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

Abstract

What makes β-cells unique is their continuous responsibility to produce, store and release the required amount of insulin to keep blood glucose 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 pregnancy). Moreover, normal blood glucose has two borders that need continuous protection. Insufficient insulin secretion should be avoided as this leads to hyperglycemia. Moreover, insulin excess causes hypoglycemia, a situation that jeopardizes brain function. Therefore, the optimal amount of β-cell activity is needed for normal health and this depends on an adequate plasticity of the functional β-cell mass (1). This Perspective examines the idea that protection of the two borders of blood glucose requires a genetically programmed β-cell phenotype with two unique faces (Fig. 1). The first depends on transcription factors that activate expression of specific proteins that mediate β-cell function. The second face depends on β-cell–specific repression of a small set of genes. We start to understand how expression of the latter genes may impair normal β-cell function. The best examples of expression of such “disallowed” genes in β-cells lead to inappropriate insulin release (2). FIG. 1. A balance between two faces of the mature β-cell. The general working hypothesis in this Perspective is that the mature β-cell needs to defend both the upper and lower normal limits of circulating glucose levels, thereby preventing the occurrence of episodes of hyperglycemia and hypoglycemia. A genetically determined β-cell program is responsible for the appropriate expression level of proteins in β-cells that allow a physiological response in terms of sufficient release of insulin when the organism needs the hormone. In parallel, some genes are specifically repressed in β-cells in order to avoid situations where β-cells respond inappropriately (induction by the wrong stimuli) or in a maladjusted manner …