Thioredoxin-interacting protein deficiency induces Akt/Bcl-xL signaling and pancreatic beta-cell mass and protects against diabetes.

Pancreatic beta-cell loss through apoptosis represents a key factor in the pathogenesis of diabetes; however, no effective approaches to block this process and preserve endogenous beta-cell mass are currently available. To study the role of thioredoxin-interacting protein (TXNIP), a proapoptotic beta-cell factor we recently identified, we used HcB-19 (TXNIP nonsense mutation) and beta-cell-specific TXNIP knockout (bTKO) mice. Interestingly, HcB-19 mice demonstrate increased adiposity, but have lower blood glucose levels and increased pancreatic beta-cell mass (as assessed by morphometry).

Exenatide blocks JAK1-STAT1 in pancreatic beta cells.

Exenatide (Ex-4) is an antidiabetic drug that acts through the glucagon-like peptide 1 receptor and has recently been approved for the treatment of type 2 diabetes mellitus. Ex-4 also has been shown to affect beta cell gene expression and increase beta cell mass in rodent models of type 1 diabetes mellitus, but the mechanisms are not fully understood. We therefore analyzed the pathways affected by Ex-4 in human islets by using oligonucleotide microarrays and the PathwayStudio software (Ariadne Genomics, Rockville, MD).

Metabolism-independent sugar effects on gene transcription: the role of 3-O-methylglucose.

Glucose effects on cellular functions such as gene expression require, in general, glucose metabolism at least to glucose-6-phosphate (G-6-P). However, the example of thioredoxin-interacting protein (TXNIP), a glucose-regulated gene involved in the cellular redox state and pancreatic beta cell apoptosis, demonstrates that this rule may not always apply. We found that aside form glucose, the nonmetabolizable sugars 2-deoxyglucose, which is still converted to G-6-P as well as 3-O-methylglucose (3-MG), which cannot be phosphorylated by glucokinase, stimulate TXNIP expression.

Calciphylaxis in the absence of end-stage renal disease.

Objective: To report a case of calciphylaxis in the absence of renal failure in a patient with secondary hyperparathyroidism and low calcium/phosphorus product, in whom total parathyroidectomy resulted in relief of pain and healing of ulcerations.

Methods: We present the clinical, laboratory, and pathologic findings in a 62-year-old woman with calciphylaxis in the absence of end-stage renal disease.

Results: A 62-year-old woman presented with painful nonhealing bilateral calf ulcerations.

Exenatide inhibits beta-cell apoptosis by decreasing thioredoxin-interacting protein.

Exenatide (Ex-4) is a novel anti-diabetic drug that stimulates insulin secretion and enhances beta-cell mass, but the mechanisms involved are not fully understood. We found that Ex-4 protects INS-1 beta-cells against oxidative stress-induced apoptosis (TUNEL) and also reduces expression (mRNA and protein) of thioredoxin-interacting protein (TXNIP), a pro-apoptotic factor involved in beta-cell glucose toxicity and oxidative stress. This reduction was observed in INS-1 cells, mouse, and human islets as well as in wild-type mice receiving Ex-4 and was accompanied by decreased expression of the apoptotic factors caspase-3 and Bax.