Pancreatic islet transplantation holds great promise for the treatment of type 1 diabetes; recent advances in islet isolation and immunosuppression have led to greatly improved results. However, major obstacles and gaps in our current scientific knowledge preclude islet transplantation from being widely adapted as a treatment for type 1 diabetes. For example, most patients require islets isolated from two pancreata to become insulin-independent and often insulin-independence is not permanent. Safe, clinically applicable approaches to increase or sustain islet mass after transplantation in humans are hampered by the inability to study islets or assess islet mass after transplantation in humans. Using a multidisciplinary approach and the transplantation of murine, non-human primate, and human islets, our team proposes to test the hypothesis that glucagon-like peptide-1 (GLP-1), a promising therapy for improving islet function in type 2 diabetes, will increase or sustain islet mass after transplantation. In response to the RFA, the proposed studies will progress from basic science studies in cultured islets and genetically modified mice (bench) to studies of islet transplantation in non-human primates (bedside). In the R-21 phase of the research, we propose the following specific aims: 1) Ascertain the physiological importance of GLP-1 R signaling in murine islet transplantation using genetically modified mice with increased or decreased GLP-1 action. 2) Determine if GLP-1 administration before and/or after transplantation improves the survival of non-human primate islets into an immunodeficient mouse model that allows for in vivo study of xenotransplanted human islets. If these results are informative, we propose a R-33 phase with the following specific aims: 1) Determine the optimal parameters for GLP-1 administration using non-human primate and human islets transplanted into an immunodeficient mouse model that allows for in vivo study of xenotransplanted human islets. 2) Determine if GLP-1 administration increases or sustains islet mass in a non-human primate model of islet transplantation. 3) Determine the optimal parameters for GLP-1 administration in a non-human primate model of islet transplantation. As multiple GLP-1 analogues are in clinical trials for the treatment of diabetes, we anticipate that information from these models will be directly relevant and quickly applicable to islet transplantation in humans and should lead to a new approach to increase or sustain islet mass after transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33DK066636-05
Application #
7283746
Study Section
Special Emphasis Panel (ZDK1-GRB-1 (O2))
Program Officer
Appel, Michael C
Project Start
2003-09-30
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2011-07-31
Support Year
5
Fiscal Year
2007
Total Cost
$504,205
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Dean, E Danielle; Li, Mingyu; Prasad, Nripesh et al. (2017) Interrupted Glucagon Signaling Reveals Hepatic ? Cell Axis and Role for L-Glutamine in ? Cell Proliferation. Cell Metab 25:1362-1373.e5
Dai, Chunhua; Hang, Yan; Shostak, Alena et al. (2017) Age-dependent human ? cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling. J Clin Invest 127:3835-3844
Westacott, Matthew J; Farnsworth, Nikki L; St Clair, Joshua R et al. (2017) Age-Dependent Decline in the Coordinated [Ca2+] and Insulin Secretory Dynamics in Human Pancreatic Islets. Diabetes 66:2436-2445
Dai, Chunhua; Kayton, Nora S; Shostak, Alena et al. (2016) Stress-impaired transcription factor expression and insulin secretion in transplanted human islets. J Clin Invest 126:1857-70
Damond, Nicolas; Thorel, Fabrizio; Moyers, Julie S et al. (2016) Blockade of glucagon signaling prevents or reverses diabetes onset only if residual ?-cells persist. Elife 5:
Saunders, Diane; Powers, Alvin C (2016) Replicative capacity of ?-cells and type 1 diabetes. J Autoimmun 71:59-68
Conrad, Elizabeth; Dai, Chunhua; Spaeth, Jason et al. (2016) The MAFB transcription factor impacts islet ?-cell function in rodents and represents a unique signature of primate islet ?-cells. Am J Physiol Endocrinol Metab 310:E91-E102
Li, Mingyu; Dean, E Danielle; Zhao, Liyuan et al. (2015) Glucagon receptor inactivation leads to ?-cell hyperplasia in zebrafish. J Endocrinol 227:93-103
Raum, Jeffrey C; Soleimanpour, Scott A; Groff, David N et al. (2015) Tshz1 Regulates Pancreatic ?-Cell Maturation. Diabetes 64:2905-14
Kayton, Nora S; Poffenberger, Gregory; Henske, Joseph et al. (2015) Human islet preparations distributed for research exhibit a variety of insulin-secretory profiles. Am J Physiol Endocrinol Metab 308:E592-602

Showing the most recent 10 out of 37 publications