At first glance, there appears to be a hierarchy of beta-cell dysfunction. We now know that proinsulin is retained, even as C-peptide response declines. However, when C-peptide is low or absent, both C-peptide and proinsulin fail to respond to stimuli [
6]. Given histological evidence that beta-cells persist long after diagnosis, the question arises: are these beta-cells ‘sleeping’ and could they be aroused? In other words, are they ‘stunned’, or functionally dead [
5,
7]? The fact that proinsulin levels are detectable, even when C-peptide is not, supports the former argument [
6]. Since proinsulin, C-peptide and insulin are secreted in equimolar quantities, but insulin is largely extracted by the liver, increased proinsulin:C-peptide (PL:CP) ratios imply accumulation and secretion of inadequately processed proinsulin, a hallmark of endoplasmic reticulum (ER) dysfunction. A cell that is unable to respond to its primary stimulus is called a ‘stunned’ cell and has the intrinsic capacity to restore competence [
7]. In the context of diabetes, one feature of such ‘stunned’ cells, is that there is not only a mismatch between insulin secretion and glucose stimulus, but also that the change can recover. ‘Stunned’ beta-cells are probably a feature of both type 2 and type 1 diabetes and can anticipate and predict both types [
7]. Such ‘stunned’ cells are conceptually distinct from ER stress, although both imply a dysfunctional beta-cell. Indeed, evidence of ER stress, using this PL:CP ratio, can be found in children at risk of type 1 diabetes and, in them, predicts the disease, especially in children under the age of 10 years [
6,
7].