Search

The transcription factor TORC2 [transducer of regulated cAMP-responsive element-binding protein (CREB) activity 2] is a major regulator of hepatic gluconeogenesis and is increased in hyperglycemic rodent models. Because chronic hyperglycemia and increased hepatic glucose production, via increased gluconeogenesis, is a key feature of type 2 diabetes, an effective in vivo method to efficiently knock down TORC2 could provide a potential therapy for treating hyperglycemia and type 2 diabetes. To assess this, primary mouse hepatocytes, high-fat diet (HFD)-fed mice, and Zucker diabetic fatty (ZDF) rats were treated with a siRNA against TORC2 (siTORC2), which was delivered via a novel lipid nanoparticle system, or control siRNA (siCON). Compared with siCON, administration of siTORC2 resulted in highly efficient, sustained (1-3 wk) knockdown of TORC2 and its gluconeogenic target genes phosphoenolpyruvate carboxykinase and glucose6-phophatase in primary mouse hepatocytes and in the livers of HFD-fed mice. In mice, this knockdown was specific to the liver and did not occur in kidney, skeletal muscle, or adipose tissue. In HFD-fed mice, siTORC2 reduced in vivo gluconeogenic capacity, fasting hepatic glucose production, and hyperglycemia, and led to improved hepatic and skeletal muscle insulin sensitivity, siTORC2 treatment also improved systemic hyperglycemia in ZDF rats. In conclusion, these results demonstrate the importance of TORC2 in modulating HGP in vivo and highlight a novel, liver-specific siRNA approach for the potential treatment of hyperglycemia and type 2 diabetes. transducer of regulated cAMP-responsive element-binding protein activity 2; diabetes; small interfering RNA doi: 10.1152/ajpendo.00158.2009.

We show that Topiramate (TPM) treatment normalizes whole body insulin sensitivity in high-fat diet (HFD)-fed male Wistar rats. Thus drug treatment markedly lowered glucose and insulin levels during glucose tolerance tests and caused increased insulin sensitization in adipose and muscle tissues as assessed by euglycemic clamp studies. The insulin-stimulated glucose disposal rate increased twofold (indicating enhanced muscle insulin sensitivity), and suppression of circulating FFAs increased by 200 to 300%, consistent with increased adipose tissue insulin sensitivity. There were no effects of TPM on hepatic insulin sensitivity in these TPM-treated HFD-fed rats. In addition, TPM administration resulted in a three- to fourfold increase in circulating levels of total and high-molecular-weight (HMW) adiponectin (Acrp30). Western blot analysis revealed normal AMPK ([Thr.sup.172]) phosphorylation in liver with a twofold increased phospho-AMPK in skeletal muscle in TPM-treated rats. In conclusion, 1) TPM treatment prevents overall insulin resistance in HFD male Wistar rats; 2) drug treatment improved insulin sensitivity in skeletal muscle and adipose tissue associated with enhanced AMPK phosphorylation; and 3) the tissue 'specific' effects are associated with increased serum levels of adiponectin, particularly the HMW component. high fat; insulin sensitization; adenosine monophosphate-activated protein kinase; adiponectin

The importance of Cbl in activating PI 3-kinase and aPKC during insulin action in 3T3/L1 adipocytes by expressing Y371F and Y731F Cb1 mutants is examined. This helps to nullify pYXXM binding of Cb1 to SH2 domains of downstream effectors.

High-power synchronous motor drives are usually fed from naturally commutated cycloconverters. The output voltage of the cycloconverter contains interharmonics/subharmonics which affect the power quality and restrict the allowable frequency range. Further, a practical circulating current-free cycloconverter usually gives rise to stator current discontinuities. The present paper deals with a simulation method to study the performance of a cycloconverter-fed synchronous motor drive in the presence of interharmonics/subharmonics taking into account the discontinuities in the output current as well as the effect of ripple in the output current on the input current of the cycloconverter. Interharmonics in output phase voltage, output phase current, input supply current, and the field current are estimated and verified with experimental results on a laboratory prototype. The significant oscillating torque components due to these interharmonics are identified in a typical case. The simulation results are useful in power quality studies for such drives and in devising methods for suppression of these interharmonics/subharmonics. Index Terms--Cycloconverter, interharmonics, power quality, simulation, subharmonics, synchronous motor.

Thiazolidinediones (TZDs) are insulin-sensitizing drugs and are potent agonists of the nuclear peroxisome proliferator-activated receptor-[gamma] (PPAR-[gamma]). Although muscle is the major organ responsible for insulin-stimulated glucose disposal, PPAR-[gamma] is more highly expressed in adipose tissue than in muscle. To address this issue, we used the Cre-loxP system to knock out Pparg, the gene encoding PPAR-[gamma], in mouse skeletal muscle. As early as 4 months of age, mice with targeted disruption of PPAR-[gamma] in muscle showed glucose intolerance and progressive insulin resistance. Using the hyperinsulinemic-euglycemic clamp technique, the in vivo insulin-stimulated glucose disposal rate (IS-GDR) was reduced by [similar]80% and was unchanged by 3 weeks of TZD treatment. These effects reveal a crucial role for muscle PPAR-[gamma] in the maintenance of skeletal muscle insulin action, the etiology of insulin resistance and the action of TZDs., Author(s): Andrea L Hevener [1, 6]; Weimin He [1, 6]; Yaacov Barak [3, 4, 6]; Jamie Le [1]; Gautam Bandyopadhyay [1]; Peter Olson [2, 4]; Jason Wilkes [1]; Ronald M [...]

Results demonstrate that increased activity of protein kinase-zeta is mediated by insulin activation of the phosphatidylinositol phosphate, 3-phosphoinositide-dependent protein kinase-1 threonine-410 loop phosphorylation, threonine-560 autophosphorylation, and pseudosubstrate autoinhibition during insulin action in rat adipocytes.

Glomus tumors are uncommon, with an estimated incidence of 1.6%. Cytological descriptions of this tumor are few. We report a 15-year-old boy presenting with a painful subungual swelling. Fine needle aspiration cytology showed uniform cells with homogeneous chromatin and scanty cytoplasm. Cytology was reported as "suggestive of glomus tumor". Histopathological examination confirmed the diagnosis. Careful cytomorphological examination supported by appropriate clinical history should suggest the diagnosis of glomus tumor and help in preoperative diagnosis.

[Figure: see text]. [ABSTRACT FROM AUTHOR]