Can J Diabetes 38 (2014) 393e395
Contents lists available at ScienceDirect
Canadian Journal of Diabetes journal homepage: www.canadianjournalofdiabetes.com
Research Update
The Canadian Diabetes Association, Canadian Society, is Funding CDN $7.5 Million in Research in 2014e2015 to Support Excellent Researchers and Research Trainees Polly VandenBerg BSc(hon) Manager, Research Knowledge Translation, Canadian Diabetes Association, Toronto, Ontario, Canada
In 2014e2015, over a 16-month period, the Canadian Diabetes Association (CDA) will be funding 20 new Operating Grants and 15 new Personnel Awards across Canada. This year’s total research investment, including new and continuing grants and awards, is CDN $7.5 million, demonstrating the CDA’s commitment to investing in excellence in science and innovation. The research being supported will help to address important issues relating to the prevention, management and treatment of diabetes and diabetes-related complications. A summary of all grants and awards funded by the CDA in 2014e2015 is summarized by category in the Table 1. The funded research will be carried out over periods of 1 to 3 years for Operating Grants and 1 to 5 years for Personnel Awards. Below are 4 top-ranked projects that were awarded funding in the 2014 competition. Dr. James D. Johnson (University of British Columbia): Operating Grant Funded 2014e2017 Pancreatic beta-cell death and dysfunction are involved in the pathogenesis of both type 1 diabetes and type 2 diabetes. Research suggests that common mechanisms involved in beta-cell death in type 2 diabetes, as well as in type 1 diabetes and islet transplantation, are dysregulated protein homeostasis and endoplasmic reticulum (ER) stress (1). Understanding the mechanisms controlling ER stress has the potential to lead to new therapies for all forms of diabetes. It is likely that type 2 diabetes is caused by gene-environment interactions, where high-fat/high-calorie diets interact with several genetic polymorphisms to confer degrees of protection from susceptibility (2). Increased apoptosis of islets has been observed in the development of type 2 diabetes in animal models (3) and in humans (3e6). However, the mechanism by which this is regulated is not understood. Dr. Johnson and others have used multiple methods to elucidate gene regulatory networks modulated by exposure to free fatty acids in mouse and human islets (7e12). Dr. Johnson and his team developed the first published multiparameter, kinetic, high-throughput imaging platforms for betacell research (13e17), which allowed his group to perform side-by-side analysis of 206 factors in an effort to identify novel factors that can protect beta cells. Dr. Johnson used this information 1499-2671/$ e see front matter Ó 2014 Canadian Diabetes Association http://dx.doi.org/10.1016/j.jcjd.2014.09.004
to study the effects of endogenous biologic factors on beta-cell survival in the context of 5 stresses. Using this unbiased dataset, and excluding factors that were toxic in other stress conditions, Dr. Johnson and his team selected 6 novel beta-cell survival factors for further study. The objective of the current funding is to further characterize novel factors that prevent beta-cell death associated with ER stress and lipotoxicity and to uncover new molecular mechanisms governing beta-cell survival under these conditions. To do this, Dr. Johnson and his team will validate the lipotoxicity- and ER stressspecific beta-cell survival factors; examine the effects of free fatty acids and specific survival factors on ER calcium; and define the roles of alternative translation initiation factors in beta-cell survival. Dr. Brian B. Rodrigues (University of British Columbia): Operating Grant Funded 2014e2017 Cardiovascular disease is the leading cause of diabetes-related death (18), resulting primarily from atherosclerotic vascular disease but also possibly because of diabetic cardiomyopathy, an intrinsic defect in the heart muscle (19e21). Changes in cardiac metabolism are considered a principal culprit in the development of cardiomyopathy, and the earliest change that occurs in the diabetic heart is reduced glucose consumption and a switch to using more fatty acids for energy (22). Although this adaptation might be beneficial in the short term, it is potentially catastrophic over the long term (23e25). Dr. Rodrigues has been receiving funds from the CDA since 1997, and in that period has described a robust expansion in coronary lipoprotein (LPL) following diabetes (26), which was immediate, unrelated to gene expression (27), and included exaggerated processing to dimeric LPL, which is catalytically active. Dr. Rodrigues has also characterized the factors required for transfer of LPL to the coronary lumen. At this location, the enzyme breaks down circulating lipoprotein triglycerides into fatty acids, which are then delivered to the heart and can initiate injury (28e33). During his current funding, Dr. Rodrigues will investigate whether the changes in coronary LPL linked to diabetes are preludes to the cardiovascular complications of diabetes. He aims to understand how endothelial cells respond to hyperglycemia by increasing the amounts of a glycoprotein, GP1HBP1, abundantly
394
P. VandenBerg / Can J Diabetes 38 (2014) 393e395
Dr. Meranda M. Nakhla (the Research Institute of McGill University Health Centre): Operating Grant Funded 2014e2017
Table 1 Summary of grants and awards 2014e2015
Operating Grants Personnel Awards Clinician Scientist Awards Scholar Awards Post-Doctoral Fellowship Awards Doctoral Student Research Awards Total
Total
New and renewed (awarded in 2014 competition)
Ongoing commitments (awarded in previous competitions)
20 15 0
40 29 5
60 44 5
0 9
4 16
4 25
6
4
10
35
69
104
found in the heart. Understanding this link would be beneficial because interrupting this process presents opportunities for novel therapeutic strategies to prevent or delay heart dysfunction in persons with diabetes. Dr. André C. Carpentier (Université De Sherbrooke): Operating Grant Funded 2014e2017 Excess exposure of lean tissues to fatty acids is a key factor in insulin resistance and impaired beta-cell function, both major risk factors for developing diabetes (34e36). Prediabetes and diabetes are associated with changes in lipid metabolism in adipose tissues. Dr. Carpentier and his team found that, after ingesting or receiving intravenous fat, people with type 2 diabetes and prediabetes showed increased amounts of nonesterified fatty acid (NEFA) spillover (37, 38); that is, NEFAs that are not taken up by adipocytes but join the plasma NEFA pool. Increased plasma NEFA and saturated fatty acids in circulating triglycerides predict the development of type 2 diabetes, independent of the degree of beta-cell dysfunction. The risk for developing diabetes improves with weight loss induced by lifestyle interventions (39) or surgery (40, 41). There are 3 types of surgical procedures that are commonly used to treat severe obesity and type 2 diabetes: restrictive procedures (such as sleeve gastrectomy); mixed restrictive and fat malabsorptive procedures (such as Roux-en-Y gastric bypass and biliopancreatic diversion); and duodenal exclusion (“metabolic” surgery) (42). Dr. Carpentier is studying people with type 2 diabetes undergoing biliopancreatic diversion and sleeve gastrectomy. Biliopancreatic diversion induces profound weight loss and is the most effective therapeutic modality to date for the treatment of type 2 diabetes (42, 43). Roux-en-Y is the most popular (44), although it is somewhat less effective than biliopancreatic diversion (43). Sleeve gastrectomy is effective to induce early weight loss, although the majority of patients regain weight (45). Dr. Carpentier’s team has recently developed the capacity to perform very complex in vivo studies shortly after bariatric surgery (46), and they have well-established approaches to measure organspecific dietary fatty acid uptake and partitioning using positron emission tomography and stable isotope methods (47, 48). During this current funding, Dr. Carpentier will take the opportunity to determine the critical role of organ-specific changes in dietary fatty acid metabolism in the rapid improvement of glucose homeostasis, insulin resistance and beta-cell dysfunction after bariatric surgery. He will examine people with and without type 2 diabetes prior to and after biliopancreatic diversion or sleeve gastrectomy. Dr. Carpentier hopes that the study will generate new insights into the role of dietary fatty acid metabolism and the antidiabetic effects of bariatric surgery, and he believes that these original findings will be directly applicable to the pathogenesis, prevention and treatment of type 2 diabetes.
Rates of diabetes in children, both type 1 and type 2 diabetes, are increasing and represent a growing public health burden (49e51). Acute complications of diabetes, such as diabetic ketoacidosis and hypoglycemic emergencies, remain leading causes of preventable hospitalizations, emergency department visits and death in the pediatric population (52e57). The medical care of children and youth with diabetes is complex and requires intense resources as well as regular access to specialized healthcare services so as to prevent complications. The transition from pediatric to adult care adds further complexity to this management. In modern psychology, young adulthood does not begin until the early 30s, and the period between 18-30 years is considered emerging adulthood (58), a stage during which people are establishing their autonomy and personal identities and making vocational and educational choices. For people with diabetes, this stage is also complicated by the daily demands of a chronic illness and the challenge of transferring from pediatric to adult care. Many emerging adults with diabetes are at high risk for dropping out of medical care after the transition from pediatric to adult care, only to re-enter the medical system later, with diabetes-related complications (59, 60). Despite the recognized importance of transition care, the medical literature concerning this topic is limited. At this moment, we know little about the transition to adult diabetes care, including the magnitude of the problem, what happens to emerging adults when they leave pediatric care, and what system-level or individual-level factors improve their outcomes (61e63). With this Canadian Diabetes Association operating grant, Dr. Nakhla will further this research. During the current study, Dr. Nakhla’s research will examine provincial administrative and clinical data in Quebec to determine the system-level and individual-level factors associated with delays in establishing adult care, diabetes-related emergency department visits and hospitalizations among emerging adults with diabetes after the transfer to adult care. This examination of health service use and outcomes around the time of transfer to adult care will provide valuable information that will inform policy makers and healthcare providers and will help to guide the delivery of transition care services.
References 1. Volchuk A, Ron D. The endoplasmic reticulum stress response in the pancreatic beta-cell. Diabetes Obes Metabol 2010;12(Suppl 2):48e57. 2. Bell GI, Polonsky KS. Diabetes mellitus and genetically programmed defects in beta-cell function. Nature 2001;414:788e91. 3. Pick A, Clark J, Kubstrup C, et al. Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat. Diabetes 1998;47:358e64. 4. Marchetti P, Del Guerra S, Marselli L, et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metabol 2004;89:5535e41. 5. Leonardi O, Mints G, Hussain MA. Beta-cell apoptosis in the pathogenesis of human type 2 diabetes mellitus. Eur J Endocrinol 2003;149:99e102. 6. Butler AE, Janson J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52: 102e10. 7. Cnop M, Abdulkarim B, Bottu G, et al. RNA-sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate. Diabetes 2014;63:1978e93. 8. Keffrey KD, Alejandro EU, Ludiani DS, et al. Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis. Proc Natl Acad Sci U S A 2008;105:8452e87. 9. Chu KY, Li H, Wada K, et al. Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions. Diabetologia 2012;55:128e40. 10. Szabat M, Kalynyak TB, Lim GE, et al. Musashi expression in beta-cells coordinates insulin expression, apoptosis and proliferation in response to endoplasmic reticulum stress in diabetes. Dell Death Dis 2011;2:e232.
P. VandenBerg / Can J Diabetes 38 (2014) 393e395 11. Chu KY, Briggs MJ, Albrecht T, et al. Differential regulation and localization of carboxypeptidase D and carboxypeptidase E in human and mouse beta-cells. Islets 2011;3:155e65. 12. Chu KY, Lin Y, Hendel A, et al. ATP-citrate lyase reduction mediates palmitateinduced apoptosis in pancreatic beta cells. J Biol Chem 2010;285:32606e15. 13. Yang YHC, Szabat M, Bragagnini C, et al. Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signaling via dependence receptors. Diabetologia 2011;54:828e42. 14. Szabat M, Johnson JD, Piret JM. Reciprocal modulation of adult beta cell maturity by activin A and follistatin. Diabetologia 2010;53:1680e9. 15. Hill JA, Szabat M, Hoesli CA, et al. A multi-parameter, high-content, highthroughput screening platform to identify natural compounds that modulate insulin and Pdx1 expression. PLoS One 2010;5:e12958. 16. Szabat M, Luciani DS, Piret JM, et al. Maturation of adult beta-cells revealed using a Pdx1/insulin dual-reporter lentivirus. Endocrinology 2009;150:1627e35. 17. Yang YH, Vilin YY, Roberge M, et al. Multi-parameter screening reveals a role of Na channels in cytokine-induced beta-cell death. Mol Endocrinol 2014;28:406e17. 18. Sowers JR, EPstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: An update. Hypertension 2001;37:1053e9. 19. Francis GS. Diabetic cardiomyopathy: Fact or fiction? Heart 2001;85:247e8. 20. Picano E. Diabetic cardiomyopathy: The importance of being earliest. J Am Coll Cardiol 2003;42:454e7. 21. An D, Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol 2006;291:H1489e506. 22. Kim MS, Wang Y, Rodrigues B. Lipoprotein lipase mediated fatty acid delivery and its impact in diabetic cardiomyopathy. Biochim Biophys Acta 2012;1821:800e8. 23. Poirier P, Bogaty P, Garneau C, et al. Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: Importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. Diabetes Care 2001;24:5e10. 24. Bertoni AG, Tsai A, Kasper EK, et al. Diabetes and idiopathic cardiomyopathy: A nationwide case-control study. Diabetes Care 2003;26:2791e5. 25. Struthers AD, Morris AD. Screening for and treating left-ventricular abnormalities in diabetes mellitus: A new way of reducing cardiac deaths. Lancet 2002;359:1430e2. 26. Rodrigues B, Cam MC, Jian K, et al. Differential effects of streptozotocin-induced diabetes on cardiac lipoprotein lipase activity. Diabetes 1997;46:1346e53. 27. Sambandam N, Abrahani MA, St Pierre E, et al. Localization of liproprotein lipase in the diabetic heart: Regulation by acute changes in insulin. Arterioscler Thromb Vasc Biol 1999;19:1526e34. 28. Pulinilkunnil T, Abrahani A, Varghese J, et al. Evidence for rapid “metabolic switching” through lipoprotein lipase occupation of endothelial-binding sites. J Molec Cell Cardiol 2003;35:1093e103. 29. An D, Pulinilkunnil T, Qi D, et al. The metabolic “switch” ampk regulated cardiac heparin-releasable lipoprotein lipase. Am J Physiol Endocrinol Metabol 2005;288:E246e53. 30. Kim MS, Kewalramani G, Puthanveetil P, et al. Acute diabetes moderates trafficking of cardiac lipoprotein lipase through p38 mitogen-activated protein kinase-dependent actin cytoskeleton organization. Diabetes 2008;57:64e76. 31. Wang F, Kim MS, Puthanveetil P, et al. Endothelial heparanase secretion after acute hypoinsulinemia is regulated by glucose and fatty acid. Am J Physiol 2009;296:H1108e16. 32. Wang Y, Zhang D, Chiu AP, et al. Endothelial heparanase regulates heart metabolism by stimulating lipoprotein lipase secretion from cardiomyocytes. Arterioscler Thromb Vasc Biol 2013;33:894e902. 33. Wang Y, Puthanveetil P, Wang F, et al. Severity of diabetes governs vascular lipoprotein lipase by affecting enzyme dimerization and disassembly. Diabetes 2011;60:2041e50. 34. Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM: Genetic and clinical implications. Diabetes 1995;44:863e70. 35. Anderson SG, Dunn WB, Banerjee M, et al. Evidence that multiple defects in lipid regulation occur before hyperglycemia during the prodrome of type-2 diabetes. PLoS One 2014;9:e103217. 36. van Raalte DH, Diamant M. Glucolipotoxicity and beta cells in type 2 diabetes mellitus: Target for durable therapy? Diabetes Res Clin Pract 2011;93(Suppl 1): S37e46. 37. Carpentier AC. Postprandial fatty acid metabolism in the development of lipotoxicity and type 2 diabetes. Diabetes Metab 2008;34:97e107.
395
38. Carpentier AC, Labbe SM, Grenier-Larouche T, et al. Abnormal dietary fatty acid metabolic partitioning in insulin resistance and type 2 diabetes. J Clin Lipidol 2011;6:703e16. 39. Borel AL, Boulet G, Nazare JA, et al. Improved plasma FFA/insulin homeostasis is independently associated with improved glucose tolerance after a 1-year lifestyle intervention in viscerally obese men. Diabetes Care 2013;36:3254e61. 40. Arterburn DE, Courcoulas AP. Bariatric surgery for obesity and metabolic conditions in adults. BMJ 2014;349:g3961. 41. Merlotti C, Morabito A, Ceriani V, et al. Prevention of type 2 diabetes in obese at-risk subjects: A systematic review and meta-analysis. Acta Diabetol 2014; 51:853e63 [Epub ahead of print]. Accessed September 9, 2014. 42. Colquitt JL, Pickett K, Loveman E, et al. Surgery for weight loss in adults. Cochrane Database Syst Rev 2014;8:CD003641. 43. Dorman RB, Rasmus NF, al-Haddad BJ, et al. Benefits and complications of the duodenal switch/biliopancreatic diversion compared to the Roux-en-Y gastric bypass. Surgery 2012;152:758e65. 44. Buchwald H, Oien DM. Metabolic/bariatric surgery worldwide 2011. Obes Surg 2013;23:427e36. 45. Braghetto I, Csendes A, Lanzarini E, et al. Is laparoscopic sleeve gastrectomy an acceptable primary bariatric procedure in obese patients? Early and 5-year postoperative results. Surg Laparosc Endosc Percutan Tech 2012;22:479e86. 46. Plourde CE, Grenier-Larouche T, Caron-Dorval D, et al. Biliopancreatic diversion with duodenal switch improves insulin sensitivity and secretion through caloric restriction. Obesity 2014;22:1838e46. 47. Labbé SM, Grenier-Larouche T, Croteau E, et al. Organ-specific dietary fatty acid uptake in humans using positron emission tomography coupled to computed tomography. Am J Physiol Endocrinol Metab 2011;300:E445e53. 48. Labbé SM, Grenier-Larouche T, Noll C, et al. Increased myocardial uptake of dietary fatty acids linked to cardiac dysfunction in glucose-intolerant humans. Diabetes 2012;61:2701e10. 49. Patterson CC, Dahlquist GG, Gyurus E, et al. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: A multi-centre prospective registration study. Lancet 2009;373:2027e33. 50. Diamond Project Group. Incidence and trends of childhood type 1 diabetes worldwide 1990-1999. Diabet Med 2006;23:857e66. 51. Amed S, Dean HJ, Panagiotoupolous C, et al. Type 2 diabetes, medicationinduced diabetes, and monogenic diabetes in Canadian children: A prospective national surveillance study. Diabetes Care 2010;33:786e91. 52. Dahlquist G, Kallen B. Mortality in childhood-onset type 1 diabetes: A population-based study. Diabetes Care 2005;28:2384e7. 53. Edge JA, Ford-Adams ME, Dunger DB. Causes of death in children with insulindependent diabetes 1990-96. Arch Dis Child 1999;81:318e23. 54. Curtis JR, To T, Muirhead S, et al. Recent trends n hospitalization for diabetic ketoacidosis in Ontario children. Diabetes Care 2002;25:1591e6. 55. Neu A, Hofer SE, Karges B, et al. Ketoacidosis at diabetes onset is still frequent in children and adolescents: A multi-center analysis of 14,664 patients from 106 institutions. Diabetes Care 2009;32:1647e8. 56. Rewers A, Chase HP, Mackenzie T, et al. Predictors of acute complications in children with type 1 diabetes. JAMA 2002;287:2511e8. 57. Tieder JS, McLeod L, Keren R, et al. Variation in resource use and readmission for diabetic ketoacidosis in children’s hospitals. Pediatrics 2013;132:229e36. 58. Arnett JJ. Emerging adulthood: A theory of development from the late teens through the twenties. Am Psychol 2000;55:469e80. 59. Frank M. Factors associated with non-compliance with a medical follow-up regimen after discharge from a paediatric diabetes clinic. Can J Diabetes Care 1996;20:13e20. 60. Nakhla M, Daeman D, To T, et al. Transition to adult care for youths with diabetes mellitus: Findings from a Universal Health Care System. Pediatrics 2009;124:e1134e41. 61. Peters A, Laffel L. American Diabetes Association Transitions Working Group. Diabetes care for emerging adults: Recommendations for transition from paediatric to adult diabetes care systems. Diabetes Care 2011;34:2477e85. 62. Pihoker C, Forsander G, Wolfsdorf J, et al. The delivery of ambulatory diabetes care to children and adolescents with diabetes. Pediatr Diabetes 2009;10: 58e70. 63. Wrigley M, Mayou R. Psychosocial factors and admission for poor glycaemic control: A study of psychological and social factors in poorly controlled insulindependent diabetic patients. J Psychosom Res 1991;35:335e43.
Contents lists available at ScienceDirect
Canadian Journal of Diabetes journal homepage: www.canadianjournalofdiabetes.com
Research Update
The Canadian Diabetes Association, Canadian Society, is Funding CDN $7.5 Million in Research in 2014e2015 to Support Excellent Researchers and Research Trainees Polly VandenBerg BSc(hon) Manager, Research Knowledge Translation, Canadian Diabetes Association, Toronto, Ontario, Canada
In 2014e2015, over a 16-month period, the Canadian Diabetes Association (CDA) will be funding 20 new Operating Grants and 15 new Personnel Awards across Canada. This year’s total research investment, including new and continuing grants and awards, is CDN $7.5 million, demonstrating the CDA’s commitment to investing in excellence in science and innovation. The research being supported will help to address important issues relating to the prevention, management and treatment of diabetes and diabetes-related complications. A summary of all grants and awards funded by the CDA in 2014e2015 is summarized by category in the Table 1. The funded research will be carried out over periods of 1 to 3 years for Operating Grants and 1 to 5 years for Personnel Awards. Below are 4 top-ranked projects that were awarded funding in the 2014 competition. Dr. James D. Johnson (University of British Columbia): Operating Grant Funded 2014e2017 Pancreatic beta-cell death and dysfunction are involved in the pathogenesis of both type 1 diabetes and type 2 diabetes. Research suggests that common mechanisms involved in beta-cell death in type 2 diabetes, as well as in type 1 diabetes and islet transplantation, are dysregulated protein homeostasis and endoplasmic reticulum (ER) stress (1). Understanding the mechanisms controlling ER stress has the potential to lead to new therapies for all forms of diabetes. It is likely that type 2 diabetes is caused by gene-environment interactions, where high-fat/high-calorie diets interact with several genetic polymorphisms to confer degrees of protection from susceptibility (2). Increased apoptosis of islets has been observed in the development of type 2 diabetes in animal models (3) and in humans (3e6). However, the mechanism by which this is regulated is not understood. Dr. Johnson and others have used multiple methods to elucidate gene regulatory networks modulated by exposure to free fatty acids in mouse and human islets (7e12). Dr. Johnson and his team developed the first published multiparameter, kinetic, high-throughput imaging platforms for betacell research (13e17), which allowed his group to perform side-by-side analysis of 206 factors in an effort to identify novel factors that can protect beta cells. Dr. Johnson used this information 1499-2671/$ e see front matter Ó 2014 Canadian Diabetes Association http://dx.doi.org/10.1016/j.jcjd.2014.09.004
to study the effects of endogenous biologic factors on beta-cell survival in the context of 5 stresses. Using this unbiased dataset, and excluding factors that were toxic in other stress conditions, Dr. Johnson and his team selected 6 novel beta-cell survival factors for further study. The objective of the current funding is to further characterize novel factors that prevent beta-cell death associated with ER stress and lipotoxicity and to uncover new molecular mechanisms governing beta-cell survival under these conditions. To do this, Dr. Johnson and his team will validate the lipotoxicity- and ER stressspecific beta-cell survival factors; examine the effects of free fatty acids and specific survival factors on ER calcium; and define the roles of alternative translation initiation factors in beta-cell survival. Dr. Brian B. Rodrigues (University of British Columbia): Operating Grant Funded 2014e2017 Cardiovascular disease is the leading cause of diabetes-related death (18), resulting primarily from atherosclerotic vascular disease but also possibly because of diabetic cardiomyopathy, an intrinsic defect in the heart muscle (19e21). Changes in cardiac metabolism are considered a principal culprit in the development of cardiomyopathy, and the earliest change that occurs in the diabetic heart is reduced glucose consumption and a switch to using more fatty acids for energy (22). Although this adaptation might be beneficial in the short term, it is potentially catastrophic over the long term (23e25). Dr. Rodrigues has been receiving funds from the CDA since 1997, and in that period has described a robust expansion in coronary lipoprotein (LPL) following diabetes (26), which was immediate, unrelated to gene expression (27), and included exaggerated processing to dimeric LPL, which is catalytically active. Dr. Rodrigues has also characterized the factors required for transfer of LPL to the coronary lumen. At this location, the enzyme breaks down circulating lipoprotein triglycerides into fatty acids, which are then delivered to the heart and can initiate injury (28e33). During his current funding, Dr. Rodrigues will investigate whether the changes in coronary LPL linked to diabetes are preludes to the cardiovascular complications of diabetes. He aims to understand how endothelial cells respond to hyperglycemia by increasing the amounts of a glycoprotein, GP1HBP1, abundantly
394
P. VandenBerg / Can J Diabetes 38 (2014) 393e395
Dr. Meranda M. Nakhla (the Research Institute of McGill University Health Centre): Operating Grant Funded 2014e2017
Table 1 Summary of grants and awards 2014e2015
Operating Grants Personnel Awards Clinician Scientist Awards Scholar Awards Post-Doctoral Fellowship Awards Doctoral Student Research Awards Total
Total
New and renewed (awarded in 2014 competition)
Ongoing commitments (awarded in previous competitions)
20 15 0
40 29 5
60 44 5
0 9
4 16
4 25
6
4
10
35
69
104
found in the heart. Understanding this link would be beneficial because interrupting this process presents opportunities for novel therapeutic strategies to prevent or delay heart dysfunction in persons with diabetes. Dr. André C. Carpentier (Université De Sherbrooke): Operating Grant Funded 2014e2017 Excess exposure of lean tissues to fatty acids is a key factor in insulin resistance and impaired beta-cell function, both major risk factors for developing diabetes (34e36). Prediabetes and diabetes are associated with changes in lipid metabolism in adipose tissues. Dr. Carpentier and his team found that, after ingesting or receiving intravenous fat, people with type 2 diabetes and prediabetes showed increased amounts of nonesterified fatty acid (NEFA) spillover (37, 38); that is, NEFAs that are not taken up by adipocytes but join the plasma NEFA pool. Increased plasma NEFA and saturated fatty acids in circulating triglycerides predict the development of type 2 diabetes, independent of the degree of beta-cell dysfunction. The risk for developing diabetes improves with weight loss induced by lifestyle interventions (39) or surgery (40, 41). There are 3 types of surgical procedures that are commonly used to treat severe obesity and type 2 diabetes: restrictive procedures (such as sleeve gastrectomy); mixed restrictive and fat malabsorptive procedures (such as Roux-en-Y gastric bypass and biliopancreatic diversion); and duodenal exclusion (“metabolic” surgery) (42). Dr. Carpentier is studying people with type 2 diabetes undergoing biliopancreatic diversion and sleeve gastrectomy. Biliopancreatic diversion induces profound weight loss and is the most effective therapeutic modality to date for the treatment of type 2 diabetes (42, 43). Roux-en-Y is the most popular (44), although it is somewhat less effective than biliopancreatic diversion (43). Sleeve gastrectomy is effective to induce early weight loss, although the majority of patients regain weight (45). Dr. Carpentier’s team has recently developed the capacity to perform very complex in vivo studies shortly after bariatric surgery (46), and they have well-established approaches to measure organspecific dietary fatty acid uptake and partitioning using positron emission tomography and stable isotope methods (47, 48). During this current funding, Dr. Carpentier will take the opportunity to determine the critical role of organ-specific changes in dietary fatty acid metabolism in the rapid improvement of glucose homeostasis, insulin resistance and beta-cell dysfunction after bariatric surgery. He will examine people with and without type 2 diabetes prior to and after biliopancreatic diversion or sleeve gastrectomy. Dr. Carpentier hopes that the study will generate new insights into the role of dietary fatty acid metabolism and the antidiabetic effects of bariatric surgery, and he believes that these original findings will be directly applicable to the pathogenesis, prevention and treatment of type 2 diabetes.
Rates of diabetes in children, both type 1 and type 2 diabetes, are increasing and represent a growing public health burden (49e51). Acute complications of diabetes, such as diabetic ketoacidosis and hypoglycemic emergencies, remain leading causes of preventable hospitalizations, emergency department visits and death in the pediatric population (52e57). The medical care of children and youth with diabetes is complex and requires intense resources as well as regular access to specialized healthcare services so as to prevent complications. The transition from pediatric to adult care adds further complexity to this management. In modern psychology, young adulthood does not begin until the early 30s, and the period between 18-30 years is considered emerging adulthood (58), a stage during which people are establishing their autonomy and personal identities and making vocational and educational choices. For people with diabetes, this stage is also complicated by the daily demands of a chronic illness and the challenge of transferring from pediatric to adult care. Many emerging adults with diabetes are at high risk for dropping out of medical care after the transition from pediatric to adult care, only to re-enter the medical system later, with diabetes-related complications (59, 60). Despite the recognized importance of transition care, the medical literature concerning this topic is limited. At this moment, we know little about the transition to adult diabetes care, including the magnitude of the problem, what happens to emerging adults when they leave pediatric care, and what system-level or individual-level factors improve their outcomes (61e63). With this Canadian Diabetes Association operating grant, Dr. Nakhla will further this research. During the current study, Dr. Nakhla’s research will examine provincial administrative and clinical data in Quebec to determine the system-level and individual-level factors associated with delays in establishing adult care, diabetes-related emergency department visits and hospitalizations among emerging adults with diabetes after the transfer to adult care. This examination of health service use and outcomes around the time of transfer to adult care will provide valuable information that will inform policy makers and healthcare providers and will help to guide the delivery of transition care services.
References 1. Volchuk A, Ron D. The endoplasmic reticulum stress response in the pancreatic beta-cell. Diabetes Obes Metabol 2010;12(Suppl 2):48e57. 2. Bell GI, Polonsky KS. Diabetes mellitus and genetically programmed defects in beta-cell function. Nature 2001;414:788e91. 3. Pick A, Clark J, Kubstrup C, et al. Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat. Diabetes 1998;47:358e64. 4. Marchetti P, Del Guerra S, Marselli L, et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metabol 2004;89:5535e41. 5. Leonardi O, Mints G, Hussain MA. Beta-cell apoptosis in the pathogenesis of human type 2 diabetes mellitus. Eur J Endocrinol 2003;149:99e102. 6. Butler AE, Janson J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52: 102e10. 7. Cnop M, Abdulkarim B, Bottu G, et al. RNA-sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate. Diabetes 2014;63:1978e93. 8. Keffrey KD, Alejandro EU, Ludiani DS, et al. Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis. Proc Natl Acad Sci U S A 2008;105:8452e87. 9. Chu KY, Li H, Wada K, et al. Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions. Diabetologia 2012;55:128e40. 10. Szabat M, Kalynyak TB, Lim GE, et al. Musashi expression in beta-cells coordinates insulin expression, apoptosis and proliferation in response to endoplasmic reticulum stress in diabetes. Dell Death Dis 2011;2:e232.
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