Comparative Analysis of Insulin Gene Promoters: Implications for Diabetes Research

Colin W. Hay; Kevin Docherty

Disclosures

Diabetes. 2006;55(12):3201-3213. 

In This Article

Implications

Investigations based on rodents and their insulin genes have provided invaluable insights into diabetes and the workings of insulin promoters. However, the findings reported here illustrate that notable dissimilarities exist between the human and rodent promoters, which may reflect both divergence and the degree to which these promoters have been studied. The atypical characteristics of rodent insulin promoters are exemplified most manifestly with the rat insulin 1 promoter, whose unusual attributes include an active dominant CCAAT site overlapping the single CRE site, HNF-1α, and HNF-4α regulatory elements; a functional Isl-1 binding site at A3/A4; a STAT-3 binding site; a potential COUP-TFII binding site; a consensus-containing E2 site; loss of GG boxes; lower conservation of A3 flanking regions; and changed spacing between regulatory elements in the C1-E1-A1 module leading to alternative synergistic interactions. The most plausible basis for the complexity of rodent insulin promoters is the duplication of their associated genes. Gene duplication can lead to functional divergence of the cis-regulatory elements[135,136] that can be swift even in recently duplicated genes.[137] In addition, the signaling pathways regulating an essential gene like insulin will undoubtedly incorporate redundancy to extend responses and to act as a buffer against the consequences of mutation of key components. The fundamental differences in regulatory elements should serve as a salutary warning to be cautious when extrapolating rodent-based data to humans.

A major obstacle in diabetes research has been the lack of a human pancreatic ß-cell line that is functionally equivalent to primary ß-cells. It is essential that new human ß-cell lines be developed and widely distributed in order that physiologically and medically relevant studies on the human insulin promoter can be carried out. This is especially true of in vivo epigenetic and ChIP-based experiments that will accurately map the position and define the role of nucleosomes and undoubtedly help to unravel the precise mechanisms responsible for insulin gene regulation.

These are exciting times as genome sequencing progresses rapidly. The availability of insulin genes from a wider range of species will provide tools that will permit the relatively straightforward answering of points raised in this report and allow us to advance our comprehension and appreciation of the subtle and sophisticated insulin promoter.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....