A differentiated β-cell results not only from cell-specific gene expression, but also from cell-selective repression of certain housekeeping genes. Indeed, to prevent insulin toxicity, β-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 β-cells. This is illustrated by two studied examples. First, low-Km hexokinases are disallowed as their high affinity for glucose would, when expressed, significantly lower the threshold for glucose-induced β-cell function and cause hypoglycaemia, as happens in patients with β-cell tumours. Thus the β-cell phenotype means not only expression of glucokinase but also absence of low-Km hexokinases. Secondly, the absence of MCTs (monocarboxylic acid transporters) in β-cells explains the pyruvate paradox (pyruvate being an excellent substrate for mitochondrial ATP production, yet not stimulating insulin release when added to β-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 β-cell is breached.

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