Dead or Alive?

T ype 1 diabetes results from an immune assault on b-cells that progresses over time until the remaining b-cells are unable to keep up with demand and the ensuing hyperglycemia leads to clinical diagnosis. Many textbooks state that this occurs when 80% of the islets are destroyed; but in truth, the amount of residual insulin secretion at the time of clinical diagnosis is variable. The standard model is that those with type 1A diabetes continue to undergo immune-mediated b-cell attack after clinical diagnosis, rapidly leading to the complete absence of b-cells (1). In the last few decades, clinical research data have increasingly been challenging the notion that b-cells are completely destroyed soon after clinical diagnosis. Once individuals receive exogenous insulin, measurement of b-cell function requires assaying C-peptide, which is secreted in equimolar concentrations with insulin from b-cells. Stimulating the b-cell with a standard liquid " mixed meal " allows for assessment of the b-cell's ability to handle daily activities. Controlling for time of day, administration of exogenous insulin, and fasting glucose level, the mixed-meal tolerance test (MMTT) is a highly reproducible and easily performed test (2). We now know that among type 1 diabetic patients enrolled in clinical trials to preserve b-cell function, it is unusual for control or placebo-treated subjects starting with a reasonable amount of C-peptide at diagnosis to completely loose function in the first 2 years (3–13). Outside of these highly controlled clinical trial situations, residual C-peptide soon after diagnosis has been well documented (14–16). The SEARCH for Diabetes in Youth Study of antibody-positive youth with diabetes reported that more than 30% of children within the first year of diagnosis have fasting C-peptide values within the fifth percentile of normal healthy adolescents and that 11% of youth 5 or more years from diagnosis have potentially clinically significant fasting C-peptide levels (17). At the other end of the spectrum, 1) the Joslin Medalist Study demonstrated that 64% of individuals who had lived with type 1 diabetes for more than 50 years had measureable C-peptide (18), 2) our data of unselected subjects at least 30 years from diagnosis found detectable levels in 50% of subjects upon initial testing, and 3) others also found persistence of C-peptide in some individuals with long-standing disease (19). Recent studies using pathologic specimens also note some patchiness to b-cell loss in those who had type 1 diabetes (1). Further, studies in pregnancy have suggested …