b-Cell–Specific Gene Repression: A Mechanism to Protect Against Inappropriate or Maladjusted Insulin Secretion?

What makes b-cells unique is their continuousresponsibility to produce, store and releasethe required amount of insulin to keep bloodglucose normal. This is no trivial task because daily insulin demands fluctuate acutely (as happens during meals) or chronically (e.g., the adaptation to obesity or preg-nancy). Moreover, normal blood glucose has two borders that need continuous protection. Insufficient insulin secre-tion should be avoided as this leads to hyperglycemia. Moreover, insulin excess causes hypoglycemia, a situation that jeopardizes brain function. Therefore, the optimal amount of b-cell activity is needed for normal health and this depends on an adequate plasticity of the functional b-cell mass (1). This Perspective examines the idea that protec-tion of the two borders of blood glucose requires a geneti-cally programmed b-cell phenotype with two unique faces (Fig. 1). The first depends on transcription factors that ac-tivate expression of specific proteins that mediate b-cell function. The second face depends on b-cell–specific repression of a small set of genes. We start to understand how expression of the latter genes may impair normal b-cell function. The best examples of expression of such “disallowed ” genes in b-cells lead to inappropriate insulin release (2)