Hammering out the role of IDX1 in diabetes

The Habener lab, which has previously implicated the transcription factor IDX-1 in pancreatic development and function, has now engineered a mouse strain in which to study the influence of this protein on diabetes. The importance of IDX-1 extends well beyond its ability to regulate insulin transcription, as seen in IDX-1-deficient mice, which lack a pancreas entirely. Since weak expression of IDX-1 leads to adult onset type II diabetes in both mice and humans, it has been proposed that diminished IDX-1 function, even in the absence of Idx1 mutations, could contribute to pathogenesis . Indeed, IDX-1 expression is reduced in hyperglycemic animals, but it has not been clear whether this change is a cause or a consequence of the progression of diabetes. To test this matter directly, Thomas et al. placed a hammerhead ribozyme specific for the IDX-1 mRNA under control of an inducible promoter. They show that the ribozyme can destabilize the IDX-1 mRNA and suppress glucose-dependent activation of the Insulin promoter. Interestingly, the effects of this ribozyme are limited because of a previously unsuspected autoregulatory loop through which loss of IDX-1 protein stimulates IDX-1 transcription. Nevertheless, when the ribozyme transgene is activated chronically, male mice show signs of glucose toxicity. Because the symptoms only become apparent in older males, Thomas et al suggest that the IDX-1 autoregulation is impaired during aging, an event that may compromise the ability of the pancreas to maintain adequate insulin expression.

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