Comparative Analysis of Insulin Gene Promoters: Implications for Diabetes Research

Colin W. Hay; Kevin Docherty


Diabetes. 2006;55(12):3201-3213. 

In This Article

Insulin Gene Expression

Humans, in keeping with the overwhelming majority of species, have a single copy of the insulin gene, which is located on chromosome 11 (p15.5).[12] Of the small number of species with two nonallelic insulin genes, the best known are Xenopus laevis[13] and the popular laboratory research rodents of rat[14] and mouse,[15] with insulin two corresponding to the single copy in most animals.

In the adult insulin is expressed almost exclusively in the ß-cells of the pancreatic islets of Langerhans,[16] hence its name from Latin insula or "island." Low levels of extrapancreatic insulin have been detected in a number of other tissues[17,18] including brain,[19] thymus,[20,21,22] lachrymal glands,[23] and salivary glands.[24] The role of insulin expression in non-ß-cells is unclear. In some tissues it may play a role in the complex hormonal communication required for the maintenance of overall energy balance[25,26] or in the establishment of immune tolerance.[27] Very little is known about the regulatory sequences that control insulin gene expression in nonpancreatic tissue, although the sequence containing variable numbers of tandem repeats (see later) has been implicated in thymus expression of insulin.

In the ß-cell, sophisticated mechanisms have evolved to control insulin expression at the correct time and place during embryonic development. In the adult related mechanisms and a variety of signaling pathways are involved in restricting insulin expression to ß-cells (notwithstanding the low level extrapancreatic expression about which little is known) and in coordinating insulin expression in response to diverse afferent signals.[16] Positive and negative crosstalk between the various signaling pathways, formation of homo- or heterodimers permitting individual transcription factors to act as activators, nonactivators or repressors, reversible phosphorylation of transcription factors, multiple isoforms of several transcription factors, and synergistic interactions between certain combinations of transcription factors extend the gamut of signals influencing the regulation of insulin gene expression.

Insulin transcriptional control is conferred by cis-acting regulatory sequences believed to be located within 300–400 bp from the transcription start site,[28] which bind ß-cell restricted and ubiquitous transcription factors.[16] The principal regulatory elements within the human insulin promoter are outlined in Fig. 1. The compact nature of the insulin promoter results in the close proximity of regulatory elements that can bind an extensive range of factors thereby permitting a multiplicity of outcomes through additive and synergistic interactions between the bound proteins.[29,30,31] In addition, regulatory elements can overlap in certain species e.g., the A3 and a cAMP response element (CRE) site in humans, introducing another layer of complexity through binding competition between alternative transcription factors.

Figure 1.

Schematic representation of the human insulin promoter. The positions of the major cis-acting elements are indicated. The scale represents nucleotides relative to the transcription start site (+1 and forward arrow).


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