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Type 1 Diabetes Research


Although type 1 diabetes can be diagnosed at any age, it is one of the most common chronic diseases of childhood. The UF Diabetes Institute is recognized internationally as one of the leading centers investigating the natural history, prediction, and prevention of this disease. UF researchers have discovered a way to test for insulin-dependent diabetes years before symptoms appear, and helped lay the groundwork to project the estimated national burden of type 1 diabetes at a figure of $14.4–14.9 billion annuallyLearn more.

Type 1 diabetes, which accounts for about 10 percent of all diabetes cases, results from the body’s failure to produce enough insulin as a result of a destructive process of the insulin-producing beta ( β) cells in the pancreas. Over the past 25 years, UF research has been fundamental to the understanding of the genetic, immune and metabolic markers associated with the disease.

Our approach to type 1 diabetes research is backed by an emphasis that the disease begins long before symptomatic onset. UF research targets five areas: identifying at risk, pre-diabetes, newly diagnosed, established diabetes and reducing complications following onset.  Together, these approaches encompass a interdisciplinary method to understanding the disease; giving prospects for an improved future for all.


Identify At Risk

genomics

Precipitating events leading to development of type 1 diabetes may occur very early. Previous studies, including many emanating from the University of Florida, have demonstrated that individuals with this disease display a number of immunological abnormalities. The contribution of specific genes to this process, as well as an understanding of interactions between specialized cells and molecules of the innate and adaptive immune systems that lead to type 1 diabetes, however, remains unclear.

  • Genetics- Patrick Concannon, Clayton Matthews, John Driver
    Collaborative efforts at UF aim to improve understanding of the genetic risk for the disease. UF researchers have identified roughly 40 chromosome regions linked to type 1 diabetes, and most are thought to involve innate immune responses; supporting the notion that genetic influences involve mechanisms which collectively contribute to aberrant immune responsiveness.
  • Immune Function- Todd Brusko, Mark Atkinson, Patrick Rowe
    Immune-system development and normal turnover of β cells might also contribute to T1D pathogenic processes. Understanding the dialogue between insulin-producing β-cells and immune cells may allow us to better understand early serological evidence of β-cell destruction—ie, altered aminoacids and auto antibodies that takes place during the early stages of type 1 diabetes.

In addition to genetic involvement, there are environmental risk factors for diabetes which may heavily influence the entire natural history of the disease. These require a new focus within research as means for primary prevention.

  • Gut Microbiome- Eric Triplett, Graciella Lorca, Joe Larkin III, Joseph Neu
  • TEDDY Study- Desmond Schatz & Michael Haller
    The Triggers and Environmental Determinants of Diabetes in the Young (TEDDY) study tracks individuals’ infectious, dietary, and other exposures and life experiences; yielding the potential to revolutionize the ability to prevent type 1 diabetes and have an enormously positive impact on public health through a diet change or vaccine for disease prevention. Hence, the study is working towards helping countless future generations of children who may be spared from type 1 diabetes.
  • JDRF nPOD- Mark Atkinson, Martha Campbell Thompson, Demond Schatz
    The University of Florida is the primary coordinating agency for the JDRF nPOD program – which attempts to extend investigations to the entire pancreas, rather than be limited by use of a biopsy sample. This nationwide consortium collects tissues from cadaveric donors with serological evidence of anti-islet autoimmunity in order to learn more about predicting onset. The program has resulted in several important novel observations – for instance, that insulin-positive β cells and the expression of glucose transporters may persist for many years after diagnosis.
  • TrialNet at UF- Desmond Schatz, Michael Haller, Michael Clare-Salzler
    The Pathway to Prevention study offers a blood test that can identify the risk for type 1 diabetes up to 10 years before symptoms actually appear. Since inception, TrialNet has screened over 112,000 participants in this study. Of these, the University of Florida TrialNet research team, has screened over 3,500 participants, and, the UF region has screened close to 10,000 participants. Learn about the benefits of enrollment.
  • Well organized trial networks- UF also participates in research networks (eg, NIH TrialNet) and registries (eg, T1D Exchange) that can identify differences in diabetes management characteristics among youth populations and test agents capable of providing a therapeutic benefit, improve patient recruitment, and increase the precision of disease prediction.

Pre-Diabetes

UF research aims to better understand and treat early loss of β-cell function in T1D onset, characterized as the “silent phase,” or relapsing/remitting diabetes. Further understanding of pancreatic pathology and intervention studies give prospects to prolonging critical threshold of remnant β-cell mass and function in the remission phase of the disease, and prevent several sequelae that are often present at symptomatic onset (eg, glucose toxicity, stress response, etc).

  • Pancreas Weight- Martha Campbell-Thompson, Michael Haller, Mark Atkinson
    UF researchers found that people at risk for type 1 diabetes (ie autoantibodies are present) have smaller pancreas than their counterparts with no risk factors7. This has led to a large multi-center, multi-year project involving traditional, non-invasive tools such as MRI and ultrasound that will help researchers better understand the trajectory of the disease and may one day help lead to interventions to prevent it.
  • Prevention/Vaccine-  Mark Atkinson, Clive Wasserfall, Todd Brusko, Ben Keselosky
    Whereas autoantibodies are important biomarkers of islet autoimmunity, the actual destruction of the β-cells results from a cell-mediated autoimmune response. UF researchers are developing a “negative vaccine” to shut down or correct an antigen-specific immune response of T-cells in the development of T1D. This novel approach involves using time-release biomaterials and combinatorial components (antigens, drugs, and immune mediators called cytokines).
  • Mechanisms of beta-cell death- Michael Clare Salzler, Brian Wilson, Clayton Matthews
  • Rate of Metabolic Decay- Clayton Matthews
    Increasing glucose excursions during recent-onset may result from altered properties of β-cells.
  • Indentifying autoimmune biomarkers for onset- Clive Wasserfall, Desmond Schatz, Todd Brusko8 Positivity for islet autoantibodies (singly or multiple islet autoantibodies)

Islet infiltrate (ie, insulitis) seen in a patient with recent-onset type 1 diabetes

Islet infiltrate (ie, insulitis) seen in a patient with recent-onset type 1 diabetes. Image courtesy of the laboratory of M Campbell Thompson, University of Florida, Gainsville, FL, USA.

Newly Diagnosed

Accurate diagnosis of this disease for individuals with new-onset diabetes is crucial for optimum care and avoiding further complications. UF T1D research at the symptomatic (insulin-dependent) stage involves a multidisciplinary approach:

  • Type 1 Diabetes New Onset (NeOn) Study- Janet Silverstein, Michael Haller, Desmond Schatz, Henry Rohrs
    The NeOn Study includes youth <19 years old at T1D diagnosis who have been followed from the time of diagnosis at seven U.S. pediatric centers, including the University of Florida. UF diabetes researchers are working to identify shared factors of individuals most associated with lower HbA1c concentration within or after 1 yr of the onset of pediatric T1D and/or use of insulin pump therapy: White race, higher socioeconomic status, two-parent household, more frequent self-monitoring of blood glucose, and low insulin requirements9,10.
  • “Asymptomatic” T1D- Patrick Concannon
    Patients with recent T1D onset often show features of an immunological contribution to disease pathogenesis (eg, autoantibodies or genetic associations with genes controlling immune responses). However, University of Florida researchers helped identify that not all patients with type 1 diabetes have these characteristics, leading to proposed classifications of type 1A (autoimmune) diabetes (for the 70–90% of patients with type 1 disease that have immunological, self-reactive autoantibodies), and type 1B (idiopathic) diabetes, representing the remainder whose specific pathogenesis remains unclear11.
  • ZnT8 Autoantibody Testing- William E. Winter
    The newest autoantibody determination to enter the clinical realm of type 1 diabetes testing is the detection of autoantibodies against the type 8 zinc transporter (ZnT8). New-onset patients with clinically suspected type 1 diabetes, who are negative for ICAGADA, IA-2A and IAA, may be positive for ZnT8A autoantibodies, affirming an autoimmune etiology for a patient’s diabetes. Testing for ZnT8A is now available from UF’s CAP-accredited, CLIA-certified  at UF Health Pathology Laboratories’ Endocrine Autoantibody Laboratory.

Established Diabetes

Following the introduction of recent technological improvements in insulin pumps, improved glucose monitoring deivces, and insulin analogs that are helping patients with type 1 diabetes manage the challenge of lifelong insulin administration, UF research focuses on optimizing glycemic control and discovering novel care options.

  • Evalutaing diabetes self-management techniques- Demond Schatz, Michael Haller, T1D Exchange
    Implement and review cost-effective strategies for managing the disease.
  • T1D Reversal- Mark Atkinson, TrialNet & Helmsley Trust
    UF has been at the forefront of growing research interest in clinical reversal of type 1 diabetes. Research aims to restore β-cell function in individuals with T1D via immune tolerance; important in helping to explain the differing rates of progression to type 1 diabetes in adults versus children.
  • Residual C-Peptide- Desmond Schatz
    Some patients still produce low concentrations of the pancreatic hormone C-peptide long after onset. A recent study12 indicated that as many as 73% of type 1 diabetes patients showed detectable C-peptide levels after a duration of 30 years. UF research aims to learn more about how long people with type 1 diabetes continue to produce insulin even after having T1D for many years, and how to retain it.
  • Metformin Therapy for Overweight Adolescents with Type 1 Diabetes- Michael Haller
    Metformin is an oral medication that is used commonly to lower blood sugar in children and adults with type 2 diabetes. An investigational  research study at UF hopes to bring new understanding to evaluating its effectiveness in the type 1 diabetes population.
  • Cord Blood and Vitamin D Infusions- Michael Haller
  • Stem Cell- Bryon Peterson β-cell mass not always zero in long-standing patients, but current replication techniques are limited
  • New Insulin- Brett Sumerlin
    Development of a novel insulin-like capsule

Reducing Complications

Individuals with type 1 diabetes have a ten-times higher risk for cardiovascular events (eg, myocardial infarction, stroke, angina, and the need for coronary artery revascularisation) than age-matched non-diabetic populations13.

UF research aims to prevent, arrest, and reverse long-term complications of type 1 diabetes and hopes to emulate therapeutic interventions from studies in animal models, particularly the NOD mouse14.

In addition, future therapies that also focus on closer emulating the physiological role of the endocrine pancreas will, hopefully, improve lifestyles in addition to preventing complications.


Selected Bibliogrpahy:

1. Gale EA. Type 1 diabetes in the young: the harvest of sorrow goes on. Diabetologia 2005; 48: 1435–38.

2. Tao B, Pietropaolo M, Atkinson M, Schatz D, Taylor D. Estimating the cost of type 1 diabetes in the US: a propensity score matching method. PLoS One 2010; 5: 11501.

3. Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med 2009; 360: 1646–54.

4. TEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY) Study. Ann NY Acad Sci 2008;1150: 1–13.

5. Campbell-Thompson M, Wasserfall C, Kaddis J, et al. Network for Pancreatic Organ Donors with Diabetes (nPOD): developing a tissue biobank for type 1 diabetes. Diabetes Metab Res Rev 2012; 28: 608–17.

6. Pugliese A, Yang M, et. al. The Juvenile Diabetes Research Foundation Network for Pancreatic Organ Donors with Diabetes (nPOD) Program: goals, operational model and emerging findings. Pediatric Diabetes 2014; 15(1):1-9.

7. Campbell-Thompson M, Wasserfall C, Montgomery EL, Atkinson MA, Kaddis JS. Pancreas organ weight in individuals with disease-associated autoantibodies at risk for type 1 diabetes. JAMA 2012; 308: 2337–39.

8. Atkinson M, Reeves W, Winter WE, Yang LJ, et al. Novel detection of pancreatic and duodenal homeobox 1 autoantibodies (PAA) in human sera using luciferase immunoprecipitation systems (LIPS) assay. Int J Clin Exp Pathol 2013; 6(6):1202-10.

9. Tamborlane WV., Lee JM, Haller MJ, etl al. for the Pediatric Diabetes Consortium. Clinical Outcomes in Youth with Type 1 Diabetes during the First Year following Diagnosis: Results of the Pediatric Diabetes Consortium T1D New Onset (NeOn) Study. Pediatric Diabetes 2013 (In-Press).

10. Klingensmith GJ, Silverstein J, Tamborlane WV., et. al for the Pediatric Diabetes Consortium. Characteristics of Pediatric Type 1 Diabetes (T1D) Associated with HbA1c One Year after Diagnosis. Pediatric Diabetes 2013 (In-Press).

11. Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med 2009; 360: 1646–54.

12. Oram RA, et al “The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells” Diabetologia 2014;57:187-191.

13. Orchard TJ, Costacou T, Kretowski A, Nesto RW. Type 1 diabetes and coronary artery disease. Diabetes Care 2006; 29: 2528–38.

14. Atkinson MA. Evaluating preclinical efficacy. Sci Transl Med 2011; 3: 96cm22.