• β-cell apoptosis;
  • β-cell mass;
  • pulsatile insulin secretion;
  • type 2 diabetes;
  • type 1 diabetes

Regulation of blood glucose concentrations requires an adequate number of β-cells that respond appropriately to blood glucose levels. β-Cell mass cannot yet be measured in humans in vivo, necessitating autopsy studies, although both pre- and postmorbid changes may confound this approach. Autopsy studies report deficits in β-cell mass ranging from 0 to 65% in type 2 diabetes (T2DM), and ∼70–100% in type 1 diabetes (T1DM), and, when evaluated, increased β-cell apoptosis in both T1DM and T2DM. A deficit of β-cell mass of ∼50% in animal studies leads to impaired insulin secretion (when evaluated directly in the portal vein) and induction of insulin resistance. We postulate three phases for diabetes progression. Phase 1: selective β-cell cytotoxicity (autoimmune in T1DM, unknown in T2DM) leading to impaired β-cell function and gradual loss of β-cell mass through apoptosis. Phase 2: decompensation of glucose control when the pattern of portal vein insulin secretion is sufficiently impaired to cause hepatic insulin resistance. Phase 3: adverse consequences of glucose toxicity accelerate β-cell dysfunction and insulin resistance. The relative contribution of β-cell loss versus β-cell dysfunction to diabetes onset remains an area of controversy. However, because cytotoxicity sufficient to induce β-cell apoptosis predictably disturbs β-cell function, it is naïve to attempt to distinguish the relative contributions of these linked processes to diabetes onset.