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  Oct 20, 2018

Insulin Gene

The polypeptide hormone insulin is required for normal glucose homeostasis. Lack of insulin or insulin insufficiency leads to diabetes that affects up to 5% of the human population.

Gene location

Insulin is formed as a precursor protein preproinsulin. This is coded by the INS gene. In some animals there are two insulin genes or two genes that code for insulin. In most animals, including humans, a single gene is present.

The hypothesis of a single gene is enhanced by the genetic studies of inheritance of defects in the insulin gene. In addition, there seems to be no sex-predilection while inheriting defects in the insulin gene. This means that the gene coding for insulin does not lie in the sex chromosomes (XX for females and XY for males) but in the autosomes (the 20 pairs of chromosomes barring the one pair of sex chromosomes).

The insulin gene has been recently uncoded in its complete form in genomic studies. Human and rat insulin genes have been cloned and the DNA has been sequenced. It was seen that mouse and rat insulins are identical and they have similar gene sequences and organization.

Similarities in genetic sequences in human have been found as well. Studies reveal that the 14-kilobase fragment that codes for insulin lies on the chromosome 11 in humans.

Gene stimulation and inhibition

The insulin gene is expressed almost exclusively in pancreatic β-cells. Glucose in blood is the major stimulant that regulates the insulin gene expression and enables the beta cells to produce insulin and maintain an adequate store of intracellular insulin to sustain the secretory demand.

Glucose in blood acts via transcription factors like pancreatic/duodenal homeobox-1 (PDX-1, mammalian homologue of avian MafA/L-Maf (MafA), Beta2/Neuro D (B2)), and controls the rate of transcription, and the stability of insulin mRNA. This helps in synthesis and secretion of insulin.

Low insulin production in diabetes may occur if there is continued high levels of glucose or lipids in blood. This leads to glucotoxicity or lipotoxicity respectively. This leads to worsening of β-cell function in type 2 diabetes, in part via inhibition of insulin gene expression.

This glucotoxicity involves decreased binding activities of PDX-1 and MafA and increased activity of C/EBPβ. High levels of glucose also leads to damage due to generation of oxidative stress. Lipotoxicity also leads to de novo ceramide synthesis and involves inhibition of PDX-1 nuclear translocation and MafA gene expression.

Genetic variants

There are several genetic mutants of the INS gene. There is a read-through gene, INS-IGF2 that can overlap with the INS gene at the 5' region and with the IGF2 gene at the 3' region.