Thioredoxin-interacting protein regulates insulin transcription through microRNA-204

Abstract

Beta-cell dysfunction and impaired insulin production are hallmarks of diabetes1, but despite the growing diabetes epidemic the molecular mechanisms involved have remained unclear. We identified thioredoxin-interacting protein (TXNIP), a cellular redox regulator, as a critical factor involved in beta-cell biology and showed that beta-cell TXNIP was upregulated in diabetes, whereas TXNIP deficiency protected against diabetes by preventing beta-cell apoptosis2–3. Here we show that TXNIP and diabetes induce beta-cell expression of a specific microRNA, miR-204, which in turn blocks insulin production by directly targeting and downregulating MafA, a known insulin transcription factor. After discovering miR-204 to be induced by TXNIP in a microRNA microarray, we confirmed the findings using INS-1 beta-cells, islets of TXNIP-deficient mice, diabetic mouse models and primary human islets. We further discovered that TXNIP induces miR-204 by controlling the activity of STAT3, a transcription factor involved in miR-204 regulation4–5 and identified MafA as a novel target downregulated by miR-204. Taken together, our results demonstrate for the first time that TXNIP controls microRNA expression and insulin production, and that miR-204 is involved in beta-cell function. The identified novel TXNIP/miR-204/MafA/insulin pathway may contribute to diabetes progression and provides new insight into TXNIP function and microRNA biology in health and disease.