Researchers at University of Alabama at Birmingham have discovered that an extremely harmful protein involved in the development of diabetes not only kills insulin-producing cells through one mechanism, but also damages the cells it does not kill through a second mechanism. The findings could lead to new treatments for diabetes, which affects almost 9% of Americans. They published their findings online on August 25 in the journal Nature Medicine.
Beta cells in the pancreas produce insulin, which regulates blood sugar. Impairment or death of these cells results in type1 diabetes. The study authors not that, at present, the molecular mechanisms underlying this disease have remained unclear. They note that they have identified thioredoxin-interacting protein (TXNIP), which a cellular redox regulator that is a crucial factor in beta cell biology. They found that beta cell TXNIP is up-regulated in diabetes; however, deficiency of these protein protects against diabetes by preventing beta cell apoptosis (death).
The investigators found that TXNIP and diabetes induce beta cell expression of a specific microRNA, miR-204, which in turn blocks insulin production by directly targeting and down-regulating MAFA, a known insulin transcription factor. They first discovered the regulation of miR-204 by TXNIP by microarray analysis, followed by validation studies in INS-1 beta cells, islets (area in the pancreas that contain the beta cells) of Txnip-deficient mice, diabetic mouse models and primary human islets. They then discovered that TXNIP induces miR-204 by inhibiting the activity of signal transducer and activator of transcription 3 (STAT3), a transcription factor that is involved in miR-204 regulation4, 5. We also identified MAFA as a target that is down-regulated by miR-204. A summary of all the aforementioned material is that the results demonstrate that TXNIP controls microRNA expression and insulin production; furthermore, that miR-204 is involved in beta cell function.
The researchers concluded that the newly identified 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. The research should provide hope for diabetics that slowing or halting progression of diabetes may become a reality in the near future.