The goal of this proposal is to continue a Clinical Center of TrialNet at the University of California at San Francisco (UCSF), with the ultimate long-term objectives to better understand the natural history and pathogenesis of type 1 diabetes mellitus (T1D), and to develop therapies to preserve endogenous insulin secretion in those with new onset T1D, and to prevent (T1D). UCSF is uniquely positioned to serve as a Clinical Center for TrialNet, given a well renowned clinical diabetes program;a large population base for subject recruitment;and a strong established track record with clinical research and autoimmune interventions for T1D. In addition, the center has Clinical and Translational Science Institute (CTSI) funding, with both a Pediatric and General Clinical Research Center (PCRC, GCRC), and investigators with extensive experience in both basic science and clinical research. This proposal will extend UCSF's past role as a Clinical Center in TrialNet. Specifically, the study goals are:
Specific Aim 1) To continue in our role as a Clinical Center for TrialNet, completing existing studies and developing and implementing new protocols in the network. To that end, we will continue our present plans to maximize recruitment for studies by increasing awareness amongst health care professionals and affected subjects and families. We will continue to foster relationships with a large affiliated network throughout Northern California and the Pacific Islands. We will recruit, enroll, and retain subjects within these studies according to the highest GCP standards.
Specific Aim 2 : We propose a novel phase II study to determine the safety and efficacy of Imatinib in preserving endogenous beta cell function in subjects with new onset T1D. This tyrosine kinase inhibitor has proven highly effective in therapy for specific cancers, and has more recently been shown to modulate autoimmunity in pre-clinical and clinical settings. In the NOD mouse, Imatinib induces remission in animals with new onset DM, and the drug can be withdrawn with the animals sustaining a durable remission, suggesting that it is tolerizing. We propose a multi-center, double-arm, blinded, placebo-controlled, 2:1 randomized, phase II clinical trial for individuals with recent onset T1D.

Public Health Relevance

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease in which insulin producing beta cells are completely destroyed by autoreactive T cells, resulting in a dependence on exogenous insulin for life. Current management of T1D is not optimal, with risk for recurrent hypoglycemia and long term complications relating to chronic hyperglycemia. The goals of the proposed studies are to prevent T1D, or to preserve endogenous insulin secretion in those with recent onset disease, so as to prevent the morbidity and mortality associated with this condition.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-R (O1))
Program Officer
Leschek, Ellen W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Ismail, Heba M; Xu, Ping; Libman, Ingrid M et al. (2018) The shape of the glucose concentration curve during an oral glucose tolerance test predicts risk for type 1 diabetes. Diabetologia 61:84-92
Culina, Slobodan; Lalanne, Ana Ines; Afonso, Georgia et al. (2018) Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors. Sci Immunol 3:
Vecchio, Federica; Lo Buono, Nicola; Stabilini, Angela et al. (2018) Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes. JCI Insight 3:
Redondo, Maria J; Steck, Andrea K; Sosenko, Jay et al. (2018) Transcription Factor 7-Like 2 (TCF7L2) Gene Polymorphism and Progression From Single to Multiple Autoantibody Positivity in Individuals at Risk for Type 1 Diabetes. Diabetes Care 41:2480-2486
Sanda, Srinath; Type 1 Diabetes TrialNet Study Group (2018) Increasing ICA512 autoantibody titers predict development of abnormal oral glucose tolerance tests. Pediatr Diabetes 19:271-276
Yeo, Lorraine; Woodwyk, Alyssa; Sood, Sanjana et al. (2018) Autoreactive T effector memory differentiation mirrors ? cell function in type 1 diabetes. J Clin Invest 128:3460-3474
Redondo, Maria J; Geyer, Susan; Steck, Andrea K et al. (2018) A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk. Diabetes Care 41:1887-1894
Greenbaum, Carla J; Speake, Cate; Krischer, Jeffrey et al. (2018) Strength in Numbers: Opportunities for Enhancing the Development of Effective Treatments for Type 1 Diabetes-The TrialNet Experience. Diabetes 67:1216-1225
Haller, Michael J; Schatz, Desmond A; Skyler, Jay S et al. (2018) Low-Dose Anti-Thymocyte Globulin (ATG) Preserves ?-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes. Diabetes Care 41:1917-1925
Redondo, Maria J; Geyer, Susan; Steck, Andrea K et al. (2018) TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes. Diabetes Care 41:311-317

Showing the most recent 10 out of 83 publications