.1172/jci.insight.98240. [Epub ahead of print]
PMID: 29669939 Free PMC Article

The cell biology of systemic insulin function.
Tokarz VL, MacDonald PE, Klip A.
J Cell Biol. 2018 Jul 2;217(7):2273-2289. doi: 10.1083/jcb.201802095. Epub 2018 Apr 5. Review.
PMID: 29622564

A post-translational balancing act: the good and the bad of SUMOylation in pancreatic islets.
MacDonald PE.
Diabetologia. 2018 Apr;61(4):775-779. doi: 10.1007/s00125-017-4543-5. Epub 2018 Jan 12.
PMID: 29330559

Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion.
Bozadjieva N, Blandino-Rosano M, Chase J, Dai XQ, Cummings K, Gimeno J, Dean D, Powers AC, Gittes GK, Rüegg MA, Hall MN, MacDonald PE, Bernal-Mizrachi E.
J Clin Invest. 2017 Dec 1;127(12):4379-4393. doi: 10.1172/JCI90004. Epub 2017 Nov 6.
PMID: 29106387 Free PMC Article

Kv2.1 Clustering Contributes to Insulin Exocytosis and Rescues Human β-Cell Dysfunction.
Fu J, Dai X, Plummer G, Suzuki K, Bautista A, Githaka JM, Senior L, Jensen M, Greitzer-Antes D, Manning Fox JE, Gaisano HY, Newgard CB, Touret N, MacDonald PE.
Diabetes. 2017 Jul;66(7):1890-1900. doi: 10.2337/db16-1170. Epub 2017 Jun 12.
PMID: 28607108 Free PMC Article

Transplantation of Human Pancreatic Endoderm Cells Reverses Diabetes Post Transplantation in a Prevascularized Subcutaneous Site.
Pepper AR, Pawlick R, Bruni A, Wink J, Rafiei Y, O'Gorman D, Yan-Do R, Gala-Lopez B, Kin T, MacDonald PE, Shapiro AMJ.
Stem Cell Reports. 2017 Jun 6;8(6):1689-1700. doi: 10.1016/j.stemcr.2017.05.004.
PMID: 28591651 Free PMC Article

N-acyl Taurines and Acylcarnitines Cause an Imbalance in Insulin Synthesis and Secretion Provoking β Cell Dysfunction in Type 2 Diabetes.
Aichler M, Borgmann D, Krumsiek J, Buck A, MacDonald PE, Fox JEM, Lyon J, Light PE, Keipert S, Jastroch M, Feuchtinger A, Mueller NS, Sun N, Palmer A, Alexandrov T, Hrabe de Angelis M, Neschen S, Tschöp MH, Walch A.
Cell Metab. 2017 Jun 6;25(6):1334-1347.e4. doi: 10.1016/j.cmet.2017.04.012.
PMID: 28591636 Free Article

SUMOylation and calcium control syntaxin-1A and secretagogin sequestration by tomosyn to regulate insulin exocytosis in human ß cells.
Ferdaoussi M, Fu J, Dai X, Manning Fox JE, Suzuki K, Smith N, Plummer G, MacDonald PE.
Sci Rep. 2017 Mar 21;7(1):248. doi: 10.1038/s41598-017-00344-z.
PMID: 28325894 Free PMC Article

Impaired "Glycine"-mia in Type 2 Diabetes and Potential Mechanisms Contributing to Glucose Homeostasis.
Yan-Do R, MacDonald PE.
Endocrinology. 2017 May 1;158(5):1064-1073. doi: 10.1210/en.2017-00148. Review.
PMID: 28323968

Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx.
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, Kim SK.
Cell Metab. 2017 Mar 7;25(3):622-634. doi: 10.1016/j.cmet.2017.01.009. Epub 2017 Feb 16.
PMID: 28215845 Free PMC Article

Decreased STARD10 Expression Is Associated with Defective Insulin Secretion in Humans and Mice.
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, Rutter GA.
Am J Hum Genet. 2017 Feb 2;100(2):238-256. doi: 10.1016/j.ajhg.2017.01.011. Epub 2017 Jan 26.
PMID: 28132686 Free PMC Article

Toward Connecting Metabolism to the Exocytotic Site.
Ferdaoussi M, MacDonald PE.
Trends Cell Biol. 2017 Mar;27(3):163-171. doi: 10.1016/j.tcb.2016.10.003. Epub 2016 Dec 5. Review.
PMID: 27932063

Interleukin-1 signaling contributes to acute islet compensation.
Hajmrle C, Smith N, Spigelman AF, Dai X, Senior L, Bautista A, Ferdaoussi M, MacDonald PE.
JCI Insight. 2016 Apr 7;1(4):e86055.
PMID: 27699257 Free PMC Article

Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease.
Koppe L, Nyam E, Vivot K, Manning Fox JE, Dai XQ, Nguyen BN, Trudel D, Attané C, Moullé VS, MacDonald PE, Ghislain J, Poitout V.
J Clin Invest. 2016 Sep 1;126(9):3598-612. doi: 10.1172/JCI86181. Epub 2016 Aug 15.
PMID: 27525435 Free PMC Article

PI3 kinases p110α and PI3K-C2β negatively regulate cAMP via PDE3/8 to control insulin secretion in mouse and human islets.
Kolic J, Manning Fox JE, Chepurny OG, Spigelman AF, Ferdaoussi M, Schwede F, Holz GG, MacDonald PE.
Mol Metab. 2016 May 11;5(7):459-471. doi: 10.1016/j.molmet.2016.05.003. eCollection 2016 Jul.
PMID: 27408772 Free PMC Article