Table 1.

Roadblocks hampering advancement of therapies for type 1 diabetes from research into the public healthcare setting.

Original Hypothesis	Current / Revised Hypothesis	Current Unknowns
Type 1 diabetes can be divided into two subsets (immune-mediated, Type 1A and β-cell-mediated Type 1B)	β-cell dysfunction and autoimmunity are thought to occur in all type 1 diabetes cases, though the extent to which each component contributes likely varies across individuals	Can type 1 diabetes be further subdivided based on different etiologies and/or natural histories? Can these sub-classifications be used to develop tailored therapies?
An environmental trigger is needed to initiate and/or perpetuate type 1 diabetes in at-risk individuals	A variety of environmental exposures may contribute toward risk for disease in susceptible individuals, but none have been directly associated with type 1 diabetes, to date	Can we identify specific environmental agents with clear contributions toward type 1 diabetes? What are the temporal factors and potential interactions involved? Do they vary by demographic group or geographic region?
β-cell mass declines in a linear fashion for months or years prior to diagnosis of type 1 diabetes.	β-cell loss may be attributable to both a decline in mass as well as dysfunction and may occur in a non-linear pattern with a sharp decline in the months immediately prior to type 1 diabetes diagnosis.	Is the pattern of β-cell loss truly relapsing/remitting? If so, how can we extend the remission periods? Are there biomarkers available to track β-cell mass and function in real time?
Loss of >85% of β-cell mass precipitates symptomatic onset of type 1 diabetes and after diagnosis, destruction continues until β-cells are no longer present	Appreciable heterogeneity exists regarding β-cell mass in healthy individuals and in those with type 1 diabetes; cells expressing insulin can often be detected in the type 1 diabetes pancreas for years, even decades, after diagnosis	How can we determine the β-cell mass in living patients (both functional and dysfunctional but potential amenable to restorative therapies)? Are dysfunctional β-cells “hiding” or masking themselves against the autoimmune attack? What factors render β-cell resistant to immune-mediated killing, and how can we provide similar protection to all β-cells in susceptible individuals?
C-peptide secretion and insulin production decline proportionally to β-cell mass.	β-cell mass/function may decline significantly prior to detectable deficits in C-peptide production and impairments in glycemic regulation	How long can residual β-cells compensate for decreasing β-cell mass and how does the increased insulin demand affect β-cell stress?
Glycemic control is normal until the onset of overt symptomatic disease and clinical diagnosis.	Stage 2 type 1 diabetes is defined by the presence of multiple disease-associated autoantibodies and impaired glycemic response to oral glucose tolerance test despite normal fasting blood glucose levels and HbA1c	How can we prevent progression from Stage 1 (multiple autoantibodies) to Stage 2 (dysglycemia)?