Why expression of some genes is disallowed in beta-cells.

A differentiated beta-cell results not only from cell-specific gene expression, but also from cell-selective repression of certain housekeeping genes. Indeed, to prevent insulin toxicity, beta-cells should handle insulin stores carefully, preventing exocytosis under conditions when circulating insulin is unwanted. Some ubiquitously expressed proteins would significantly jeopardize this safeguard, when allowed to function in beta-cells. This is illustrated by two studied examples. First, low-K(m) hexokinases are disallowed as their high affinity for glucose would, when expressed, significantly lower the threshold for glucose-induced beta-cell function and cause hypoglycaemia, as happens in patients with beta-cell tumours. Thus the beta-cell phenotype means not only expression of glucokinase but also absence of low-K(m) hexokinases. Secondly, the absence of MCTs (monocarboxylic acid transporters) in beta-cells explains the pyruvate paradox (pyruvate being an excellent substrate for mitochondrial ATP production, yet not stimulating insulin release when added to beta-cells). The relevance of this disallowance is underlined in patients with exercise-induced inappropriate insulin release: these have gain-of-function MCT1 promoter mutations and loss of the pyruvate paradox. By genome-wide ex vivo mRNA expression studies using mouse islets and an extensive panel of other tissues, we have started to identify in a systematic manner other specifically disallowed genes. For each of those, the future challenge is to explore the physiological/pathological relevance and study conditions under which the phenotypically disallowed state in the beta-cell is breached.