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Conjugated linoleic acid (CLA) isomers have a number of beneficial health effects, as shown in biomedical studies with animal models. Previously, we reported that a mixture of CLA isomers improved glucose tolerance in ZDF rats and activated peroxisome proliferator-activated receptor (PPAR)-gamma response elements in vitro. Here, our aim was to elucidate the effect(s) of specific CLA isomers on whole-body glucose tolerance, insulin action in skeletal muscle, and expression of genes important in glucose and lipid metabolism. ZDF rats were fed either a control diet (CON), one of two CLA supplemented diets (1.5% CLA) containing differing isoforms of CLA (47% c9,t11; 47.9% c10,t12, 50:50; or 91% c9,t11, c9,t11 isomers), or were pair-fed CON diet to match the intake of 50:50. The 50:50 diet reduced adiposity and improved glucose tolerance compared with all other ZDF treatments. Insulin-stimulated glucose transport and glycogen synthase activity in skeletal muscle were improved with 50:50 compared with all other treatments. Neither phosphatidlyinositol 3-kinase activity nor Akt activity in muscle was affected by treatment. Uncoupling protein 2 in muscle and adipose tissue was upregulated by c9,t11 and 50:50 compared with ZDF controls. PPAR-gamma mRNA was downregulated in liver of c9,t11 and pair-fed ZDF rats. Thus, the improved glucose tolerance in 50:50 rats is attributable to, at least in part, improved insulin action in muscle, and CLA effects cannot be explained simply by reduced food intake.

The mouse mammary gland is a complex tissue, which is continually undergoing changes in structure and function. Embryonically, the gland begins with invasion of the underlying fat pad by a rudimentary ductal structure. Postnatal growth occurs in two phases: ductal growth and early alveolar development during estrous cycles, and cycles of proliferation, differentiation, and death that occur with each pregnancy, lactation, and involution. The variety of epithelial structures and stromal changes throughout the life of a mammary gland makes it a challenge to study. The purpose of this histological review is to give a brief representation of the morphological changes that occur throughout the cycle of mouse mammary gland development so that developmental changes observed in mouse models of mammary development can be appreciated.

Use of a novel impermeable biotinylated photolabeling reagent to assess insulin- and hypoxia-stimulated cell surface GLUT4 content in skeletal muscle from type 2 diabetic patients. J W Ryder , J Yang , D Galuska , J Rincón , M Björnholm , A Krook , S Lund , O Pedersen , H Wallberg-Henriksson , J R Zierath and G D Holman Department of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden. Abstract Cell surface GLUT4 levels in skeletal muscle from nine type 2 diabetic subjects and nine healthy control subjects have been assessed by a new technique that involves the use of a biotinylated photo-affinity label. A profound impairment in GLUT4 translocation to the skeletal muscle cell surface in response to insulin was observed in type 2 diabetic patients. Levels of insulin-stimulated cell surface GLUT4 above basal in type 2 diabetic patients were only approximately 10% of those observed in healthy subjects. The magnitude of the defect in GLUT4 translocation in type 2 diabetic patients was greater than that observed for glucose transport activity, which was approximately 50% of that in healthy subjects. Reduced GLUT4 translocation is therefore a major contributor to the impaired glucose transport activity in skeletal muscle from type 2 diabetic subjects. When a marked impairment in GLUT4 translocation occurs, the contribution of other transporters to transport activity becomes apparent. In response to hypoxia, marked reductions in skeletal muscle cell surface GLUT4 levels were also observed in type 2 diabetic patients. Therefore, a defect in a common late stage in signal transduction and/or a direct impairment in the GLUT4 translocation process accounts for reduced glucose transport in type 2 diabetic patients.

Muscle fiber type-specific defects in insulin signal transduction to glucose transport in diabetic GK rats. X M Song , Y Kawano , A Krook , J W Ryder , S Efendic , R A Roth , H Wallberg-Henriksson and J R Zierath Department of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden. Abstract To determine whether defects in the insulin signal transduction pathway to glucose transport occur in a muscle fiber type-specific manner, post-receptor insulin-signaling events were assessed in oxidative (soleus) and glycolytic (extensor digitorum longus [EDL]) skeletal muscle from Wistar or diabetic GK rats. In soleus muscle from GK rats, maximal insulin-stimulated (120 nmol/l) glucose transport was significantly decreased, compared with that of Wistar rats. In EDL muscle from GK rats, maximal insulin-stimulated glucose transport was normal, while the submaximal response was reduced compared with that of Wistar rats. We next treated diabetic GK rats with phlorizin for 4 weeks to determine whether restoration of glycemia would lead to improved insulin signal transduction. Phlorizin treatment of GK rats resulted in full restoration of insulin-stimulated glucose transport in soleus and EDL muscle. In soleus muscle from GK rats, submaximal and maximal insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and IRS-1-associated phosphatidylinositol (PI) 3-kinase activity were markedly reduced, compared with that of Wistar rats, but only submaximal insulin-stimulated PI 3-kinase was restored after phlorizin treatment. In EDL muscle, insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1-associated PI-3 kinase were not altered between GK and Wistar rats. Maximal insulin-stimulated Akt (protein kinase B) kinase activity is decreased in soleus muscle from GK rats and restored upon normalization of glycemia (Krook et al., Diabetes 46:2100-2114, 1997). Here, we show that in EDL muscle from GK rats, maximal insulin-stimulated Akt kinase activity is also impaired and restored to Wistar rat levels after phlorizin treatment. In conclusion, functional defects in IRS-1 and PI 3-kinase in skeletal muscle from diabetic GK rats are fiber-type-specific, with alterations observed in oxidative, but not glycolytic, muscle. Furthermore, regardless of muscle fiber type, downstream steps to PI 3-kinase (i.e., Akt and glucose transport) are sensitive to changes in the level of glycemia.

Microstructural white matter changes have been reported in the brains of patients across a range of psychiatric disorders. Evidence now demonstrates significant overlap in these regions in patients with affective and psychotic disorders, thus raising the possibility that these conditions share common neurobiological processes. If affective and psychotic disorders share these disruptions, it is unclear whether they occur early in the course or develop gradually with persistence or recurrence of illness. Utilisation of a clinical staging model, as an adjunct to traditional diagnostic practice, is a viable mechanism for measuring illness progression. It is particularly relevant in young people presenting early in their illness course. It also provides a suitable framework for determining the timing of emergent brain alterations, including disruptions of white matter tracts. Using diffusion tensor imaging, we investigated the integrity of white matter tracts in 74 patients with sub-syndromal psychiatric symptoms as well as in 69 patients diagnosed with established psychosis or affective disorder and contrasted these findings with those of 39 healthy controls. A significant disruption in white matter integrity was found in the left anterior corona radiata and in particular the anterior thalamic radiation for both the patients groups when separately contrasted with healthy controls. Our results suggest that patients with sub-syndromal symptoms exhibit discernable early white matter changes when compared with healthy control subjects and more significant disruptions are associated with clinical evidence of illness progression.

Trastuzumab is an effective treatment for patients with metastatic breast cancer (MBC) that overexpresses HER-2. A high incidence of brain metastases (BM) has been noted in patients receiving trastuzumab. A retrospective chart review was conducted of 100 patients commencing trastuzumab for metastatic breast cancer from July 1999 to December 2002, at the Christie Hospital. Seven patients were excluded; five patients developed central nervous system metastases prior to starting trastuzumab, and inadequate data were available for two. Out of the remaining 93 patients, 23 (25%) have developed BM to date. In all, 46 patients have died, and of these 18 (39%) have been diagnosed with BM prior to death. Of the 23 patients developing BM, 18 (78%) were hormone receptor negative and 18 (78%) had visceral disease. Univariate analysis showed a significant association between the development of cerebral disease and both hormone receptor status and the presence of visceral disease. In conclusion, a high proportion of patients with MBC treated with trastuzumab develop symptomatic cerebral metastases. HER-2-positive breast cancer may have a predilection for the brain, or trastuzumab therapy may change the disease pattern by prolonging survival. New strategies to address this problem require investigation in this group of patients.

Recently, it has been proposed that leptin, the ob gene product, influences some steps in the insulin-signaling cascade. The purpose of the present study was to determine whether leptin exerts direct effects on glucose transport in insulin target tissues. Epitrochlearis muscles or isolated adipocytes from male SD rats were incubated in the absence or presence of recombinant leptin (3–1,000 ng/ml), and in the absence or presence of submaximal or maximal insulin concentrations. In skeletal muscle, insulin increased 3-O-methylglucose transport (1.88 ± 0.21, 4.06 ± 0.59, and 9.35 ± 1.90 umol ·μmol · ml−1 ·h−1, for 0, 0.6, and 12.0 nmol/1 insulin, respectively). Leptin exposure (300 ng/ml) for 2 h did not alter the basal, submaximal, or maximal response of glucose transport to insulin in skeletal muscle (1.50 ± 0.14,4.76 ± 0.58, and 9.04 ± 1.09 umol · ml−1 · h−1 for 0, 0.6, and 12.0 nmol/l insulin, respectively). Insulin increased glucose transport in rat adipocytes (0.194 ± 0.007,1.059 ± 0.029, and 3.367 ± 0.143 pmol [14C]glucose · 0.5 ml−1 cell suspension · min−1 for 0,0.8, and 80 nmol/l insulin, respectively); in vitro exposure to leptin (300 ng/ml) did not alter glucose transport (0.220 ± 0.006,1.269 ± 0.046, and 3.221 ± 0.285 pmol [14C]glucose · 0.5 ml−1 cell suspension · min−1 for 0, 0.8, and 80 nmol/1 insulin, respectively). Similar to our findings in the epitrochlearis muscle, leptin had no direct effect on basal or insulin-stimulated glucose uptake in soleus muscle from ob/ob or lean mice or adipocytes from normal mice. In summary, in vitro exposure of skeletal muscle or adipocytes to recombinant leptin did not alter glucose transport in the absence of insulin, nor did it affect the sensitivity or responsiveness of the glucose transport system to insulin.

The effect of utilising granulocyte colony-stimulating factor (G-CSF) to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma (NHL) on long-term mortality patterns has not been formally evaluated. We analysed prolonged follow-up data from the first randomised controlled trial investigating this approach. Data on 10-year overall survival (OS), progression-free survival (PFS), freedom from progression (FFP) and incidence of second malignancies were collected for 80 patients with aggressive subtypes of NHL, who had been randomised to receive either VAPEC-B chemotherapy or VAPEC-B+G-CSF. Median follow-up was 15.7 years for surviving patients. No significant differences were found in PFS or OS. However, 10-year FFP was better in the G-CSF arm (68 vs 47%, P =0.037). Eleven deaths from causes unrelated to NHL or its treatment occurred in the G-CSF arm compared to five in controls. More deaths occurred from second malignancies (4 vs 2) and cardiovascular causes (5 vs 0) in the G-CSF arm. Although this pharmacovigilance study has insufficient statistical power to draw conclusions and is limited by the lack of data on smoking history and other cardiovascular risk factors, these unique long-term outcome data generate hypotheses that warrant further investigation.

Evidence against a direct effect of leptin on glucose transport in skeletal muscle and adipocytes. J R Zierath , E U Frevert , J W Ryder , P O Berggren and B B Kahn Department of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden. jrz@klinfys.ks.se Abstract Recently, it has been proposed that leptin, the ob gene product, influences some steps in the insulin-signaling cascade. The purpose of the present study was to determine whether leptin exerts direct effects on glucose transport in insulin target tissues. Epitrochlearis muscles or isolated adipocytes from male SD rats were incubated in the absence or presence of recombinant leptin (3-1,000 ng/ml), and in the absence or presence of submaximal or maximal insulin concentrations. In skeletal muscle, insulin increased 3-O-methylglucose transport (1.88 +/- 0.21, 4.06 +/- 0.59, and 9.35 +/- 1.90 micromol x ml-1 x h-1, for 0, 0.6, and 12.0 nmol/l insulin, respectively). Leptin exposure (300 ng/ml) for 2 h did not alter the basal, submaximal, or maximal response of glucose transport to insulin in skeletal muscle (1.50 +/- 0.14, 4.76 +/- 0.58, and 9.04 +/- 1.09 micromol x ml-1 x h-1 for 0, 0.6, and 12.0 nmol/l insulin, respectively). Insulin increased glucose transport in rat adipocytes (0.194 +/- 0.007, 1.059 +/- 0.029, and 3.367 +/- 0.143 pmol [14C]glucose x 0.5 ml-1 cell suspension x min-1 for 0, 0.8, and 80 nmol/l insulin, respectively); in vitro exposure to leptin (300 ng/ml) did not alter glucose transport (0.220 +/- 0.006, 1.269 +/- 0.046, and 3.221 +/- 0.285 pmol [14C]glucose x 0.5 ml-1 cell suspension x min-1 for 0, 0.8, and 80 nmol/l insulin, respectively). Similar to our findings in the epitrochlearis muscle, leptin had no direct effect on basal or insulin-stimulated glucose uptake in soleus muscle from ob/ob or lean mice or adipocytes from normal mice. In summary, in vitro exposure of skeletal muscle or adipocytes to recombinant leptin did not alter glucose transport in the absence of insulin, nor did it affect the sensitivity or responsiveness of the glucose transport system to insulin.