Residual C-peptide in type 1 diabetes: what do we really know?

Connecting peptide, or C-peptide, is a protein that joins insulin's α and B chains in the proinsulin molecule. During insulin synthesis, C-peptide is cleaved from proinsulin and secreted in an equimolar concentration to insulin from the β cells. Because C-peptide experiences little first-pass clearance by the liver, and because levels are not affected by exogenous insulin administration, it may be used as a marker of endogenous insulin production and a reflection of β-cell function. Residual β-cell function, as measured by C-peptide in those with type 1 diabetes (T1D), has repeatedly been demonstrated to be clinically important. The Eisenbarth model of type 1 diabetes postulated immune-mediated linear loss of β cells, with clinical diagnosis occurring when there was insufficient insulin secretion to meet glycemic demand. Moreover, the model also implied that all individuals with T1D rapidly and inevitably progressed to absolute insulin deficiency. Correspondingly, it was assumed that most people with longstanding T1D would show little to no residual C-peptide secretion. While more than a quarter century of data confirms that this model remains largely true and appropriately serves as the basis for prevention studies, accumulating evidence suggests that the natural history of β-cell function before, during and after diagnosis is more complex. In this review, we discuss the clinical benefits of residual insulin secretion and present recent data about the natural history of insulin secretion in those with, or at risk for T1D.