Research Summary

The ‘Laboratory of Molecular and Cellular Medicine’ consists of students (graduate & undergraduate), technicians and postdoctoral fellows dedicated to developing novel and innovative therapeutic approaches for diabetes. Our research typically involves sophisticated molecular techniques and studies at the cellular and physiological level. We believe that gene and cell based therapies may be the medicine of the future.
In 1923, Canadians Banting, Macleod, Best and Collip shared the Nobel Prize for their discovery of insulin. For millions of people around the world, this was a life-saving discovery. However, insulin is not a cure for diabetes. A diagnosis of type 1 diabetes still means thousands of insulin injections and blood glucose tests every year. Moreover, as it is virtually impossible to maintain optimal blood glucose levels by insulin injections, patients still suffer from several debilitating complications and reduced life-span.

Transplantation of pancreatic islets has proven to be effective in controlling blood glucose levels in subjects with type 1 diabetes. The results demonstrate the potential to treat diabetes by transplanting as little as a teaspoon of insulin-producing cells. However, this procedure is dependent upon obtaining tissue from recently deceased individuals and currently requires the use of chronic immunosuppression.

In our Laboratory we are investigating a variety of approaches to achieve the same result, without relying on tissue from donors. Ideally, we would like to develop a therapy that uses the patient’s own cells. While their insulin producing beta-cells may be absent or dysfunctional, it is possible that we may be able to stimulate sufficient numbers of beta-cells to grow back, or generate new beta-cells from stem cells. Alternatively we may be able to genetically modify other cells in the body to produce insulin or other anti-diabetic factors automatically in a meal-dependent manner.

Projects

Meal-Regulated Insulin Secretion from Gut K-Cells
K-Cells lining the intestine share many similarities with beta-cells, particularly the ability to release a hormone in proportion to the amount of glucose contained in meals. Therefore, we propose that they might be ideal targets to modify to produce insulin, in order to re-establish automatic physiologic release of insulin in subjects with diabetes. Remarkably, as reported in Science, K-cells engineered to produce insulin can sufficiently replace insulin production by beta-cells. With support from JDRF, and in collaboration with a local biotech company (enGene, Inc.) we are now pursuing several projects to further develop this therapeutic approach. We are also assessing the potential to deliver other anti-diabetic and anti-obesity agents from these cells.

Conversion of Gut Stem Cells to Beta-Cells
During development, the pancreas buds off of the gut tube. As there is becoming a greater understanding of the factors that regulate this process, there is the possibility of developing strategies to recapitulate development. Moreover, the gut is a bountiful source of stem cells and there are many common features between the differentiated cells lining the intestine and those of the pancreas. With support from the Stem Cell Network and LifeScan, we are conducting research to evaluate the feasibility of converting adult gut stem cells into insulin-producing cells to treat diabetes.

Leptin Regulation of Glucose Homeostasis
Approximately 80% of individuals with type 2 diabetes are obese, yet the reason for this correlation remains poorly understood. The fat-derived hormone leptin may provide a common link. Animals with a mutation in the leptin gene develop severe obesity and diabetes. Interestingly, leptin therapy can cure diabetes overnight, well before significant weight loss occurs. With support from CIHR and the MSFHR, we are trying to elucidate the mechanisms by which leptin exerts these powerful actions on glucose homeostasis. Currently our studies are focusing on the effects of leptin on liver and beta-cells.

GLP-1 Gene Therapy for Diabetes
GLP-1 is a gut hormone that like GIP, is release during meals and functions to stimulate insulin production and release in a glucose-dependent manner and inhibit glucagon release and gastric emptying. As a result of these complementary anti-diabetic actions GLP-1 based therapies are being actively pursued by the pharmaceutical industry. The first GLP-1 mimetic Byetta™ was recently approved by the FDA. With support by the CDA and JDRF, we are developing novel gene therapy approaches to deliver GLP-1, in order to obviate the need for repeated delivery by needle injection.

Bio

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

Awards

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

Publications

Selected Publications

The following publications are examples that reflect the areas of interest of the Laboratory. For more complete publication listings, see Google Scholar and PubMed.

  1. Wideman RD, Gray SL, Covey SD, Webb GC and Kieffer TJ. Transplantation of PC1/3-Expressing alpha-cells Improves Glucose Handling and Cold Tolerance in Leptin-resistant Mice. Mol. Ther. Oct, 2008 (Epub ahead of print).
  2. Fujita Y, Chui J, King D, Zhang T, Pownall S, Cheung A and Kieffer TJ. Pax6 and Pdx1 are required for production of glucose-dependent insulinotropic polypeptide (GIP) in proglucagon expressing L-cells. Am J Physiol. 295(3):E648-57 (2008).
  3. Unniappan S and Kieffer TJ. Leptin Extends the Anorectic Effects of Chronic PYY(3-36) Administration in Ad lib Fed Rats. Am J Physiol Regul Integr Comp Physiol, 29:51-58 (2008).
  4. Oosman SN, Lam AW, Harb G, Unniappan S, Lam NT, Webber T, Bruch D, Zhang QX, Korbutt GS, and Kieffer TJ. Treatment of obesity and diabetes in mice by transplant of gut cells engineered to produce leptin. Mol Ther 16: 1138-1145 (2008).
  5. Wideman RD, Covey SD, Webb GC, Drucker DJ, and Kieffer TJ. 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: 2744-2752 (2007).
  6. Wideman RD, Yu IL, Webber TD, Verchere CB, Johnson JD, Cheung AT, and Kieffer TJ. Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1). Proc Natl Acad Sci U S A 103: 13468-13473 (2006).
  7. Unniappan S, McIntosh CH, Demuth HU, Heiser U, Wolf R, and Kieffer TJ. Effects of dipeptidyl peptidase IV on the satiety actions of peptide YY. Diabetologia 49: 1915-1923 (2006).
  8. Covey SD, Wideman RD, McDonald C, Unniappan S, Huynh F, Asadi A, Speck M, Webber T, Chua SC, and Kieffer TJ. The pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis. Cell Metab 4:291-302 (2006).
  9. Wideman RD, Yu IL, Webber TD, Verchere CB, Johnson JD, Cheung AT, and Kieffer TJ. Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1). Proc Natl Acad Sci USA 103:13468-13473 (2006).
  10. Laubner K, Kieffer TJ, Lam NT, Niu X, Jakob F and Seufert J. Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic beta-cells. Diabetes 54:3410-3417 (2005).
  11. Nyberg J, Anderson MF, Meister B, Alborn A-M, Ström A-K, Brederlau A, Illerskog A-C, Nilsson O, Kieffer TJ, Ricksten A and Eriksson P.S. Glucose-dependent insulinotropic polypeptide is expressed in adult hippocampus and induces progenitor cell proliferation. J Neurosci 25:1816-1825 (2005).
  12. Stock S, Leichner P, Wong ACK, Ghatei MA, Kieffer TJ, Bloom SR, Chanoine J-P and Ghrelin, PYY. GIP and hunger responses to a mixed meal in anorexic, obese and control female adolescents. J Clin Endorinol Metab 90:2161-2168 (2005).
  13. Lam NT, Lewis JT, Cheung AT, Luk LT, Wang J, Kolls JK and Kieffer TJ. Leptin increases hepatic insulin sensitivity and protein tyrosine phosphatase-1B expression. Mol Endocrinol 18:1333-1345 (2004).
  14. Fujita Y, Cheung AT and Kieffer TJ. Harnessing the gut to treat diabetes. Pediatr Diabetes 5 Suppl. 2:57-69 (2004).
  15. Cheung AT and Kieffer TJ. Gene therapy for metabolic disease. In: Diabetes Mellitus: A Fundamental and Clinical Text, 3rd Edition, D. LeRoith, SI Taylor and M Olefsky (eds), Lippincott Williams & Wilkins, Philadelphia PA pp 747-762 (2004).
  16. Cheung AT, Dayanandan B, Lewis JT, Korbutt GS, Rajotte RV, Boylan MO, Wolfe MM and Kieffer TJ. Glucose-dependent insulin release from genetically engineered K cells. Science 290:1959-1962 (2000).
  17. Kieffer TJ and Habener JF. The adipoinsular axis: effects of leptin on pancreatic beta-cells. Am J Physiol 278:E1-E14 (2000).
  18. Stoffers DA, Kieffer TJ, Hussain MA, Drucker DJ, Bonner-Weir S, Habener JF and Egan JM. Insulinotropic glucagon-like peptide-1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 49:741-748 (2000).
  19. Lewis JT, Dayanandan B, Habener JF and Kieffer TJ. Glucose-dependent insulinotropic polypeptide confers early phase insulin release to oral glucose in rats: demonstration by a receptor antagonist. Endocrinology 141:3710-3716 (2000).
  20. Seufert JR, Kieffer TJ and Habener JF. Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-deficient ob/ob mice. Proc Natl Acad Sci USA 96:674-679 (1999).
  21. Kieffer TJ and Habener JF. The glucagon-like peptides. Endocr Rev 20:1-38 (1999).
  22. Kieffer TJ, Heller RS, Leech CA, Holz GG and Habener JF. Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic ß-cells. Diabetes 46:1087-1093 (1997).
  23. Kieffer TJ, McIntosh CHS and Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide (GIP) and truncated glucagon-like peptide-1 (tGLP-1) in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136:3585-3596 (1995).
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