Research InterestsWe aim to develop novel therapeutic strategies to treat and even cure Type 1 diabetes (T1D) and Type 2 diabetes (T2D)
Degrees: Ph.D. 1988.
Courses Taught : PSL1034H, Advanced Topics: Metabolic Disorders (course coordinator)
Research Interests: Diabetic individuals cannot properly produce and/or secrete insulin, or use it appropriately. This chronic disease which afflicts approximately 3 million Canadians is associated with many debilitating and often fatal complications including heart disease, stroke, kidney disease, and impaired vision. The immense complexity of the disease has prompted our lab to take different approaches to investigate diabetes. In doing so, we aim to develop novel therapeutic strategies to treat and even cure Type 1 diabetes (T1D) and Type 2 diabetes (T2D). Our research interests include:
Circulating metabolites have enormous potential to lead us to the cause of beta cell failure in diabetes. Using global screening platforms, we identify metabolites elevated in and therefore likely associated with diabetes pathophysiology. Once identified, our lab assays these metabolites for their contribution to beta cell failure and explores mechanisms underlying their effects. Finally, we work to explore novel ways to preserve or restore beta cell function by neutralizing the effects of the identified metabolites.
Identifying Targets to Improve Endocrine Cell Function
Glucagon-like peptide-1 (GLP-1) is an incretin hormone mainly produced in the intestinal L cells. By activating its conjugating receptor GLP-1R, a GPCR, GLP-1 augments glucose-dependent insulin secretion (GSIS) from pancreatic beta cells. Therapeutic strategies targeting GLP-1 and GLP-1R have been developed to treat T2D, however, adverse side effects are associated with these GLP-1-based anti-diabetic agents due to the complex nature of GLP-1 action. Recently, a wide array of accessory proteins have been identified to interact directly with the GPCRs, modulating their functions in a context-specific manner. In order to fully understand GLP-1R signaling, our lab uses a novel membrane based yeast two hybrid system (MYTH) to uncover and functionally characterize the entire GLP-1R interactome.
In T2D, inappropriate glucagon secretion—in addition to insulin—leads to abnormal blood sugar levels. While many receptors have been shown to be involved in complex interacting networks that dramatically alter function and activity, little is known about the glucagon receptor interactome. Through discovery based, high-throughput screening of the glucagon receptor using mass spectrometry, we have identified over 30 potential interactors, and determined the effects these interactors have on receptor function. A number of these interactors have been shown to significantly alter glucose production in cell lines and primary hepatocytes, and represent potential avenues of treatment in the future.
In T1D the immune system attacks the insulin-producing pancreatic beta cells, completely eliminating the body’s endogenous source of insulin. The field of regenerative medicine is working towards developing beta cells from stem cells in vitro that can be transplanted into T1D patients, restoring an endogenous insulin supply and eliminating the need for blood glucose monitoring and insulin therapy. Unfortunately, current differentiation protocols are only able to produce immature beta-like cells. Using cells from two stem cell sources, human embryonic stem cells (hESCs) and adult-derived Pancreatic Multipotent Precursors (PMPs), we characterize the beta-like cells that are produced using current differentiation protocols and develop targeted strategies to improve differentiation.
Pancreas cells, adenovirus, electrophysiology, Elisa, gene expression analysis, immunohistochemistry, immunocytochemistry, in vitro electrophysiology, mass spectrometry, microarrays, patch clamp, proteomics, qRT-PCR, RIA, RT-PCR, signal transduction characterization, siRNA, vessel cannulation, voltage clamp, western blot, stem cells, islet isolation, primary hepatocyte isolation
Amplifier, analytical balances, benchtop centrifuge, blotting apparatus, calcium imaging system, confocal microscope, culture hood, culture incubators, cryostat, deconvolution fluorescence microscope, departmental beta and gamma counters, digidata, digital microscope, dissecting microscope, electrometer, electrophysiology rig, EMCCD, fluorescence microscope, fresh tissue sectioning systems, gel apparatus, HPLC, infusion apparatus, low- and high-speed centrifuge, low and ultralow freezers, mass spectrometer, micropipette puller, microwave oven, mini vortexer, monochromator, motorized micromanipulators, plate reader, pneumatic picopump, pressure osmometer, ProBlot hybridization oven, real-time/thermocycler, setups for electropherosis, stimulator, stirrer/hot plate, vibratome, water baths
Publications and Awards
LKB1 couples glucose metabolism to insulin secretion in mice.
Fu A, Robitaille K, Faubert B, Reeks C, Dai XQ, Hardy AB, Sankar KS, Ogrel S, Al-Dirbashi OY, Rocheleau JV, Wheeler MB, MacDonald PE, Jones R, Screaton RA.
Diabetologia. 2015 Apr 16. [Epub ahead of print]
Zip4 mediated zinc influx stimulates insulin secretion in pancreatic Beta cells.
Hardy AB, Prentice KJ, Froese S, Liu Y, Andrews GK, Wheeler MB.
PLoS One. 2015 Mar 25;10(3):e0119136. doi: 10.1371/journal.pone.0119136. eCollection 2015.
Liver-specific Expression of Dominant Negative Transcription Factor 7-like 2 Causes Progressive Impairment in Glucose Homeostasis.
Ip W, Shao W, Song Z, Chen Z, Wheeler MB, Jin T.
Diabetes. 2015 Jan 9. pii: db141329. [Epub ahead of print]
PTEN deletion in pancreatic α-cells protects against high-fat diet-induced hyperglucagonemia and insulin resistance.
Wang L, Luk CT, Cai EP, Schroer SA, Allister EM, Shi SY, Wheeler MB, Gaisano HY, Woo M.
Diabetes. 2015 Jan;64(1):147-57. doi: 10.2337/db13-1715. Epub 2014 Aug 4.
Progesterone receptor membrane component 1 is a functional part of the glucagon-like peptide-1 (GLP-1) receptor complex in pancreatic β cells.
Zhang M, Robitaille M, Showalter AD, Huang X, Liu Y, Bhattacharjee A, Willard FS, Han J, Froese S, Wei L, Gaisano HY, Angers S, Sloop KW, Dai FF, Wheeler MB.
The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction.
Prentice KJ, Luu L, Allister EM, Liu Y, Jun LS, Sloop KW, Hardy AB, Wei L, Jia W, Fantus IG, Sweet DH, Sweeney G, Retnakaran R, Dai FF, Wheeler MB.
A novel humanized GLP-1 receptor model enables both affinity purification and Cre-LoxP deletion of the receptor.
Jun LS, Showalter AD, Ali N, Dai F, Ma W, Coskun T, Ficorilli JV, Wheeler MB, Michael MD, Sloop KW.
PLoS One. 2014 Apr 2;9(4):e93746. doi: 10.1371/journal.pone.0093746. eCollection 2014.
Isolation and immortalization of MIP-GFP neurons from the hypothalamus.
Wang ZC, Wheeler MB, Belsham DD.
Endocrinology. 2014 Jun;155(6):2314-9. doi: 10.1210/en.2013-2128. Epub 2014 Mar 10.
The identification of novel proteins that interact with the GLP-1 receptor and restrain its activity.
Huang X, Dai FF, Gaisano G, Giglou K, Han J, Zhang M, Kittanakom S, Wong V, Wei L, Showalter AD, Sloop KW, Stagljar I, Wheeler MB.
Mol Endocrinol. 2013 Sep;27(9):1550-63. doi: 10.1210/me.2013-1047. Epub 2013 Jul 17.
The loss of Sirt1 in mouse pancreatic beta cells impairs insulin secretion by disrupting glucose sensing.
Luu L, Dai FF, Prentice KJ, Huang X, Hardy AB, Hansen JB, Liu Y, Joseph JW, Wheeler MB.
Diabetologia. 2013 Sep;56(9):2010-20. doi: 10.1007/s00125-013-2946-5. Epub 2013 Jun 20.
Nostro MC, Sarangi F, Ogawa S, Holtzinger A, Corneo B, Li X, Micallef SJ, Park IH, Basford C, Wheeler MB, Daley GQ, Elefanty AG, Stanley EG, Keller G.
StemBook [Internet]. Cambridge (MA): Harvard Stem Cell Institute; 2008-.
2012 Jun 10.