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Thioredoxin-interacting protein (Txnip) inhibits thioredoxin NADPH-dependent reduction of protein disulfides. Total Txnip knockout (TKO) mice adapted inappropriately to prolonged fasting by shifting fuel dependence of skeletal muscle and heart from fat and ketone bodies to glucose. TKO mice exhibited increased Akt signaling, insulin sensitivity, and glycolysis in oxidative tissues (skeletal muscle and hearts) but not in lipogenic tissues (liver and adipose tissue). The selective activation of Akt in skeletal muscle and hearts was associated with impaired mitochondrial fuel oxidation and the accumulation of oxidized (inactive) PTEN, whose activity depends on reduction of two critical cysteine residues. Whereas muscle-and heart-specific Txnip knockout mice recapitulated the metabolic phenotype exhibited by TKO mice, liverspecific Txnip knockout mice were similar to WT mice. Embryonic fibroblasts derived from knockout mice also accumulated oxidized (inactive) PTEN and had elevated Akt phosphorylation. In addition, they had faster growth rates and increased dependence on anaerobic glycolysis due to impaired mitochondrial fuel oxidation, and they were resistant to doxorubicin-facilitated respiration-dependent apoptosis. In the absence of Txnip, oxidative inactivation of PTEN and subsequent activation of Akt attenuated mitochondrial respiration, resulting in the accumulation of NADH, a competitive inhibitor of thioredoxin NADPH-reductive activation of PTEN. These findings indicate that, in nonlipogenic tissues, Txnip is required to maintain sufficient thioredoxin NADPH activity to reductively reactivate oxidized PTEN and oppose Akt downstream signaling.mitochondrial respiration ͉ redox

Thioredoxin-interacting protein (Txnip) is a ubiquitous protein that binds with high affinity to thioredoxin and inhibits its ability to reduce sulfhydryl groups via NADPH oxidation. HcB-19 mice contain a nonsense mutation in Txnip that eliminates its expression. Unlike normal animals, HcB-19 mice have ϳ3-fold increase in insulin levels when fasted. The C-peptide/insulin ratio is normal, suggesting that the hyperinsulinemia is due to increased insulin secretion. Fasted HcB-19 mice are hypoglycemic, hypertriglyceridemic, and have higher than normal levels of ketone bodies. Ablation of pancreatic ␤-cells with streptozotocin completely blocks the fasting-induced hypoglycemia/hypertriglyceridemia, suggesting that these abnormalities are due to excess insulin secretion. This is supported by increased hepatic mRNA levels of the insulin-inducible, lipogenic transcription factor sterol-responsive element-binding protein-1c and two of its targets, acetyl-CoA carboxylase and fatty acid synthase. During a prolonged fast, the hyperinsulinemia up-regulates lipogenesis but fails to down-regulate hepatic phosphoenolpyruvate carboxykinase mRNA expression. Hepatic ratios of reduced:oxidized glutathione, established regulators of gluconeogenic/glycolytic/lipogenic enzymes, were elevated 30% in HcB-19 mice, suggesting a loss of Txnip-enhanced sulfhydryl reduction. The altered hepatic enzymatic profiles of HcB-19 mice divert phosphoenolpyruvate to glyceroneogenesis and lipogenesis rather than gluconeogenesis. Our findings implicate Txnip-modulated sulfhydryl redox as a central regulator of insulin secretion in ␤-cells and regulation of many of the branch-points of gluconeogenesis/glycolysis/lipogenesis.

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Although proton acceleration often is observed at interplanetary shocks, electron acceleration rarely has been reported. In contrast, many of the shocks identified so far by instruments on the ISEE 3 spacecraft show significant increases in the spin averaged electron flux at energies greater than 2 keV. At 2 keV, the spin averaged electron flux usually increased by a factor of 2 to 3 but on several occasions increased to more than 10 times its preshock level. Often, the behavior of the electrons is similar to higher energy (several MeV) proton spikes: the electrons are field aligned before the shock and are highly anisotropic with the flux maximum perpendicular to the magnetic field at the shock and immediately after the shock. This is the signature of the shock drift model of acceleration where the gradient in the magnetic field causes the particles to move in the direction of lower potential energy in the convection electric field. Given that a primary assumption of the shock drift model is that the gyroradius is much larger than the shock thickness, and that this assumption is invalid for electrons, it is initially surprising that electrobs and ions can act similarly at shocks. A closer look shows that by conserving the first adiabatic invariant, electrons obey the same expressions for reflected and transmitted particles as ions.of the ratio of thermal to magnetic energy fl(---1). The mach number for the bow shock is in the range 6-10 whereas interplanetary shocks are generally lower at 2-3. Ion acceleration is now a well known phenomenonat both interplanetary shocks [Bryant eta!., 1962; Armstrong eta!., 1977] and the earth's bow shock [Asbridge eta!., 1968; Lin eta!., 1974; Paschmann eta!., 1980]. Less frequently observed is electron acceleration. Some early reports at the bow shock are by Anderson [1968, 1969]. More recently, Anderson et al. [1979a] report that electrons are accelerated in thin sheets along field lines tangent to the shock. The only reports of electron acceleration at interplanetary shocks seem to be Armstrong and Krimigis [1976] on October 29, 1972, for energies >200 keV, McGuire [1976] for December 16 and 17, 1971, and May 15, 1972, for energies as low as 0.5 keV, and three unpublished events referred to by Decker [1981]. This paper reports that electron acceleration occurs at many shocks. INSTRUMENTATION The ISEE 3 (International Sun Earth Explorer) spacecraft is ideally suited for making measurements of interplanetary particles without interference from the Earth. Launched August 12, 1978, its unique orbit about the libration point on the earth-sun line (Ll, 230 Re from the earth) places it continuously in the interplanetary medium. The University of California energetic particles experiment [Anderson eta!., 1978; Potter, 1981] was designed to measure electrons from 2 to 1000 keV and ions from 50 keV to 40 MeV with high sensitivity. Briefly, the electrostatic analyzer consists of---10-cm diameter hemisphere