Elevated Toll-Like Receptor 4 Expression and Signaling in Muscle From Insulin-Resistant Subjects

OBJECTIVE— Tall-like receptor (TLR)4 has been implicated in the pathogenesis of free fatty acid (FFA)-induced insulin resistance by activating inflammatory pathways, including inhibitor of κB (IκB)/nuclear factor κB (NFκB). However, it is not known whether insulin-resistant subjects have abnormal TLR4 signaling. We examined whether insulin-resistant subjects have abnormal TLR4 expression and TLR4-driven (IκB/NFκB) signaling in skeletal muscle

Outcomes of surgical treatment for upper urinary tract transitional cell carcinoma: Comparison of retroperitoneoscopic and open nephroureterectomy

<p>Abstract</p> <p>Objectives</p> <p>To determine the surgical and oncologic outcomes in patients who underwent retroperitoneoscopic nephroureterectomy (RNU) in comparison to standard open nephroureterectomy (ONU) for upper urinary tract transitional cell carcinoma (TCC).</p> <p>Patients and methods</p> <p>From April 2001 to January 2007, 60 total nephroureterectomy were performed for upper tract TCC at Siriraj Hospital. Of the 60 patients, thirty-one were treated with RNU and open bladder cuff excision, and twenty-nine with ONU. Our data were reviewed and analyzed retrospectively. The recorded data included sex, age, history of bladder cancer, type of surgery, tumor characteristics, postoperative course, disease recurrence and progression.</p> <p>Results</p> <p>The mean operative time was longer in the RNU group than in the ONU group (258.8 versus 190.6 min; p = 0. < 001). On the other hand, the mean blood loss and the dose of parenteral analgesia (morphine sulphate) were lower in the RNU group (289.3 versus 313.7 ml and 2.05 versus 6.72 mg; p = 0.868 and p = 0.018, respectively). There were two complications in each group. No significant difference in p stage and grade in both-groups (p = 0.951, p = 0.077). One patient with RNU had lymph node involvement, three in ONU. Mean follow up was 26.4 months (range 3–72) for RNU and 27.9 months (range 3–63) for ONU. No port metastasis occurred during follow up in RNU group. Tumor recurrence developed in 11 patients (bladder recurrence in 9 patients, local recurrence in 2 patients) in the RNU group and 14 patients (bladder recurrence in 13 patients, local recurrence in 1 patient) in the ONU group. No significant difference was detected in the tumor recurrence rate between the two procedures (p = 0.2716). Distant metastases developed in 3 patients (9.7%) after RNU and 2 patients (6.9%) after ONU. The 2 year disease specific survival rate after RNU and ONU was 86.3% and 92.5%, respectively (p = 0.8227).</p> <p>Conclusion</p> <p>Retroperitoneoscopic nephroureterectomy is less invasive than open surgery and is an oncological feasible operation. Thus, the results of our study supported the continued development of laparoscopic technique in the management of upper tract TCC.</p

Insulin stimulation regulates AS160 and TBC1D1 phosphorylation sites in human skeletal muscle

INTRODUCTION: Individuals with obesity and type 2 diabetes (T2D) are typically insulin resistant, exhibiting impaired skeletal muscle glucose uptake. Animal and cell culture experiments have shown that site-specific phosphorylation of the Rab-GTPase-activating proteins AS160 and TBC1D1 is critical for GLUT4 translocation facilitating glucose uptake, but their regulation in human skeletal muscle is not well understood. METHODS: Here, lean, obese and T2D subjects underwent a euglycemic-hyperinsulinemic clamp, and vastus lateralis muscle biopsies were obtained before, and at 30 and 180 min post insulin infusion. RESULTS: Obese and T2D subjects had higher body mass indexes and fasting insulin concentrations, and T2D subjects showed insulin resistance. Consistent with the clamp findings, T2D subjects had impaired insulin-stimulated phosphorylation of AS160 Thr(642), a site previously shown to be important in glucose uptake in rodents. Interestingly, insulin-stimulated phosphorylation of TBC1D1 Thr(590), a site shown to be regulated by insulin in rodents, was only increased in T2D subjects, although the functional significance of this difference is unknown. CONCLUSION: These data show that insulin differentially regulates AS160 and TBC1D1 phosphorylation in human skeletal muscle. Impaired insulin-stimulated glucose uptake in T2D subjects is accompanied by dysregulation of AS160 and TBC1D1 phosphorylation in skeletal muscle, suggesting that these proteins may regulate glucose uptake in humans

Physiological and molecular determinants of insulin action in the baboon

OBJECTIVE-To quantitate insulin sensitivity in lean and obese nondiabetic baboons and examine the underlying cellular/ molecular mechanisms responsible for impaired insulin action to characterize a baboon model of insulin resistance. RESEARCH DESIGN AND METHODS-Twenty baboons received a hyperinsulinemic-euglycemic clamp with skeletal muscle and visceral adipose tissue biopsies at baseline and at 30 and 120 min after insulin. Genes and protein expression of key molecules involved in the insulin signaling cascade (insulin receptor, insulin receptor substrate-1, p85, phosphatidylinositol 3-kinase, Akt, and AS160) were sequenced, and insulin-mediated changes were analyzed. RESULTS-Overall, baboons show a wide range of insulin sensitivity (6.2 \ub1 4.8 mg \ub7 kg -1 \ub7 min -1), and there is a strong inverse correlation between indexes of adiposity and insulin sensitivity (r =-0.946, P < 0.001 for % body fat; r =-0.72, P < 0.001 for waist circumference). The genes and protein sequences analyzed were found to have 3c 98% identity to those of man. Insulin-mediated changes in key signaling molecules were impaired both in muscle and adipose tissue in obese insulin-resistant compared with lean insulin-sensitive baboons. CONCLUSIONS-The obese baboon is a pertinent nonhuman primate model to examine the underlying cellular/molecular mechanisms responsible for insulin resistance and eventual development of type 2 diabetes