ARNT2: A Novel Target for Diabetes

Joslin Diabetes Center, Inc.
posted on 03/09/2009

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The invention is based on the discovery of new targets not previously known to be linked to diabetes. Microarray analysis of human pancreatic islets from people with Type 2 diabetes compared to controls with normal glucose tolerance showed that the transcription factor aryl hydrocarbon nuclear receptor translocator (ARNT) was down-regulated in the diabetic individuals. This factor was expressed in all of the control individuals but expression was not detected in microarray analysis of samples from any of the diabetic subjects, and beta-cell specific knockout mice lacking the ARNT gene developed beta cell dysfunction and diabetes. Because ARNT is known to act as a heterodimer, the inventors then investigated the role of potential partners for ARNT, and discovered that the transcription factor ARNT2 (homologous to ARNT but expressed from a different gene) also has an effect, but an opposite one, on glucose metabolism. Knocking down ARNT2 expression using RNAi resulted in significantly increased glucose stimulated insulin secretion, and decreased ARNT2 expression was accompanied by increased expression of genes known to be involved in glucose metabolism. It therefore appears that inhibition of ARNT2 would be desirable to alleviate the symptoms of diabetes, while enhancement of ARNT function would be desirable for the same purpose. Salsalate or other nonacetylated salicylates can be used as a novel treatment for insulin resistance and type 2 diabetes, and to treat or prevent CV disease. The salicylates, and salsalate in particular, have been used for decades in human therapeutics, and are known to have very favorable human safety profiles. The inventors’ proof-of-principle clinical studies have shown that salsalate, in safe and tolerable doses, reduces glycemia, improves lipid homeostatis, and may improve inflammatory cardiovascular risk indexes in overweight individuals. More extensive clinical trials are now underway, which could provide support for ultimate FDA approval for such therapies.