Insulin, as measured by C-peptide, is produced for decades after onset of type 1 diabetes, and even very low levels of C-peptide have clinical significance. In this chapter we show that two distinct pathophysiological subtypes of type 1 diabetic subjects can be distinguished. Early-onset diabetic subjects (≤20 years) have rapid loss of C-peptide, whereas late-onset diabetic subjects (>20 years) have slower C-peptide declines over decades. Early-onset diabetics have significantly lower levels of persistent autoreactive CD8+ T cells than do late-onset diabetic subjects. In late-onset disease, robust production of autoreactive T-cells occurs even in the absence of C-peptide. Metabolomics analysis reveals frequent differences between the two subtypes of subjects in the levels of amino acids, carbohydrates, cofactors, lipids, peptides, and xenobiotics. There are statistically significant differences related to protective islet functions, islet health, development, blood sugar control, and regulation of exocrine pancreas function. Taken together these findings suggest that pancreas pathobiology, as well as durability of abnormal T-cell response should be considered in immune targeting treatments. Therapies aimed at immune defects alone are likely to work best in late-onset diabetics. Therapies aimed at islet cell preservation in early-onset diabetic subjects likely have greater efficacy if administered shortly after disease onset.