Biomarkers Consortium - Diabetes Drug Development: Identification and Validation of Markers That Predict Long-Term Beta Cell Function and Mass

The Biomarker Consortium’s Diabetes Drug Development: Identification and Validation of Markers That Predict Long-Term Beta Cell Function and Mass (Beta Cell Project) is the first project in a two-stage strategy that seeks to characterize beta cell function to 1) allow prediction of long-term beta cell response to an intervention based on short-term measures and 2) identify those whose beta cell function may be at risk for rapid deterioration. The goal of the initial project is to characterize some of the key methodological issues in the assessment of beta cell function. The project involves critical evaluations of the Mixed Meal Tolerance (MTT) and Arginine Stimulation Tests against the standard Frequently Sampled Intravenous Glucose Tolerance (FSIGT) Test in a series of clinical studies. The second stage, which may be planned as a separate project, will be a longitudinal study to qualify short-term markers as predictors of future beta cell function.

The series of fundamental clinical studies proposed in this project will provide a foundation for the effective and confident use of selected methodologies in long-term, multi-center clinical trials in the second project. Taken together, the work from both stages should enable multiple stakeholders to undertake consistent studies of the pathophysiology and natural history of diabetes, as well as study therapeutic effects of new interventions in a more effective manner. The Beta Cell Project is a 7-year, $5.1 million project, which launched in 2011, scheduled to complete by the end of the year 2018.

Goals

  • To evaluate MMT and Arginine Stimulation tests as validated methods in the assessment of beta cell function.
  • To enable development of biomarkers that assess long-term beta cell function, particularly in response to interventions for diabetes.

Results & Accomplishments

Key accomplishments include: (1) four clinical studies completed; (2) multiple abstracts accepted at the American Diabetes Association and the European Association for the Study of Diabetes meetings; and (4) two manuscripts published, one currently in-press and another one under review; (5) Established decision making method for designing interventional clinical trials using MMTT and AST with confidence across the glucose tolerance spectrum; (6) In-house utilization of MMT and Arginine Stimulation at multiple partner companies for drug-development decision-making, resulting in significant cost reduction and process efficiency improvements.

Scientific Publications

Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of Beta Cell Function: Results from the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series. Shankar SS, Vella A, Raymond RH, Staten MA, Calle RA, Bergman RN, Cao C, Chen D, Cobelli C, Dalla Man C, Deeg M, Dong JQ, Lee DS, Polidori D, Robertson RO, Ruetten H, Stefanovski D, Vassileva MT, Weir GC, Fryburg DA. Diabetes Care. Accepted July 2016.

Arginine is preferred to glucagon for stimulation testing of B-cell function. Robertson, RP, Raymond, RH, Lee, DS, Calle, RA, Ghosh A, Savage, PJ, Shankar, SS, Vassileva, MT, Weir GC, & Fryburg, DA. American Journal of Physiology – Endocrinology and Metabolism. 2014; 307 (8): E720-E727.

Outpatient Versus Inpatient Mixed Meal Tolerance and Arginine Stimulation Testing Yields Comparable Measures of Variability for Assessment of Beta Cell Function (in press)

"Mixed Meal and intravenous L-arginine tests both stimulate incretin release across glucose tolerance in man: lack of correlation with β-cell function" Ruetten et al., just accepted in journal "Metabolic Syndrome and Related Disorders"

Partners

AstraZeneca Pharmaceuticals, LP
American Diabetes Association
Cedars Sinai
Eli Lilly and Company
Janssen
JDRF
Joslin Clinic
Merck
Mayo Clinic
National Institutes of Health/National Institute of Diabetes, and Digestive and Kidney Diseases
Novartis
NovoNordisk
Pfizer Inc
ROI BioPharma
R-squared Solutions
Sanofi
Takeda
University of Padua
University of Pennsylvania
University of Washington
U.S. Food and Drug Administration
Wright Biomarker

Contact

Tania Kamphaus, Scientific Program Manager, Metabolic Disorders, TKamphaus@fnih.org