The insulin gene (abbreviated INS^[1]) is the gene coding for the hormone insulin.

It is mainly expressed in beta-cells in the pancreas, but also in the yolk sac, CNS, other endocrine cells in the pancreas and gastrointestinal tract and in the thymus.

Mechanism

The insulin gene encodes the mRNA for pre-proinsulin. After removal of the precursor signal peptide, proinsulin is post-translationally cleaved into two chains (peptide A and peptide B) that are covalently linked via two disulfide bonds. Binding of this mature form of insulin to the insulin receptor (INSR) stimulates glucose uptake.

Alleles

A variety of mutant alleles with changes in the coding region have been identified. There is a read-through gene, INS-IGF2, which overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region.^[2]

Regulation

There are several regulatory sequences in the promoter region of the human insulin gene, to which transcription factors bind.

In general, the A-boxes bind to Pdx1 factors, E-boxes bind to NeuroD, C-boxes bind to MafA and cAMP response elements to CREB.

There are also silencers that inhibit transcription.

Overview table

By dietary intake

Glucose has both stimulatory and inhibitory effects on insulin gene transcription, while fatty acids act in an inhibitory way;

Glucose increases transcription by promoting A-box-Pdx1 and C-box-MafA. At the same time, however, it causes production of reactive oxygen species (ROS), which acts on MafA in an inhibitory way.^[5] ROS also causes activation of C-Jun N-terminal kinases that inhibit NeuroD1.^[5] In addition, fatty acids also inhibits transcription by, in fatty acid metabolism, creating ceramide, which inhibits Pdx1 and MafA.^[5]

Mutations

Notable mutations are e.g. C65R (the cysteine (C) residue 65 is exchanged for an arginine (R)), wherein only proinsulin is generated.

Another is B10H, wherein the product is stuck in the endoplasmatic reticulum, causing ER stress and apoptosis of the beta cells.

References

Further reading