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Chronic ethanol consumption is known as an independent risk factor for type 2 diabetes, which is characterized by impaired glucose homeostasis and insulin resistance; however, there is a great deal of controversy concerning the relationships between alcohol consumption and the development of type 2 diabetes. We investigated the effects of chronic ethanol consumption on pancreatic ␤-cell dysfunction and whether generated peroxynitrite participates in the impaired glucose homeostasis. Here we show that chronic ethanol feeding decreases the ability of pancreatic ␤-cells to mediate insulin secretion and ATP production in coordination with the decrease of glucokinase, Glut2, and insulin expression. Specific blockade of ATF3 using siRNA or C-terminally deleted ATF3(⌬C) attenuated ethanol-induced pancreatic ␤-cell apoptosis or dysfunction and restored the down-regulation of glucokinase (GCK), insulin, and pancreatic duodenal homeobox-1 induced by ethanol. GCK inactivation and down-regulation were predominantly mediated by ethanol metabolism-generated peroxynitrite, which were suppressed by the peroxynitrite scavengers N ␥ -monomethyl-L-arginine, uric acid, and deferoxamine but not by the S-nitrosylation inhibitor DTT, indicating that tyrosine nitration is the predominant modification associated with GCK down-regulation and inactivation rather than S-nitrosylation of cysteine. Tyrosine nitration of GCK prevented its association with pBad, and GCK translocation into the mitochondria results in subsequent proteasomal degradation of GCK following ubiquitination. This study identified a novel and efficient pathway by which chronic ethanol consumption may induce GCK down-regulation and inactivation by inducing tyrosine nitration of GCK, resulting in pancreatic ␤-cell apoptosis and dysfunction. Peroxynitrite-induced ATF3 may also serve as a potent upstream regulator of GCK down-regulation and ␤-cell apoptosis.

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SUMMARYThis paper presents a generalized finite element method (GFEM) based on the solution of interdependent global (structural) and local (crack)-scale problems. The local problems focus on the resolution of fine-scale features of the solution in the vicinity of three-dimensional cracks, while the global problem addresses the macro-scale structural behavior. The local solutions are embedded into the solution space for the global problem using the partition of unity method. The local problems are accurately solved using an hp-GFEM and thus the proposed method does not rely on analytical solutions. The proposed methodology enables accurate modeling of three-dimensional cracks on meshes with elements that are orders of magnitude larger than the process zone along crack fronts. The boundary conditions for the local problems are provided by the coarse global mesh solution and can be of Dirichlet, Neumann or Cauchy type. The effect of the type of local boundary conditions on the performance of the proposed GFEM is analyzed. Several three-dimensional fracture mechanics problems aimed at investigating the accuracy of the method and its computational performance, both in terms of problem size and CPU time, are presented.