Kieffer


About
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PhD Physiology, University of British Columbia

Post-Doctoral Fellowship, Molecular Endocrinology, Massachusetts General Hospital & Harvard Medical School

Instructor, Medicine, Harvard Medical School

Assistant, Biochemistry, Massachusetts General Hospital

Assistant Professor, Medicine and Physiology, University of Alberta

Associate Professor, Medicine and Physiology, University of Alberta

Professor, Cellular & Physiological Sciences and Surgery, University of British Columbia

Senior Scholar Award, Michael Smith Foundation for Health Research

Scholarship, Canadian Diabetes Association

Scholarship, Alberta Heritage Foundation for Medical Research

Career Development Award, Juvenile Diabetes Research Foundation

Scholar Award, Michael Smith Foundation for Health Research

Early Career Scholar Award, Peter Wall Institute for Advanced Studies

Projects
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We seek to improve life for people affected by diabetes, by contributing to the development of new therapies, and ultimately a cure.  We are pursuing many different approaches in the laboratory that all have tremendous potential to yield significant impact.

We believe the best therapies for diabetes will come from approaches that re-establish automatic release of insulin within the body.  Clinical studies involving transplant of pancreatic islets validate the effectiveness of this approach.  Islets are small clusters of hormone producing cells, including the insulin producing beta-cells, and constitute only a few percent of the pancreas tissue.  A few labs in Canada, including the Ike Barber Human Islet Transplant Laboratory here in Vancouver, can produce relatively pure preparations of islets isolated from the pancreas of recently deceased organ donors, and then transplant these into patients with diabetes.  Since the amount of insulin producing tissue is small, only a few teaspoons, the transplant is relatively quick and simple (an infusion), and the patient can return home the same day.  The results can be truly remarkable; with normal regulation of blood glucose levels achieved, such that patients can often stop taking insulin injections. Despite the clear success with islet transplant, the widespread adoption of this procedure is severely limited by: 1) the challenging islet isolation procedure; 2) the reliance upon limited organ donations; 3) the need for recipients to take chronic immunosuppression to prevent rejection of the transplanted cells.  Our research seeks to address these limitations.

Stem cells are very special cells that have the ability to multiply, and also to become all cell types of the human body.  Stem cells can now be made from a patient’s own skin cells (induced pluripotent stem cells), thanks to methods developed by Shinya Yamanaka at Kyoto University, work that earned him a Nobel Prize in 2012.  It is possible to grow large quantities of stem cells in the laboratory, and then to coax them into insulin producing cells.  Research, including that of our own, indicates that these cells can effectively reverse diabetes after implant.  Therefore, stem cells may be capable of providing a virtually unlimited supply of cells to treat millions of patients with diabetes.  The California company ViaCyte, Inc. is now testing this approach in patients with type 1 diabetes, and we hope to initiate trials of this extremely promising therapy in Vancouver.

Encapsulation is a method to put a protective layer around the cells prior to implant, in order to prevent immune cells from attacking the new cells, while still allowing glucose and other nutrients to reach the cells, and insulin released from the encapsulated cells to enter the bloodstream.  We have already conducted several successful experiments with macro-encapsulation devices that are designed for transplant under the skin, and this approach is being tested in patients by ViaCyte.  If successful, this may permit the implant of insulin producing cells derived from stem cells into patients with diabetes, without the need for chronic immunosuppression.

Powerful new methods in genetic engineering, such as CRISPR, now enable us to readily edit the genome of our cultured stem cells.  In some patients diabetes is caused by a specific mutation in a gene important for the development and/or function of insulin producing beta-cells.  Genetic engineering may enable us to correct such genes in patient derived induced pluripotent stem cells from which we can then use to generate functional beta-cells to transplant back into the patient in the hopes of curing their diabetes.  We can also use genomic editing to disrupt the function of specific genes in stem cells to subsequently probe their function once the cells are differentiated to beta-cells.  In this manner, we can use human stem cells as a very powerful model to better understand how diabetes develops.

Our ability to manufacture large quantities of human insulin producing cells also enables us to hunt for new drugs to treat diabetes by using high content screening. Using our robotics and high content, high throughput imagers, we can conduct thousands of experiments at a time, investigating the effects of small molecules on the survival and function of the insulin producing beta-cells.  This research could identify novel approaches to treat diabetes.

As an alternative to cell transplantation, it may be possible to genetically engineer surrogate beta-cells by coaxing different cells in the body to take over insulin production.  However, a key criteria for insulin replacement is that it must be produced in a meal dependent manner.  We are exploring the feasibility of using gut K-cells for this purpose.  These cells are located within the lining of the intestine and produce the hormone glucose-dependent insulinotropic polypeptide (GIP), a hormone that was discovered by Drs. John Brown and Raymond Pederson at UBC in the early 1970’s.  Like beta-cells, the K-cells have the ability to sense glucose and rapidly release a hormone into the bloodstream.  Thus the circulating profiles of GIP and insulin are very similar.  Remarkably, as we reported in Science, K-cells engineered to produce insulin can entirely replace insulin production by beta-cells.  Moreover, we found that insulin producing K-cells escape the autoimmune attack that destroys pancreatic beta-cells.  In addition, insulin produced in the intestine appears to dampen the immune attack on beta-cells, raising the possibility that this approach could be used to prevent diabetes.  Dr. Kieffer co-founded enGene, Inc., a biotech company that is striving to develop a gene pill, or oral formulation, to facilitate the clinical translation of this approach for the regulated delivery of insulin, and other peptides that may improve glucose homeostasis and lower body weight.

Perhaps an ideal way to cure diabetes will be to regenerate pancreatic beta-cells in patients with diabetes.  Does the pancreas contain precursor cells that can be activated to form more beta-cells?  Our studies with Dr. van der Kooy’s lab suggest there may be, although this remains controversial.  We are studying beta-cells in zebrafish, as they have the remarkable capacity to rapidly regenerate beta-cells when needed.  Moreover, beta-cell formation can be watched directly in the developing embryos, which are see-through.  We have strains of zebrafish in which we can selectively destroy beta-cells to study the regenerative process, facilitated by the marking of beta-cells with fluorescent proteins that can be visualized under the microscope.  Moreover, we have the ability to conduct these studies using our robotics and high content, high throughput imagers, such that we can screen thousands of compounds for small molecules that promote beta-cell regeneration.  Zebrafish embryos are also highly amenable to genetic engineering to probe gene function and also generate novel lines of fish to facilitate new research.  For example, we have generated zebrafish in which the beta-cells emit light when they are activated to release insulin.  In this manner, we can screen the fish for small molecules that stimulate insulin secretion as a method to look for novel compounds that could be effective therapies for diabetes.

Hormones are powerful regulators of metabolism and we are very interested in elucidating how hormones coordinate the precise regulation of glucose homeostasis.  We are particularly interested in the pancreatic islet cells and hormone producing cells found in the intestine, including how the cells develop and how they function.  It has widely been assumed that insulin is the only hormone that can be used to control glycemia in diabetes, but it is now emerging that other hormones also have potent effects on blood glucose levels and these actions may be harnessed therapeutically.  For example, during his PhD work at UBC with Dr. Raymond Pederson and Christopher McIntosh, Dr. Kieffer discovered that the insulinotropic actions of the gut hormones GIP and GLP-1 are limited by the enzyme DPP4.  As a result of this finding, DDP4 inhibitors and DPP4 resistant GLP-1 analogs have been developed into new products to boost insulin levels in patients with type 2 diabetes.  These drugs are now taken by millions of patients around the world.  We have developed novel bioassays that report activity of GIP, GLP-1 and glucagon and are using these to look for small molecule modulators of these receptors that may be taken orally to treat diabetes and obesity.

Another hormone with potent glucose-lowering actions is leptin. Originally isolated from fat and found to act in the brain to induce satiety and increase energy expenditure, leptin has clinical utility for promoting weight loss, although leptin resistance limits its effectiveness in most obese patients.  The actions of leptin to regulate glucose homeostasis are even more potent; even in the setting of type 1 diabetes, leptin can dramatically lower blood glucose levels.  We are using multiple complementary approaches to elucidate how leptin has these actions in the hopes of identifying new therapeutic targets.  We are also investigating how leptin resistance develops in the context of obesity in the hopes of identifying novel approaches to promote weight loss.

Glucagon is a powerful counter-regulatory hormone that opposes the action of insulin; when glucose levels are too low, glucagon produced from the neighbouring pancreatic islet alpha-cells acts to raise blood glucose.  Interestingly, inappropriately high glucagon levels contribute to excess levels of glucose in the blood, such that glucagon antagonists are being investigated to treat diabetes.  We are further probing the actions of glucagon and seeking novel ways to reduce its action.

Publications
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The following publications are examples that reflect the areas of interest of the Laboratory. For a more complete publication listing, click here.

  1. Bruin JE, Saber N, Braun N, Fox JK, Mojibian M, Asadi A, Drohan C, O’Dwyer S, Balzer D, Rezania A, Kieffer TJ (2015). Treating diet-induced diabetes and obesity with macroencapsulated human embryonic stem cell-derived progenitor cells and antidiabetic drugs. Stem Cell Reports. 4(4):605-20.
  2. Denroche HC, Kwon MM, Quong WL, Neumann UH, Kulpa JE, Karunakaran S, Clee SM, Brownsey RW, Covey SD, Kieffer TJ (2015). Leptin induces fasting hypoglycaemia in diabetic mice through the depletion of glycerol. Diabetologia. 58(5):1100-8.
  3. Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I, Asadi A, O’Dwyer S, Mojibian M, Albrecht T, Yang YHC, Johnson JD, Kieffer TJ. (2014). Reversal of diabetes with insulin producing cells derived in vitro from human pluripotent stem cells. Nature Biotechnology. 32(11): 1121-1133.
  4. Mojibian M, Lam AW, Fujita Y, Asadi A, Grassl GA, Dickie P, Tan R, Cheung AT, Kieffer TJ (2014). Insulin-producing intestinal K cells protect nonobese diabetic mice from autoimmune diabetes. Gastroenterology. 147(1): 162-171.
  5. D’souza AM, Asadi A, Johnson JD, Covey SD, Kieffer TJ (2014). Leptin deficiency in rats results in hyperinsulinemia and impaired glucose homeostasis. Endocrinology. 155(4): 1268-79.
  6. Neumann UH, Chen S, Tam YY, Baker RK, Covey SD, Cullis PR, Kieffer TJ (2014). IGFBP2 is neither sufficient nor necessary for the physiological actions of leptin on glucose homeostasis in male ob/ob mice. Endocrinology. 155(3): 716-25.
  7. Rezania A , Bruin JE, Xu J , Narayan K , Fox JK, O’Neil JJ, Kieffer TJ. (2013). Enrichment of human embryonic stem cell-derived NKX6.1-expressing pancreatic progenitor cells accelerates the maturation of insulin-secreting cells in vivo. Stem Cells. 31(11): 2432-42.
  8. Mojibian M, Harder B, Hurlburt A, Bruin JE, Asadi A, Kieffer TJ (2013). Implanted islets in the anterior chamber of the eye are prone to autoimmune attack in a mouse model of diabetes. Diabetologia. 56(10): 2213-21.
  9. Bruin JE, Rezania A , Xu J , Narayan K , Fox JK, O’Neil JJ , Kieffer TJ. (2013). Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice. Diabetologia. 56(9): 1987-98.
  10. Denroche HC, Quong WL, Bruin JE, Tuduri E, Asadi A, Glavas MM, Fox JK, Kieffer TJ. (2013). Leptin administration enhances islet transplant performance in diabetic mice. Diabetes. 62(8): 2738-46.
  11. Huynh FK, Neumann UH, Wang Y, Rodrigues B, Kieffer TJ, Covey SD. (2013). A role for hepatic leptin signaling in lipid metabolism via altered very low density lipoprotein composition and liver lipase activity in mice. Hepatology. 57(2): 543-54.
  12. Erener S, Mojibian M, Fox JK, Denroche HC, Kieffer TJ. (2013). Circulating miR-375 as a biomarker of β-cell death and diabetes in mice. Endocrinology. 154(2): 603-8.
  13. Levi J, Huynh FK, Denroche HC, Neumann UH, Glavas MM, Covey SD, Kieffer TJ. (2012). Hepatic leptin signalling and subdiaphragmatic vagal efferents are not required for leptin-induced increases of plasma IGF binding protein-2 (IGFBP-2) in ob/ob mice. Diabetologia. 55(3): 752-62.
  14. Riedel MJ, Asadi A, Wang R, Ao Z, Warnock GL, Kieffer TJ (2012). Immunohistochemical characterisation of cells co-producing insulin and glucagon in the developing human pancreas. Diabetologia. 55(2): 372-81.
  15. Levi J, Gray SL, Speck M, Huynh FK, Babich SL, Gibson WT, Kieffer TJ (2011). Acute disruption of leptin signaling in vivo leads to increased insulin levels and insulin resistance. Endocrinology. 152(9): 3385-95.
  1. Denroche HC, Levi J, Wideman RD, Sequeira RM, Huynh FK, Covey SD, Kieffer TJ (2011). Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes. 60(5): 1414-23.
  2. Rezania A, Riedel MJ, Wideman RD, Karanu F, Ao Z, Warnock GL, Kieffer TJ (2011). Production of functional glucagon-secreting α-cells from human embryonic stem cells. Diabetes. 60(1): 239-47.
  3. Huynh FK, Levi J, Denroche HC, Gray SL, Voshol PJ, Neumann UH, Speck M, Chua SC, Covey SD, Kieffer TJ (2010). Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance. Diabetes. 59(12): 3032-40.
  4. Gray SL, Donald C, Jetha A, Covey SD, Kieffer TJ (2010). Hyperinsulinemia precedes insulin resistance in mice lacking pancreatic beta-cell leptin signaling. Endocrinology. 151(9): 4178-86.
  5. Fujita Y, Wideman RD, Asadi A, Yang GK, Baker R, Webber T, Zhang T, Wang R, Ao Z, Warnock GL, Kwok YN, Kieffer TJ (2010). Glucose-dependent insulinotropic polypeptide is expressed in pancreatic islet alpha-cells and promotes insulin secretion. Gastroenterology. 138(5): 1966-75.
  6. Fujita Y, Wideman RD, Speck M, Asadi A, King DS, Webber TD, Haneda M, Kieffer TJ (2009). Incretin release from gut is acutely enhanced by sugar but not by sweeteners in vivo. American Journal of Physiology – Endocrinology and Metabolism. 296(3): E473-9.
  7. Oosman SN, Lam AW, Harb G, Unniappan S, Lam NT, Webber T, Bruch D, Zhang QX, Korbutt GS, Kieffer TJ (2008). Treatment of obesity and diabetes in mice by transplant of gut cells engineered to produce leptin. Molecular Therapy. 16(6): 1138-45.
  8. Wideman RD, Covey SD, Webb GC, Drucker DJ, Kieffer TJ (2007). A switch from prohormone convertase (PC)-2 to PC1/3 expression in transplanted alpha-cells is accompanied by differential processing of proglucagon and improved glucose homeostasis in mice. Diabetes. 56(11): 2744-52.
  9. Covey SD, Wideman RD, McDonald C, Unniappan S, Huynh F, Asadi A, Speck M, Webber T, Chua SC, Kieffer TJ (2006). The pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis. Cell Metabolism. 4(4): 291-302.
  10. Wideman RD, Yu IL, Webber TD, Verchere CB, Johnson JD, Cheung AT, Kieffer TJ (2006). Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1). Proceedings of the National Academy of Sciences of the United States of America. 103(36):13468-73.
Further publications can be found here.
Lab
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  • Travis Webber (Lab Manager)
  • Ali Asadi (Technician)
  • Shannon O’Dwyer (Technician)
  • Dr. Alex Yuen (Technician)
  • Priye Iworima (Technician)
  • Dr. Robert Baker (Research Associate)
  • Dr. Majid Mojibian (Research Associate)
  • Dr. Maria Glavas (Research Associate)
  • Dr. Suheda Erener Dr. Suheda Erener
  • Dr. Sandra Pereira (Postdoctoral Fellow)
  • Dr. Nina Quiskamp (Postdoctoral Fellow)
  • Dr. Davide Pacitti (Postdoctoral Fellow)
  • Dr. Cara Ellis (Postdoctoral Fellow)
  • Ursula Neumann (Graduate Student)
  • Anna D’souza (Graduate Student)
  • Chiara Toselli (Graduate Student)
  • Michelle Kwon (Graduate Student)
  • Adam Ramzy (Graduate Student)
  • Nelly Saber (Graduate Student)
  • Mitchell Braam (Graduate Student)
  • Brayden Wilkinson (Undergraduate Student)
  • Julia Toews (Undergraduate Student)
  • Victor So (Undergraduate Student)
  • Niklas von Krosigk (Undergraduate Student)

The Laboratory of Molecular & Cellular Medicine is currently looking for graduate students and postdoctoral fellows. Applicants are not required to have their own funding, but must be extremely motivated with a keen interest in diabetes research. In order to preserve our funding for research, as opposed to salary, candidates are encouraged to eventually apply for external salary awards (i.e. studentships, fellowships) and thus must have a competitive CV (i.e. first class marks, appropriate experience/publications).

Candidates should apply directly to Dr. Kieffer via email with an attached CV.