Thioredoxin-Interacting Protein Is Killing My β-cells!
- Department of Medicine, the Comprehensive Diabetes Center, University of Alabama in Birmingham, Birmingham, Alabama
- Address correspondence and reprint requests to John Corbett, Shelby Building, 12th floor, 1530 3rd Ave. So., UAB, Birmingham, AL 35294. E-mail:
The oxidation of glucose is required for the secretion of insulin by pancreatic β-cells. The product of this oxidation, ATP, stimulates the closure of potassium channels and calcium-dependent exocytosis of insulin. This system is beautifully regulated such that the precise amount of insulin is delivered to the bloodstream to regulate whole-body glucose metabolism. On the other hand, when insulin fails to function properly or when the demand for insulin is greater than the levels released by β-cells, blood glucose concentrations rise and diabetes ensues. In a subset of individuals with type 2 diabetes, there is a significant loss of β-cell mass. The mechanisms by which β-cells are lost under conditions in which glucose levels are elevated have yet to be fully elucidated. Proposed mechanisms to explain β-cell toxicity to elevated glucose concentrations include (but are not limited to) the generation of free radicals in β-cells during oxidative metabolism of glucose (1), the production of proinflammatory cytokines such as interleukin-1, which are known to be toxic to β-cells (2), and the induction of endoplasmic reticulum (ER) stress in β-cells (3). It has been proposed that each of these damaging pathways results in loss of β-cells due to apoptosis. In the current issue of Diabetes, Chen et al. (4) provide evidence that the loss of β-cell mass in response to elevated concentrations of glucose is the results of enhanced expression of a single protein, thioredoxin-interacting protein (TXNIP).
TXNIP participates in control of the redox state of a cell by interacting and inhibiting thioredoxin (5). Thioredoxin contains conserved active-site cysteine …