Thioredoxin-Interacting Protein Is Killing My β-cells!

  1. John A. Corbett
  1. Department of Medicine, the Comprehensive Diabetes Center, University of Alabama in Birmingham, Birmingham, Alabama
  1. Address correspondence and reprint requests to John Corbett, Shelby Building, 12th floor, 1530 3rd Ave. So., UAB, Birmingham, AL 35294. E-mail: corbettj{at}uab.edu

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 …

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