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Obesity causes insulin resistance, which has been interpreted as reduced downstream insulin signaling. However, changes in access of insulin to sensitive tissues such as skeletal muscle may also play a role. Insulin injected directly into skeletal muscle diffuses rapidly through the interstitial space to cause glucose uptake. When insulin resistance is induced by exogenous lipid infusion, this interstitial diffusion process is curtailed. Thus, the possibility exists that hyperlipidemia, such as that seen during obesity, may inhibit insulin action to muscle cells and exacerbate insulin resistance. Here we asked whether interstitial insulin diffusion is reduced in physiological obesity induced by a high-fat diet (HFD).
Dogs were fed a regular diet (lean) or one supplemented with bacon grease for 9–12 weeks (HFD). Basal insulin (0.2 mU · min−1 · kg−1) euglycemic clamps were performed on fat-fed animals (n = 6). During clamps performed under anesthesia, five sequential doses of insulin were injected into the vastus medialis of one hind limb (INJ); the contralateral limb (NINJ) served as a control.
INJ lymph insulin showed an increase above NINJ in lean animals, but no change in HFD-fed animals. Muscle glucose uptake observed in lean animals did not occur in HFD-fed animals.
Insulin resistance induced by HFD caused a failure of intramuscularly injected insulin to diffuse through the interstitial space and failure to cause glucose uptake, compared with normal animals. High-fat feeding prevents the appearance of injected insulin in the interstitial space, thus reducing binding to skeletal muscle cells and glucose uptake.
Insulin resistance is associated with a number of diseases, including cardiovascular disease, hypertension (1), cancer (2), and obesity (1,3), as well as type 2 diabetes. Much research into insulin resistance has focused on insulin signaling, suggesting that target cell (e.g., skeletal muscle) response to insulin is the primary defect. Most recently, mitochondrial dysfunction (4,5) and intracellular fat accumulation (6) have been proposed as primary causes of insulin resistance. Despite these efforts, there is no definitive conclusion as to the primary cause of cellular insulin resistance.
There are a number of loci where insulin action can be altered, including the direct effect of inflammatory cytokines to attenuate distribution of blood flow and glucose uptake (7), and direct effects of plasma free fatty acids (FFAs) to impede insulin signaling in the cell (4) and/or reduce capillary recruitment (8). To act, insulin must cross the capillary endothelium, traverse the interstitial fluid compartment, and thence access and bind to insulin receptors. A reduction in insulin's ability to diffuse through the interstitial space in lipid-induced insulin resistance (9) suggests that access to sensitive tissues (such as skeletal muscle) may be important in addition to cellular insulin resistance. In insulin-resistant situations, it is therefore important to examine whether insulin can access cells prior to stimulating cell signaling.
A high-fat diet (HFD), which induces obesity and leads to deposition of fat in tissues (10,11), does not always increase basal FFAs in humans or canines (12,13); but large elevations of FFAs can be observed at night in canines (13) and humans (14). Given the uncertainty regarding the effect of HFDs on FFA levels in the circulation, it is not yet known whether the effects of lipid infusion on insulin action can be extrapolated to explain how an HFD per se would affect insulin action and the ability of insulin to diffuse through skeletal muscle.
Previous studies in our laboratory have shown that insulin injected directly into healthy muscle is disseminated throughout the interstitial space, where the hormone accesses myocytes and stimulates glucose uptake (15). In a model of insulin resistance where plasma FFAs were raised by lipid infusion, injected insulin was surprisingly not detected in the interstitial space (lymph) of skeletal muscle, supporting absence of elevated interstitial insulin. Under this condition there was little stimulation of glucose disposal (9). This latter result suggests that high plasma FFAs may prevent insulin's access to skeletal muscle, resulting in insulin resistance. It cannot be concluded whether this is a direct effect of elevated plasma FFAs, or of acute insulin resistance induced by lipid infusion. Therefore, it was important to examine whether lipid elevated physiologically by an HFD would similarly limit insulin's access to muscle cells. For example, in dogs fed a control diet, insulin stimulates the extravascular distribution of insulin without effects on vascular distribution volume (16), suggesting that insulin can increase its own access to insulin-sensitive tissues. This effect was lost after induction of insulin resistance by an HFD (17), possibly due to an alteration in the diffusion of insulin through the interstitial space. In the present report, we examined whether insulin resistance induced by an HFD would simulate lipid infusion studies in which injected insulin was not detected in lymph. If so, this would implicate insulin access to muscle cells as an important factor in dietary fat–induced insulin resistance.
One-year-old male mongrel dogs were housed in individual cages in the University of Southern California Medical School Vivarium and were kept under controlled conditions (12-h light/12-h dark). Animals had free access to water, and were fed once per day from 9:00–10:00 a.m. with 825 g dry chow (60% Prolab Canine 2000, 40% Laboratory High Density Canine Diet 5LI8; PMI Nutrition International, Brentwood, MO) and one can of Purina Pro-Plan Puppy Classic (Nestle Purina PetCare, St Louis, MO). For fat feeding, animals were subjected to the basal diet, supplemented with 6 g/kg bacon grease, presented to the dogs for the remainder of the study (15.2 ± 0.8 weeks). We have previously published data from injecting insulin into normal-weight dogs (lean) fed ad lib dry chow (15); these previous results are reproduced with permission herein for comparison and were not different when performed before or after the HFD experiments. Dogs were used for experiments only if they were judged to be in good health as determined by visual observation, body weight, hematocrit, and body temperature. Protocols were approved by the University of Southern California Institutional Animal Care and Use Committee and were in accordance with the Principles of Laboratory Animal Care.
Weekly fasted (basal) plasma samples for measurement of FFAs were taken into tubes with 50 μl EDTA and paraoxon to inhibit lipase activity and centrifuged, and the plasma was frozen before analysis using a colorimetric kit (NEFA-HR(2); Wako Diagnostics, Richmond, VA). Prior to beginning the HFD, each animal (n = 6) underwent magnetic resonance imaging (MRI) of the abdominal area as outlined below, and a hyperinsulinemic euglycemic clamp (EGC) for determination of insulin sensitivity (SI) and glucose turnover. Once these baseline parameters were established, the HFD was administered, and the MRIs and EGCs were repeated (weeks 12–13). Finally, an acute injection procedure was performed prior to death to determine the local dynamics of injected insulin as detailed below. Lean animals received the acute injection procedure, but did not receive MRIs or EGCs.
On the morning of each MRI scan, a subcutaneous injection of acepromazine (0.04 mg/kg; Bioceutical, St Joseph, MO) and atropine sulfate (0.1 mg/kg, 1/120 grain; Western Medical, Arcadia, CA) was administered for preanesthesia; dogs then received intravenous anesthesia of ketamine HCl (10 mg/kg; Phoenix Pharmaceutical, St Joseph, MO) and diazepam (0.2 mg/kg; Abbott Laboratories, North Chicago, IL). Body composition was then assessed in 30 1-cm axial abdominal images using 1.5 Tesla Horizon Magnet (version 5.7 software). Each MRI slice was analyzed using Scion Image Software (Windows 2000 version Beta 4.0.2; Scion, Frederick, MD), which quantifies fat tissue (pixel values 121–254) and nonfat tissue (pixel values 20–120). The total pixels of fat and nonfat tissue were used to calculate the area of fat located within the peritoneal cavity in an 11-cm region of the thorax identified by the central landmark slice, where the left renal artery branches from the abdominal aorta. Subcutaneous fat volume was calculated as total fat in the assessment region minus the visceral fat volume.
A primed infusion of [3-H3]-d-glucose tracer was started at t = −120 min (25-μCi bolus + 0.25 μCi/min; DuPont-NEN, Boston, MA) into the saphenous vein in conscious animals. An infusion of insulin (0.75 mU · min−1 · kg−1; Lilly, Indianapolis, IN) and somatostatin (1.0 μg · min−1 · kg−1; Bachem California, Torrance, CA) was initiated at time 0, and radiolabeled dextrose (2.0 μCi/g, [3-H3]-d-glucose, 50% dextrose) was variably infused to maintain euglycemia and specific activity. Blood samples were drawn from the cephalic vein every 10 min from t = −30 to 180 min. Euglycemia was defined as the average basal glucose and steady state as the final 30 min of the clamp. SI was calculated using the equation SI = ΔGinf/(ΔIxG), where ΔGinf = change in glucose infusion at steady state from basal, ΔI = change in plasma insulin at steady state from basal, and G = steady-state plasma glucose concentration.
These experiments were terminal studies performed under anesthesia. Injection studies were performed on lean animals and on animals given 15.2 ± 0.8 weeks of HFD. Animals were fasted 15 h before the experiment, which began at 6:00 a.m. They were preanesthetized with acepromazine maleate (Prom-Ace, 0.22 mg/kg; Aueco, Fort Dodge, IA) and atropine sulfate (0.11 ml/kg; Western Medical). Anesthesia was induced with sodium pentobarbital (0.44 ml/kg; Western Medical) and maintained with isoflurane (Western Medical). Dogs were placed on heating pads to maintain body temperature. Indwelling catheters were inserted into the right jugular vein for a continuous saline drip (~1 l for the first 60 min of surgery and a slow drip thereafter) and into the left carotid artery for sampling and blood pressure monitoring (model 90603A; Space Labs, Issaquah, WA). Intracatheters were inserted into the left cephalic vein for variable glucose infusion and the right cephalic vein for insulin and somatostatin infusion. Indwelling catheters were also placed into both the right and left femoral arteries and veins for blood sampling. Two perivascular ultrasonic flowprobes (2-mm diameter; Transonic, Ithaca, NY) were placed around both right and left femoral arteries proximal to the femoral catheter. Left and right hind limb lymphatic vessels were cannulated by placing polyethylene catheters (PE10) into the afferent lymphatic vessels of the deep inguinal lymph node. Blood pressure, heart rate, O2 saturation, and CO2 were monitored continuously. At the conclusion of these experiments, animals were killed with an overdose of sodium pentobarbital (Eutha-6, 65 mg/kg; Western Medical).
Immediately after starting surgical procedures (t = −180 min), simultaneous systemic infusions of somatostatin (1 μg · min−1 · kg−1) and basal insulin replacement (0.2 mU · min−1 · kg−1) were begun and continued for the duration of the study (Fig. 1). Exogenous 20% glucose was infused at variable rates to maintain euglycemia at the basal level based on glucose measurements from the injected leg's (INJ) femoral artery plasma glucose (measured prior to insulin infusion) throughout the entire experimental period (t = −240 to 300 min). Samples were taken simultaneously from the right and left femoral arteries and veins. Left and right hind limb lymph vessels were sampled by gently massaging the hind limb distal to the site of catheterization from 2 min prior to 2 min after each blood sample.
As previously described (15), at times 0, 60, 120, 180, and 240 min, porcine insulin (0.3, 0.5, 0.7, 1, and 3 U, represented as I1, I2, I3, I4, and I5, respectively) was injected directly into the vastus medialis of the quadriceps femoris of one leg. At each time point, two 30-gauge needles with a volume of 0.5 ml per syringe injected the appropriate concentration of insulin at ~0.6 ml/min. For individual experiments, either right or left hind limb was chosen at random for injections (INJ) and the noninjected contralateral limb (NINJ) was used for comparison. Plasma and lymph samples were taken every 10 min after each injection.
Plasma and lymph samples were collected in microtubes that were precoated with lithium-heparin (Becton Dickinson, Franklin Lakes, NJ) and assayed for insulin and glucose. Arterial and venous tubes also contained 50 μL EDTA (Sigma Chemicals). Blood samples were centrifuged immediately, and the supernatant was transferred and stored at −20°C until further assay. INJ femoral artery plasma samples were immediately assayed for glucose with a YSI 2700 auto analyzer (Yellow Springs Instruments, Yellow Springs, OH) before freezing at −20°C. Lymph samples were stored at −20°C after sampling. Samples were assayed for insulin by ELISA (Linco Research) adapted for canine plasma with a standard provided by Novo Nordisk, and for glucose with a YSI 2700 auto analyzer.
Glucose uptake across each limb was calculated based on the Fick principle: LGU = (GA − GV) × BF, where LGU = local glucose uptake; GA = arterial glucose; GV = venous glucose; and BF = femoral blood flow.
All experimental data are expressed as the means ± SE. Statistical analyses were performed with unpaired Student t tests, or one- or two-way ANOVAs with Tukey pairwise comparisons as appropriate. The lean and HFD groups were compared using unpaired t tests and two-way ANOVAs.
Fourteen weeks of fat feeding caused an increase in body weight, as shown in Fig. 2A, and also resulted in an increase in both subcutaneous and abdominal fat, as measured by MRIs shown in Fig. 2B. On average, fat- fed dogs increased visceral fat by 79.4% (from 462.5 ± 81.4 cm3 to 803.2 ± 154.3 cm3, P = 0.02) and subcutaneous fat by 108.9% (from 902.2 ± 183.1 cm3 to 1952.3 ± 502.1 cm3, P = 0.03).
Basal-fasted plasma FFAs decreased with fat feeding from 0.66 ± 0.11 mmol/l to 0.40 ± 0.07 mmol/l (P = 0.02). During the course of the experiment, the plasma FFA levels dropped to levels virtually undetectable by the FFA assay used (data not presented), as inhalant isoflurane anesthesia is known to suppress lipolysis (18).
As expected, HFD induced significant peripheral insulin resistance determined by the hyperinsulinemic euglycemic clamp in conscious dogs (week 0: 8.72 ± 0.27 to week 12: 3.15 ± 0.65 dl · pM−1 · mg−1 · kg−1, P = 0.02) (Fig. 3A). Glucose disposal (Rd) decreased from 11.49 ± 1.53 mg · min−1 · kg−1 prior to fat feeding to 7.26 ± 1.55 mg · min−1 · kg−1 after 12 weeks of HFD (P = 0.03) (Fig. 3B). Endogenous glucose production showed a trend to increase (week 0: 0.18 ± 0.27 to week 12: 0.69 ± 0.41 mg · min−1 · kg−1, P = 0.36) (Fig. 3C). HFD caused the dogs to become insulin resistant, and this was more evident in the periphery than in the liver.
As previously reported, insulin injections caused a small increase in both INJ and NINJ femoral artery insulin over the course of the experiment (INJ: 0 min, 11.9 ± 1.0; 300 min, 35.9 ± 1.9 mU/l, P < 0.001. NINJ: 0 min, 12.4 ± 1.2; 300 min, 36.6 ± 2.5 mU/l, P < 0.001) (Fig. 4A). Femoral vein insulin was significantly increased after the final injection in INJ compared with NINJ (300 min: NINJ, 35.8 ± 2.0; INJ, 64.0 ± 10.5 mU/l, P = 0.02) (Fig. 4B), demonstrating a washout of insulin injected into the muscle that then entered the systemic circulation to cause the small elevations in arterial insulin. INJ lymph insulin concentrations increased after the second injection compared with NINJ and remained significantly elevated until the end of the experiment (300 min: NINJ, 13.2 ± 2.3; INJ, 73.8 ± 7.1 mU/l, P < 0.01) (Fig. 4C). The concentration of insulin in the interstitial fluid of NINJ remained approximately half of that of the arterial insulin supply. Insulin injection into muscle induced an increase in glucose infusion required to maintain euglycemia in lean animals, as well as a significant increase in local glucose uptake in the injected limb (300 min: NINJ, 9.5 ± 4.5; INJ, 27.3 ± 4.0 mg · min−1 · kg−1, P = 0.03) (Fig. 5A).
In HFD-fed animals, in sharp contrast to lean animals, INJ lymph insulin concentrations showed no elevation in lymph insulin during injection into the muscle compared with the contralateral noninjected limb (300 min: NINJ, 20.9 ± 1.4; INJ, 26.6 ± 4.9 mU/l, P = 0.232) (Fig. 4C). The minor increase in femoral artery insulin over time was observed similar to lean animals and not different between legs (INJ: 0 min, 15.7 ± 1.1; 300 min, 47.6 ± 2.4 mU/l, P < 0.001. NINJ: 0 min, 17.3 ± 1.4; 300 min, 46.8 ± 3.2 mU/l, P < 0.001) (Fig. 4A). INJ femoral vein insulin was significantly increased compared with NINJ (300 min: HFD NINJ, 49.6 ± 5.55; HFD INJ, 133.9 ± 22.9 mU/l, P = 0.03) and lean INJ (300 min: HFD INJ, 133.9 ± 22.9; lean INJ, 64.0 ± 10.5 mU/l, P = 0.01), reflecting a significantly greater washout of insulin from the injected area in HFD-fed compared with lean animals from 210 min to the end of the experiment (Fig. 4B). The interstitial fluid insulin concentration in NINJ was approximately half the arterial insulin concentration; this was not significantly different compared with lean animals and did not change throughout the experiment. The glucose infusion for fat-fed animals was not significantly different from lean animals, however the femoral artery glucose was significantly higher than in the lean animals due to a higher basal glucose measured prior to insulin and somatostatin infusion (lean: 96.0 ± 2.1; HFD: 11.6 ± 4.8 mg/dl, P = 0.01, unpaired t test). There was no significant glucose uptake due to insulin injection (300 min: INJ 5.9 ± 7.14; NINJ 4.68 ± 6.2 mg · min−1 · leg−1, P = 0.328), which was significantly lower than in lean animals (P = 0.02) (Fig. 5). There was no significant difference in blood flow (Fig. 6), mean arterial pressure (lean: 63.82 ± 3.01; HFD: 68.83 ± 3.56 mmHg), or heart rate (lean: 110.09 ± 4.79; HFD: 111.67 ± 5.72 bpm) between groups.
Physiological insulin resistance induced by feeding an HFD for 14 weeks caused a failure of insulin injected into skeletal muscle to be detected in lymph and prevented glucose uptake in response to the injection compared with lean animals. This is reminiscent of previously published results that show experimentally elevated plasma lipids likewise inhibit the ability of injected insulin to diffuse through muscle and initiate glucose uptake (9). Interestingly, the ability of the HFD to impair insulin dispersion in muscle occurs in the absence of a rise in plasma FFAs, either under basal-fasting conditions or during the clamp.
There was no significant difference between the injected and noninjected arterial insulin in the fat-fed animals, as the arterial supply to both legs should be the same and the insulin injection occurs distal to the arterial sampling point. Also, there is no significant difference between the femoral artery and vein insulin concentrations of the noninjected leg, so the increase observed in the femoral vein insulin concentration of the injected leg was due to insulin overflow from the local area of the injection. Among the high-fat–fed animals, there was variation in the ability of lymph to reflect the more concentrated insulin injections. As the ratio of NINJ lymph to arterial insulin was maintained in the face of increasing systemic insulin, the ability of lymph to detect whole-body insulin changes was not altered.
Lymph measures of interstitial insulin have previously been used in this laboratory (9,15–17,19,20) and others (21–24), and agree with other measures of interstitial insulin such as microdialysis (25). Further, gold injected into the interstitium has been shown to concentrate in lymph vessels (26). Due to the low flow rate and apparent lack of size exclusion of lymph vessels, rapid equilibration of lymph with the intracellular fluid can occur similar to that used in microdialysis, and as such is an appropriate tool for measuring interstitial insulin concentrations, reflecting the makeup of the interstitial fluid to which myocytes are exposed. One limitation in our study is that the lymph vessel insulin concentration is a mixture across the entire leg, whereas insulin is injected into a small area of one muscle; thus the interstitial concentration of insulin in the injected area may be higher than in lymph due to dilution of lymph from uninjected muscle. However, previous results have shown a significant increase in lymph insulin in lean dogs (15), thus HFD has impaired the appearance of insulin in lymph.
We show that the ability of insulin to access myocytes is impaired in physiological insulin resistance, and several proposed causes of insulin resistance are unable to describe the results we observe here. For example, mitochondrial dysfunction has been proposed as a critical component of insulin resistance (27), yet in our study, cells are not exposed to elevated insulin, and as such, mitochondrial dysfunction is unlikely to be responsible for the impaired dispersion of insulin. Studies in obese mice have shown that mitochondrial dysfunction is evident in adipose tissue, but not in skeletal muscle (28), and although stimulating FFA oxidation in skeletal muscle reduces insulin resistance (29), it does not necessarily follow that mitochondrial function is the primary cause of skeletal muscle insulin resistance. Similarly, it is unlikely that downstream signaling impairment in myocytes (30,31) or intracellular fat accumulation (6,32) impaired glucose uptake in our study, as there was apparently no measurable elevation of interstitial insulin to cause insulin's cellular effects. However, we cannot discount that myocytes would exhibit insulin resistance if the cells were actually exposed to injected insulin in our model.
The mechanism(s) by which HFD prevents injected insulin from appearing in the interstitial space cannot be clarified from the experiments presented here. As acute hyperlipidemia also resulted in reduced insulin appearance in the interstitial fluid (9), it is unlikely to be a structural change. One possibility is a lipid-induced alteration in permeability of the endothelial cell (33,34), which might allow a more rapid egress of insulin from the interstitial compartment into the bloodstream. However, this permeability theory does not identify the location of the injected insulin prior to appearance in the vein, which may occur as much as 1 h later. It was noted that, although insulin was not detected in lymph, venous insulin had not dropped to preinjection levels even 1 h after injection. As less than 30% of the injected insulin is removed by the vein during the course of the experiment, the remainder must in theory be contained within the muscle, although is not detected in the interstitial space. The excess may be taken up into some cells. Insulin is internalized by endothelial cells en route to the vein (35), and, as endothelial cells exhibit insulin resistance (36), this internalization may be increased in obesity to overcome the impaired insulin signaling, thus removing insulin from the interstitial space. As there is no insulin in the interstitial space, only myocytes immediately adjacent to the area of injection may internalize insulin. Alternatively, in lean animals, injected insulin could increase the perfusion of muscle and augment the blood flow to the area, therefore increasing the dispersion of insulin through the muscle (37). Obese rats (38) and those with pharmacologically elevated lipids (8) have impaired insulin-mediated capillary recruitment; insulin injected into the muscle may be trapped in the small area of injection, without the means to increase its dispersion area. It is also possible that the local high insulin concentration after injection is in the interstitial space, although not in an area sampled by the lymph. In lean animals, injected insulin would cause an increase in the distribution volume to allow more complete dissemination of insulin through the muscle, and therefore detection in the lymph. Adiposity would prevent this increase in distribution volume (39) and reduce the appearance of insulin in the lymph, as less of the muscle is exposed to insulin.
The role of the endothelial cell in the transport of insulin is unclear—evidence exists for both paracellular and transcellular transport of insulin. A recent study has shown that in cell culture, endothelial cells concentrate insulin (38); whether this occurs in vivo has not been determined, and there is no indication of whether this is unidirectional or can move from plasma to interstitium and back. As lean animals show significant insulin appearance in the vein, insulin can move in both directions. Although endothelial cells exhibit insulin resistance (36), effects on insulin transport are not known; however, insulin resistance can impair the appearance of insulin in the interstitium (20,23), and transport is known to be rate limiting to insulin action (19,20,22).
Although we have shown that insulin resistance, either chronic (HFD) or acute (9), prevents dissemination of insulin through the muscle, the mechanism is not yet known. As the HFD does not increase, and in fact suppresses basal plasma FFAs, and isoflurane anesthesia reduces plasma FFAs by 70% (17), plasma FFAs are unlikely to be the primary cause of the impaired dissemination of injected insulin. However, as plasma lipids are elevated nocturnally by an HFD (13), it is possible that whereas plasma FFAs are not a direct cause of insulin resistance in our study, tissue FFA levels may be. Intramyocellular lipid content can be altered by diet (11) and acutely by lipid infusion (40); as many cells are not exposed to injected insulin, it is unlikely that the intracellular lipid would affect our results, although there is the possibility of extracellular fat accumulation. It is unclear whether lipids must be in the interstitial space to inhibit dispersion of intramuscularly injected insulin, or whether another factor may be inhibiting the dispersion of insulin.
The HFD dogs were subjected to a significantly higher glucose level than the lean animals throughout the injection procedure, as their plasma glucose level after anesthesia and prior to insulin and somatostatin infusion was higher. The arterial glucose of animals infused with lipid is not significantly different from either lean or HFD-fed animals, and values appear to be intermediate (9). Endothelial dysfunction may be caused by both acute hyperglycemia (41) and hyperlipidemia (42), which may prevent insulin-induced capillary recruitment. Thus, impaired insulin dispersion observed with lipid infusion (9) and fat feeding may result from different plasma factors that ultimately affect the capillary endothelium. Further studies are necessary to determine whether elevated glucose affects the dispersion of injected insulin.
In conclusion, in an HFD, which induces chronic insulin resistance, insulin injected directly into the muscle is not detectable in the interstitial space (lymph), but appears to wash out in the venous blood flow. This is similar to previous results (9) that demonstrate acute lipid-induced insulin resistance prevented injected insulin from diffusing through the interstitium. The apparent cellular insulin resistance occurs because myocytes are not exposed to insulin; potential downstream effectors such as mitochondrial dysfunction, intramyocellular fat accumulation, and signaling impairment are unlikely to be responsible for the inability of injected insulin to diffuse through the interstitial space in this diet-induced insulin resistance. Although the injection study is not a physiological situation, there are clear differences in how insulin is dealt with in the interstitium, and its access to muscle. Therefore, studies on the insulin sensitivity of individual cells should consider whether insulin was able to access the tissue prior to any perceived defect in insulin signaling or response.
This study was supported by grants from the National Institutes of Health (NIH DK029867 and DK27619). C.M.K. was supported by a Mentor-Based Postdoctoral Fellowship from the American Diabetes Association.
No potential conflicts of interest relevant to this article were reported.
Parts of this study were presented in abstract form at the 69th Scientific Sessions of the American Diabetes Association, New Orleans, Louisiana, 5–9 June 2009, and the 27th annual meeting of the Obesity Society, Washington, D.C., 24–28 October 2009.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


text:
Virginiabigfootresearch.org ranks
#17,630,269 in the world and generates
121 Page views for daily.
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$265 USD for it's visitor traffic that has the potential for CPC and Display-based advertising.
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|Views Per-User
3 Month
Virginia Bigfoot Research
Includes sightings, maps, information, pictures, and links.
Unknown Primates Bigfoot
Google Safe Browsing - Safe website. Clean from Viruses, Malicious Worms, Adwares, Trojans, Spywares and Suspicious Phishing Attacks.
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subset: commoncrawl


text:
It's an android app, will need Null Rom on the Gear
Available on Google Play Store
Beta version with more features:
SWApp Link is intended for use with Smartwatches running Android OS.
Some compatible Smartwatches:
Samsung Gear 1 (with android ROM), Omate TS, AI Watch, Neptune Pine, Inwatch Z, AW-414, AW-420, Callisto 100.
Call Notifications:
• Displays the caller's photo.
• Option to take the call, reject the call, or reply via SMS (composed on the watch and sent through the phone.)
• During call: options to end the call, toggle mute, and toggle the loudspeaker.
SMS Notifications:
• Displays the SMS text and contact photo.
• Option to reply via SMS.
App Notifications:
• Displays notifications, from the apps of your choice, on the watch.
• Fully optimized notifications for specific apps (with more coming), including:
• Email - Notifications now display the email's content instead of just displaying "[number of] New Emails".
• Hangouts - Notifications now display the message content instead of just displaying "[number of] New Notification(s) from [name]".
• WhatsApp - Notifications now display the full message content, even within groups, including the message's text and image.
• Customizable notification layouts: choice of colors for the message text and the message background, option to automatically resize the message text based on its length, and more.
Full notification management:
• Browse through all the previous notifications (SMS and app), with the option to display the most recent ones first or the oldest ones first, search through them by text, and more.
Powerful clock engine which can be set as the watch's lockscreen. Many exclusive features, including:
• Both Analog and Digital watch faces.
• Smooth seconds hand with dynamic shadow.
• Unread notification indicator.
• Battery, 3G, and Wi-Fi indicators for both the watch AND the phone (with options to display the indicators side by side, or toggle between them by tapping on them.)
• On Screen Display (OSD) Modules including a stopwatch, timer, day timer, second time, date, next alarm info and more (the OSD is shown/hidden by tapping on the clock.)
• Option to choose the Font Color with the color picker.
• Choice of backgrounds.
• Choice of date formats (Mon. 20 June / 20-06 / 06-20 ...).
• Choice of hour formats (12H / 24H).
• Complex animations.
Call Log Sync: Displays the phone's call log with the option to place a call or send an SMS to anyone on it.
Remote Call: Remotely place a call to one of your contacts, favorites or recently used numbers, or dial a number to call remotely.
Remote SMS: Remotely send an SMS to one of your contacts, favorites or recently used numbers, or input a number to SMS remotely.
Remote App Launch: Remotely launch apps on the phone.
Remote Clipboard: Send content from the phone to the watch's clipboard.
Remote Media Control: Remotely control the phone's media player from the watch and see track info.
Find My Phone: Remotely set off the phone's or watch's ringer.
Remote Battery info: Displays the remote device's battery level (with a low battery notification option.)
Remote Lock: Remotely lock the phone from the watch (in case of loss, for example.)
BT Virtual Leash: Automatically lock the phone and display a notification on the watch if the BT connection is lost.
Remote GPS Location: Display the phone's GPS coordinates on the watch.
Megaphone: Establishes a phone call between both devices and puts the remote on speaker (establishes a communication with people near the remote device, sim watches only.)
Microphone: Establishes a phone call between both devices (enables you to hear what's happening around the remote device, sim watches only.)
Connection methods:
Direct Bluetooth Connection
SMS - Sends and intercepts SMSs to communicate between the devices.
XDA:DevDB Information
SWApp Link Companion App, App for the Samsung Galaxy Gear
Version Information
Status: Beta
Current Beta Version: 0.934
Beta Release Date: 2014-04-23
Created 2014-04-23
Last Updated 2016-01-14


text:
GraphicRiver Amaing Vector Posterization Kit 6126656
GraphicRiver Amaing Vector Posterization Kit 6126656
Add-on \ Photoshop \ Actions \ Photo Effects
Image \ Action \ Poster \ Vector \ Effects \ Graphicriver \ Premium \ Hope
Add-on - Amaing Vector Posterization Kit 6126656 by mrcharlesbrown @ GraphicRiver
Add-on \ Photoshop \ Actions \ Photo Effects
Add-on Files Included: Photoshop PAT, Photoshop ATN ; Minimum Adobe CS Version: CS4 ; Works With: TIFF, PSD, CMYK, JPG .
- Package name: Amaing Vector Posterization Kit
- Software version: Photoshop CS5
- Copyright: Nov. 12, 2013
- Author: Charles Brown
- Items: – ATN and PAT files
- Complexity: Well-labeled 'ACTION' operation and easy to modify to suit your need. This action will duplicate the main document before rendering the image effect thereby leaving your main document (design) intact in case you want to modify it and render it again.
- - Action renders effect accordingly and properly grouped and labeled for easy customization.
- - Time saver
- - Incredible result
- - Easy color customization
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Barros heads Bridgestone brigade to take Mugello podium Alex Barros led the Bridgestone brigade in Mugello this afternoon taking an impressive third place to score his debut podium of the season, his first on Bridgestone tyres, and the tenth ...
Barros heads Bridgestone brigade to take Mugello podium
Alex Barros led the Bridgestone brigade in Mugello this afternoon taking an impressive third place to score his debut podium of the season, his first on Bridgestone tyres, and the tenth individual podium result of 2007 for a Bridgestone-shod rider.
The battling Brazilian bumped Ducati Corse's Casey Stoner into fourth spot with just three laps of the race remaining. Stoner retains his lead at the head of the championship but sees his advantage cut to nine points after Valentino Rossi's victory in front of 85,000 passionate Italian fans this afternoon.
Behind Stoner followed a train of Bridgestone-shod riders with Suzuki's John Hopkins finishing fifth, his third top five result of the year so far, Honda Gresini's Toni Elias in sixth, Ducati's Loris Capirossi in seventh, French GP winner Chris Vermeulen in eighth and Italian Honda Gresini rider Marco Melandri in ninth.
The weather has been the most influential factor this weekend with dry practice time restricted to just two cool morning sessions. Nevertheless, Bridgestone was able to identify the most suitable compounds for this afternoon's race and the performance level, while not being able to help its riders challenge for Mugello victory, was still on podium pace.
Akira Nishimura - Bridgestone Corporation - General Manager Motorcycle Sport Department
"An excellent performance by Alex Barros this afternoon was rightly rewarded with his debut podium position on Bridgestone tyres, something that is very pleasing. He becomes the seventh Bridgestone-shod rider to take a podium result this season which shows how versatile our tyres are with each of the five teams we are supplying this season. Congratulations to the entire Pramac d'Antin team for an exceptional result and to Ducati for a podium in their home GP. Although he missed out on the podium, Casey Stoner's fourth place keeps him at the head of the championship at this still early stage of the season while many other riders were able to score valuable championship points this afternoon."
Atsushi Tomura - Bridgestone Motorsport - General Manager, Motorcycle Race Tyre Development
"This weekend has really been conditioned by the unsettled weather conditions that reduced the amount of running we had in full dry conditions, but I think we can be pleased with the consistency of our tyres this afternoon. We perhaps missed a bit of performance compared to the two leading riders in the middle stages of the race, but we demonstrated that our range of medium compounds were capable of challenging for the podium in Mugello, as shown by Alex Barros's third place result. We would like to thank our teams for another positive technical collaboration in such difficult circumstances this weekend."
Alex Barros - Pramac d'Antin - 3rd Position (+5.956s from race winner)
"I am of course really happy to have achieved my first podium of this season and it has come at the perfect time. Mugello is the home race for Ducati and Pramac, so I am pleased to be able to give them a fitting result. I would like to say thanks to the entire Pramac d'Antin team for a very good job and to Bridgestone for providing me with tyres capable of scoring the podium. After the fourth place we got in Turkey, I have had my share of bad luck in recent races, so it is good to get such a competitive result, also at a circuit I like very much. Now, I hope we can continue to show our competitiveness for the rest of the season."
-credit: bridgestone


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Park Address: 4088 Stallings Road, Harrisburg, NC 28075
Shelter Address: 4050 Stallings Road, Harrisburg, NC 28075
Park Hours: Sunrise to Sunset, Monday through Sunday from 8:00am to 8:00pm*
*Winter Season (November - February)
Operational Hours, Sunrise to Sunset
Monday through Sunday from 9:00am to 5:00pm
Tennis Court Hours: Monday through Sunday: 8am-10pm
Stallings Road Park is 12.72 acres and is located next to Harrisburg Elementary School. The Harrisburg Parks & Recreation Office is also located at Stallings Road Park and is next to the tennis courts.
Park amenities include:
- 12.72 Acres
- One picnic shelter (available for rental):
- Can accommodate 72 people
- 12 picnic tables
- Two charcoal grills
- Electricity and lighting available
- Two baseball/softball fields
- Three tennis courts
- Playground
- Restrooms
- A walking trail with rock dust surface
- A Yoshino Cherry Tree Grove that includes over 51 Yoshino Cherry tree


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Shaun White apologises for arrest after Patrick Carney's wedding
The sportsman has been accused of allegedly trashing his suite at a Nashville hotel and setting off several fire alarms in the building following a confrontation with management staff.
He tried to make a hasty exit, but slipped and fell, sustaining a cut to his head, and was subsequently arrested by police on suspicion of public intoxication and vandalism.
White has now opened up about the incident in a post on his Facebook.com page, admitting he behaved badly after drinking too much while celebrating the wedding of his musician pal Patrick Carney on Saturday night (15Sep12).
Expressing regret over his actions, he writes, "I want to apologize for the unwise choices I made over the weekend and for any inconvenience it caused my family, friends, business partners, the hotel and their guests. I was celebrating a happy occasion with a ton of family and friends and got carried away. I'm truly sorry for my poor behavior."
Black Keys star Carney wed Emily Ward on Saturday in the backyard of their Nashville home. Further details about the drummer's nuptials were not available as WENN went to press.


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Vancouver, Canada (PressExposure) November 04, 2009 -- Battling the Blessings is author Terry Fulgham's life story which spans over fifty years, reflecting on his childhood, the teen years, and into his adulthood. Fulgham changed the names of the characters, including his own, to protect the innocent.
We meet Reggie Manchester-Pallor as a nine-year-old in 1956. Reggie lived in Flint, Michigan with his grandparents, who he lovingly referred to as "Big Mama" and "Papa Manchester." The Manchester house was a caring, respectful, and disciplined Christian home. Growing up then was different than it is today; children only spoke to adults when they were spoken to. If a kid stepped out of line, they were spanked. Reggie saw his share of spankings, or whippings, as he called them. Reggie was very close to his grandparents and, as his father was not around; Papa Manchester was his only male influence.
The passing of Papa Manchester left a profound emptiness in 10-year-old Reggie's life, leaving him with a feeling of helplessness. A few months after the loss of his grandfather, Reggie met Jesse "Pancake" Stoner. Reggie was small for his age and a favorite target of bullies. Pancake was one of the biggest kids in school. With Pancake around, no one bothered Reggie. Pancake and Reggie grew to be as close as brothers, and together were both respected and feared in their neighborhood. At age 13, Reggie, Pancake and their friends began drinking wine, smoking, and later, stealing cars.
Reggie was the only one of his friends to graduate from high school. In the last few years of school, he held numerous jobs where he was known as a hard and dedicated worker. This weekday life differed greatly from his weekends, as he continued to love the street life. Drinking alcohol and cough syrup (for a codeine high), popping pills, fighting, stealing, and chasing girls filled his off work hours. Big Mama doubted Reggie would see his 21st birthday if he didn't stop his street life.
The failure of his second marriage and the death of a close friend had Reggie drinking more than ever and deeper into drugs and his life of crime. It took losing a fight to a younger man, being severely beaten, and his mother's desperate pleading for him to straighten out his life to get Reggie to take his sobriety seriously and pray, "Lord, stop me from drinking."
Much more than a story of addiction, Battling the Blessings is a snapshot of American history. Fulgham treats us with his memories of growing up in the 50's and 60's, using the slang and lingo of that time in his realistic dialogue. He adds the music, clothes, hairstyles, and vehicles of the day and tells his riveting story with his own unique style to take us back to that turbulent time.
Battling The Blessings isn't simply a kid-gets-hooked-on-booze-and-drugs-and-turns-his-life-around story. It is an unflinching and inspiring telling of a man's struggle with himself and his demons. Fulgham doesn't make excuses for his actions; he takes full responsibility. Reggie isn't a bad guy-he is a smart, compassionate person who just made many bad choices. I found myself cheering for him, hoping that he would one day leave the street life behind and make himself and his family proud.
This is Fulgham's first book. However, he writes with the skill of a seasoned author. He knows how to spin a story in a way that will affect and captivate his reader. Often, I was laughing at his humour, shaking my head in shock, and misting up at a sad passage all in the same chapter. I highly recommend this entertaining glimpse into a remarkable life.
Lulu 2008 978-1-4357-5705-9


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Mark Feuerstein, from Royal Pains, visits the Golden Globes Celebrity Style Lounge sponsored in part by MicroTouch grooming products.
The event was the perfect way to kick-off the big Academy Award weekend as nominees and talent were treated to an event that benefitted Farm Sanctuary and Hope For Paws.
The following celebrities were in attendance; Adina Porter (Nominated TV show "True Blood"), Ashley Argota ("The Fosters" Nominated TV show), Jason Ritter ("Parenthood"), Jenji Kohan (Nominated for the "Orange is the New Black"), Josh Brener (Nominated for "Silicon Valley"), Mark Feuerstein ("Royal Pains"), Mekhi Phifer ("Divergent"), Neil McDonough ("Suits"), Omar Dorsey (Nominated for "Selma"), Beau Casper, and Ronit Elkabetz and Shlomi Elkabetz (Nominated for Best Actress and Best Director respectively for "Gett: The trial of Viviane Amsalem").


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Tigers seal double deal
Hull City have completed the £3million signing of Seyi Olofinjana and agreed a loan deal for Jozy Altidore.
Last Updated: 06/08/09 3:01pm
Hull City have completed the £3million signing of Seyi Olofinjana from Stoke City and agreed a loan deal for Jozy Altidore.
Olofinjana has opted to sign a four-year contract at the KC Stadium after turning down the chance to join French outfit Monaco.
He only joined the Potters last summer from Wolves, but struggled to command a first-team spot in Tony Pulis' side in the second half of last season.
Pulis admitted on Wednesday that he would be strengthening a Premier League rival by selling Olofinjana to Hull, but he did not want to hinder the Nigerian's career.
Tigers boss Phil Brown has also continued his recruitment drive by bringing in Altidore, subject to the United States international receiving a work permit.
Altidore joins on loan for the season from Villarreal with the option for the striker to secure a permanent deal with the Tigers.


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Free Space Combat Game Downloads
A space combat game is a type of video game were players have to battle their opponents is a space-themed environment.
This collection includes several space-themed combat games that you can play in either single on multiplayer mode.
All these games are free to play.
Free Space Combat Game download selection by Bill White. April 10, 2015


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Vadodara, Feb 11 (PTI) The Competition Commission ofIndia (CCI) has written to the Centre seeking formulation of aNational Competition Policy, a member of the anti-trust bodysaid today.
The CCI wrote to the Government about six months forformulating a National Competition Policy and it is awaiting areply, Ratneshwar Prasad, a member of CCI, said whileaddressing the members of the Federation of Gujarat Industries(FGI) here this evening.
"The commission has stopped banks from collectingcharges from the customers for repayment of full housing loansbefore the tenure," he said.
Prasad criticised companies forming cartel and raisingprices by creating shortage of materials in markets.
"There is a need for competition for getting atcompetitive power tariffs for which more numbers of energycompanies are needed in the sector."
"The Competition Act, 2002 was enacted to prevent anti-competitive practises, promote and sustain competition,protect the interests of the consumers and ensure freedom oftrade," Prasad said, adding CCI was created by the Act.
"This Act brings India at par with the UK, USA and EUin regulating free market," he said, adding the commission isvested with both regulatory and quasi-judicial powers.
Prasad said this legislation has the potential toincrease the GDP of the country by 2-3 per cent by curbingunfair trade practises and breaking cartels, which hindergrowth.


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?Several new teachers hired at Austin schools
Written by Marty Randall
Wednesday, 30 July 2008 00:00
?? ? Teaching jobs have been filled at Scott School District 1, according to information released by Superintendent Berley Goodin this week.
Sheila Carter will serve as a teacher and the director of the district's new preschool program for four-year-olds. Tara Branch will also be a teacher in the program, which has been set up in what were formerly first grade classrooms at Austin Elementary School. Another teacher, Tiffany Cole, will be added to the preschool staff if numbers of children increase to what school officials are expecting.
Susie Bowman will work in elementary special education this year.
Last Updated on Wednesday, 30 July 2008 10:42
Read more...
?Washington County woman is latest fatality in I-65 cross-over accident
Written by Marty Randall
Wednesday, 30 July 2008 00:00
??? For the second time this year, emergency vehicles responded to calls of a fatal accident on Interstate 65 between Scottsburg and Austin that involved a vehicle crossing the grassy median and striking a semi-tractor-trailer.
This time, the mishap occurred just south of the Austin interchange late Monday morning, July 21. A woman motorist, identified as Deborah Gunn, 55, Pekin, was headed south on I-65 on a clear morning around 11:45 a.m. when her silver-colored 1996 Ford Taurus suddenly crossed the median and struck the left rear tandems of a northbound semi-tractor operated by Kenneth J. Yeadon, 55, Mooresville.
Yeadon, who was not injured in the accident, apparently saw the car crossing and slowed and then tried to avoid contact by going nearly off the road. Nothing worked; the car went under the rear trailer and disintegrated as the truck continued north.
Last Updated on Wednesday, 30 July 2008 10:45
Read more...
?Nine suspects arrested at mobile home on Scottsburg's east side
Written by Marty Randall
Wednesday, 30 July 2008 00:00
? A total of nine suspects were placed under arrest by Indiana State Police in connection with a probation check last Thursday afternoon, July 17.
A local probation officer accompanied by ISP troopers went to the home on East McClain Avenue to perform a probation check on the occupant, Michelle R. Brewer, 38.
In the search of Brewer's residence, methamphetamine was discovered under a bed and in a bathroom, the probable cause affidavit prepared by Master Trooper Barry Brown indicated. Under three grams of the illegal substance was seized.
Additionally, M/Trp. Brown stated paraphernalia was found as well as a quantity of pills, all of which officers said were controlled substances. Brewer was placed under arrest and transported to the Scott County Security Center.
Then, things got rather interesting for the officers.
Last Updated on Wednesday, 30 July 2008 10:48
Read more...
?Clark County River Friendly Farmer to be honored
Written by Janna Ross
Wednesday, 30 July 2008 00:00
? ?Their conservation plans include no-tilling farming, water and sediment control basins, filter strips, grassed waterways or other best management practices that allow them to manage their farms as one applicant said "in a way to address all resource concerns...from soil erosion on cropland, to water quality...to wildlife habitat." Their ultimate goal is to preserve and protect Indiana's natural resources for their own family farm and for future generations.
They are the 2008 recipients of the River Friendly Farmer Award- an annual honor presented by the Indiana Association of Soil and Water Conservation District (LASWCD) and its 92 Soil and Water Conservation Districts (SWCDs). The award is a join venture with Indiana Farm Bureau, Inc. and the ISDA Division of Soil Conservation. The 65 statewide recipients will be honored on Farmer's Day during the Indiana State Fair this year. The ceremony will be held on Wednesday, August 13 at 2 p.m. in the 4-H Exhibit Hall auditorium, and the public is invited to attend.
Last Updated on Wednesday, 30 July 2008 11:00
Read more...
?New locker room almost ready
Written by Janna Ross
Wednesday, 30 July 2008 00:00
?? The Silver Creek High School football program just got even better! This year's senior classmen are now eligible to participate in this season's football program.
This is great news for everyone on the team. For anyone interested in joining the high school football program, you can start now by coming to the conditioning and practice sessions being held Monday, Wednesday and Thursday from 4:15 to 6 p.m. Participants should sign in at the newly equipped high school weight room.
Beginning August 4, high school practices will be held daily from 3:15 to 5 p.m.
Last Updated on Wednesday, 30 July 2008 11:07
Read more...
More Articles...
?NCOC hosting Backpack Blast
?Charlestown to receive Office of Community & Rural Affairs grant
?Wage increase for superintendent and principals of West Washington Schools
?Economic development money–where does it go?
Page 1228 of 1243


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Tosc (2275m) from the summit...
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Tosc (2275m) from the summit of Triglav (2864m). Below is Ledine plateau and Planika (2401m) hut. Below the cloud that is right of Tosc is Velo Polje (1700m) field. Same cloud hugs the Vernar (2225m).
Photo: Aleksandar Gospic
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Saturday, 16 April 2016 14:38
Why Toms Shoe Always Flat And Which Material And Supplier Of Toms Shoe Sole
Lets check out what maaterial does TOMS shoe made of first
Actually , Toms shoe sole is made of EVA material , if you still do not know what EVA is , please check the link before http://dosole.com/index.php/articles/about-soles/item/5what-is-eva-out-soles-and-eva-material-features
However , Toms EVA sole is not injected sole, we need to produce the eva sheet with what pattern or thickness you need , then cut it into pieces with designed size. It sounds like making a cookie on weekends.
Published in Brands story


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starting out one sided
View Single Post
Join Date: Nov 2010
Location: The Big Apple
Posts: 10,083
Well, it's not a race or competition. Odd that you call it one-sided -- as if the two of you, individuals that you are, are supposed to move forward at the same pace and have the same experiences as you go along in your lives.
Just remember that the goal should be to connect with other people and develop those relationships naturally, not to keep pace with each other and make sure that you both are equal in "acquiring" lovers. That kind of focus would create a dynamic of objectifying the people you meet, because you would then see them as a thing to have in order to say that you and she are "even" now. Honor the people you meet by seeing them for who they are and cultivating any new relationships on its own terms, not as an addendum to your marriage.
In other words, now it isn't all about you and her anymore. You will have others to consider and no one you meet would want to be a prize that you seek in order to compete with her. Not saying that is your attitude, but it is something to keep in check.
That being said, it is quite common for one partner to find a lover before the other does, and very often the woman in a M-F partnership is the one who finds a lover first. There are a gazillion posts here just like yours.
I say, be
that you are both not involved with others at the same time just yet!!
This is new to you both. One of you having an additional partner, going through NRE and such, changes to the time you spend together, and the emotions that arise, will already have a huge impact on the dynamic between you two, so now you have the opportunity to absorb it and adjust to it slowly. Take your time, allow feelings to come up and handle them, examine your boundaries and agreements, and adjust accordingly. Then when you meet someone, you both will have some experience and know what to expect in dealing with all the changes and the new energy of sharing emotional and physical intimacy with an additional person in your life. No need to rush it!
The world opens up... when you do.
"Oh, oh, can't you see? Love is the drug for me."
~Bryan Ferry
"Love and the self are one . . ."
~Leo Buscaglia
Click here for a Solo Poly view on hierarchical relationships
Click here to find out why the Polyamorous Misanthrope is feeling disgusted.
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Risen Trailer (2010)
The story of Howard Winstone is a compelling one. Howard became Featherweight Champion of the World at the age of 29 in 1968. What makes Howard's story quite remarkable is that as a young man he lost the tips of three fingers in an industrial accident of his home town of Merthyr Tydfil.
Watch the official Risen 2010 trailer in HD below or find more Risen videos on Vidimovie.


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Available Products
Terry Dean has created numerous products especially about internet business. All of the products below are sold by his primary company of MyMarketingCoach, LLC and finance this blog.
Complete Christian Guide to Financial Freedom
This was written and recorded from Terry's financial experiences…from being in debt to learning to pray for wisdom to becoming a successful internet entrepreneur.
God's will for you Is Financial Freedom. So why does it seem so hard for Christians to get ahead? In most churches you only hear part of the story. You hear about giving, but you don't hear about the other elements that are essential to receive God's blessings on your finances. Learn the truths God has hidden in his Word for us:
Internet Business Products
All the products below are from the internet business training products. They were not specifically created for the Christian market, but Terry does strive to focus on Christian principles of integrity and providing value in all of his business strategies. If you're interested in running your own internet business or expanding a brick-and-mortar business onto the web for lead generation, you will find these very valuable to you.
Monthly Mentor Club
Everyone needs a mentor, but one-on-one coaching can be very expensive (and Terry's coaching is usually booked for months in advance). He shares a print newsletter that goes out monthly to his subscribers plus online training…with a LOAD of bonuses about websites, copywriting, sales, lead generation, and more just for giving it a try. If you're even considering starting or expanding an internet business, you need to join this Club.
A-to-Z Internet Marketing Truthprints
If you're interested in running your own infopreneurial business, this online course will get you started in the right way. Find out how to research your market, create products, run ads, write convincing sales copy, and generate traffic. In addition discover how you can get started as a professional speaker earning more in an hour than many people do all month. Hear the reality of the work it takes in this business instead of pipe dreams being pushed from most sites.


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'A culture changes by example and a licentious old man being found guilty will help do that,' says a leader in the Times. Perhaps, but I would be much more impressed if it were a licentious younger man.
We can all moralise away in retrospect about what the BBC and others allowed Rolf Harris CBE or Sir James Savile to get away with. It is easy to attack them when they are old or dead. You still very rarely hear of sex charges against current performers.
I would not dream of suggesting that Russell Brand is a sex criminal, but we know, from his own account, that he has slept with a great many women. He even, with Jonathan Ross, telephoned the elderly actor Andrew Sachs, and they left a message on his answering machine boasting of how Brand had slept with his granddaughter. The BBC broadcast this as comedy. If the wheel of celebrity fortune ever went against Brand, would it be surprising if some of the women who have slept with him decided to accuse him of 'inappropriate' acts?
Would the BBC then find the whole thing less funny? I am not saying that Rolf Harris is innocent — I have faith in juries — but I am saying that sexual accusations against old celebrities are not a challenge to the current culture, but an attack on those whose power has waned.
This is an extract from Charles Moore's Notes in this week's Spectator.
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|Home > Heaven
♀ Heaven
What does Heaven mean?
Heaven ▲ as a girls' name is of Old English origin, and the meaning of Heaven is "sky; abode of God". Place name from heofon. Use may be inspired by a Virginia C. Andrews novel with that title.
ASSOCIATED WITH He-, -en, old english, sky (heaven), novel (literary)
VariationsCREATIVE FORMS
Heaven Grace (H.G.), ..
How popular is Heaven?
Heaven is an uncommon given name for women but a very popular surname for all people (#36716 out of 150436, Top 24%). (2000 U.S. DEMOGRAPHICS)
Heaven was first listed in 1980-1989 and reached its highest position of #245 in the U.S. in 2005, and is at #351 currently. (2015 U.S. SSA RECORDS)
Which version is better?
Haven (#330 IN RECENT RANKINGS) and Heavenly (#967) are the prominent alternative forms of Heaven (#351) appearing in the Top 2000. These forms of Heaven were favored in 2015 (ADOPTION OF 0.1%). Heaven has been the most popular choice, though Haven is now ranked higher.
Similar Names
Suggested similar-sounding names are Aven, Belen▲, Bergen, Calen, Caren, Casen, Daveen, Deneen, Deren, Deven, Eaden, Faren, Galen, Hadee, Halea, Haley▼, Hanan, Hava, Hazel, Heath, Heather▼, Hebe, Hedlea (see Hadley), Hedley, Hedvig, Hedwenn, Hege, Heide, Heidee, Heidey, Heike, Heleen, Heleena, Helen▼, Helena, Helene▼, Helje, Helle, Hellee, Hellen▼, Hellena, Hellene, Henie, Hepsey, Hesper, Hester▼, Hether, Hette, Heulwen, Jaden▼, Jeaneen, Jeneen, Kalen, Karen▼, Kellen, Keren, Laken, Laren, Maren, Meave, Megen, Pegeen, Perren, Raven▼, Rayven, Sharen, Taren and Valen. These names tend to be more frequently used than Heaven.See names in meaning and etymology.


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Growing Yourself As A Leader
Brian Sutton (author), Robina Chatham (author)
Technical Leadership Capabilities
UK Price: £9.99 £7.49 EU Price: €12.99 €9.74 ROW (USD) Price: $14.99 $11.24
Format: Paperback
Dimensions: 129 x 198
Number of pages: 106
Publication date: 19 FEB 2018
Publisher: BCS, The Chartered Institute for IT
The development of technical leadership capabilities is often overlooked as a training requirement in organisations but these are key to business success. In this book, management experts Brian Sutton and Robina Chatham describe six management techniques including unlocking your creative potential, learning by developing others and managing your time. These techniques will help you develop your leadership capabilities and grow as a leader; with real life examples, tips and mini exercises, you'll also boost your soft skills as you progress your personal and professional development.
Prof. Brian Sutton has over 40 years' management and leadership experience. He has developed comprehensive information systems strategies, conducted large-scale re-engineering initiatives and led major organisational change. Dr. Robina Chatham has over 35 years' experience in IT. She specialises in management development and executive coaching and is the author of a number of books including 'The Art of IT Management'.
''The structure of the book is constantly engaging and it's encouraged me to think in entirely new ways about established topics.''
Simon La Fosse, Founder & Chairman of La Fosse Associates
Simon La Fosse, Founder & Chairman of La Fosse Associates


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MOVIE SYNOPSIS [ General Audiences ] Having as main character to Greg Grunberg (see cast), this film directed by Michael J. Sarna was premiered in theaters in 2014. The movie "A Tiger's Tail" comes from USA. You can watch A Tiger's Tail online on TV cable or theaters with original audio in English at different dates. This film premiered in theaters in 2014.
Rating: 5 by 53 users./
Runtime: 100 minutes
Greg Grunberg, Darlene Vogel, Christopher Judge, Will Spencer, Zachary Friedman, Merit Leighton, Daniel DiMaggio, Logan Gould, Joe Camp, Veronika Bonell, Ellis Ann Jackson and Catrina Kopell.
100-minute film (full movie) directed by Michael J. Sarna.
The original audio of A Tiger's Tail has dialogues in Dolby Digital, it was produced in USA.
It premiered in cinemas or television in 2014.
Screenplay written by Michael J. Sarna and Rolfe Kanefsky.
Erick M. Crespo.
Patrick Ewald, Shaked Berenson, Sarah Gyldenvand, Catrina Kopell, John Heinsen, Tammy Maples, Greg Grunberg, Joe Camp, Michael J. Sarna, Salvy Maleki and Klaus von Sayn-Wittgenstein.
This film was produced and / or financed by Wittgenstein Ventures, Film Entertainment Services and Inmotion Entertainment.
Composed by Glen Matisoff and Alan Ett.
Epic Pictures Group, Program Store and Icon Film Distribution.
Without commercial breaks, the full movie A Tiger's Tail has a duration of 100 minutes; the official trailer can be watched in streaming on the Internet. You can watch this full movie free in EnglishDolby Digital in movie TV channels, renting the DVD or with VoD services (Video On Demand player, Hulu) and PPV (Pay Per View, Netflix).
See the page of this full movie, A Tiger's Tail in FULLTV Movies.


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Mars Jobs: How You Could Earn a Living on the Red Planet
It's easy to dismiss talk about Mars and the space race as mere science fiction. After all, we're living in the new century 16 years already, and nowhere does it look like the living room at the Jetson's condo. However, with major players like Boeing and SpaceX setting their sights on Mars (and everywhere in between), it's not just those with the Right Stuff who are going to win a shot at space.
So what jobs are going to be hot with the new space race to Mars?
Before we get to Mars, we're going to be flying a LOT of missions on futuristic spacecraft. But these won't be manned by just astronauts, they're going to be commercial flights with pilots at the helm. Want to get a job on a SpaceX ship or a (to be built) Boeing space explorer? Try working to become the very best pilot out there. Chuck Yeager might have set the bar pretty high for pilots breaking new (sound) barriers, but he won't be the last. Right now, commercial pilots make around $65,000 per year.
Flight Attendant
Think that those space drinks are going to serve themselves? Wrong! Flight attendants will still have a place, even in space. Think of all the tasks that will be created by long-range flight. Everything from assuaging the fears of first time orbiters, to making darn sure everyone's seat belts are fastened when you're coming in to landing on a distant planet, are going to be really REALLY important in the future. You can't put a price on good customer service, but right now, flight attendants are paid around $38,000 per year.
Hotel Worker
Yes, there will be hotels in space. If you're good with having time away from family and friends (like, a long time) then maybe you should think about working in a space hotel. It can't be worse than some remote locations, right? And hotel general managers make around $52,000 per year, and that's right here on terra firma, so that's a good start.
Yep, we'll need ways to grow food on Mars. If we're gone for almost a year, just in transit, we'll need ways to get food from somewhere other than Peapod. And while we're likely not going to grow potatoes like Matt Damon did in The Martian, scientists still need to figure out ways to produce food on Mars, and other places not on Earth. So we need super smart farmers to figure out even more about how plants grow. Farmer/Scientists, if you will. The more we can learn about roots, soil, nutrients, and yes, even genetic engineering of food, the better we'll all be. And farmers don't do too badly, salary-wise: they earn on average around $39,000 per year.
Wow, do we love to dream about colonizing Mars. From Ray Bradbury to the latest budding architects, we love thinking about what houses might look like on far away planets. There are already loads of conceptual contests for building structures on Mars, since the planet's environment is so formidable, and some of them look pretty cool! Architects have always been well-paid, so why not become one and get paid to dream a little, too? Design Architects earn on average $59,000 per year.
While we've started to survey Mars from space, and from the surface, using robots, there will hopefully come a time when people will stand on the surface and mark out hills and valleys. While the scientists, geologists, physicists, and other –ists get to have all the technical fun, surveyors are a historically significant profession that even Thomas Jefferson once counted on his own resume. Who wouldn't want to be a surveyor on Mars? I bet you can even get to name some cool stuff! Here on Earth, professional land surveyors earn on average $68,000 a year.
Yeah, teachers. If we want anyone in future generations to remember about why space is an important place to be dreaming about, not just an answer to a standardized test, we're going to have to inspire a new generation of teachers, too. Learn about resources for teachers who want to spread the word about how cool Mars is, including emphasis on STEM education and professional development for teachers. High school teachers earn on average $47,000 per year.
Look, 2016 has been pretty rough. If we're going to stay sane, we have to find some light to hold on to in 2017. One thing that won't diminish as the New Year gets going is our desire to make something great out of exploring new places and new worlds. This time, we get to set our sights on Mars, and even folks like you and me can dream a little about seeing it one day. That's pretty cool.
Tell Us What You Think
What job do you want on Mars? We want to hear from you! Leave a comment or join the discussion on Twitter.
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5 Comments on "Mars Jobs: How You Could Earn a Living on the Red Planet"
No one alive today will be going to space without a college degree. Also, the pay levels for those jobs, in space, likely to be quite a bit higher.
Yes, be good at whatever you do, and get a degree. Work for NASA, or don't, it won't matter that much, but have useful skills and a degree and see where it takes you.
It sure would be interesting to see how living on Mars would be like. I certainly wouldn't mind visiting at least once. If I'm not mistaken though, some of the salaries listed are too high.
I don't have any work history in those you've listed. I managed an apartment complex and I was a cna/pct. I'd love to be a flight attendant. But would prefer to work in a medical setting or back into property management. Do you think there might be any jobs like those I listed?
Well, I think the first basic jobs over there will far more scientific and technical than that. We can think geologist, mining engineers, chemical engineers, physicians, physicist, chemists, biologists, etc.
I want to be on the Mars Planet to conduct a research that will make living on the Mars Planet relating to earth experiences.
My hypothesis is based on the fact that our life started in the Mars Planet then there were floods that killed everyone like the Noah's Ark that life was removed from the fourth planet to the third planet which is earth.
Mars does have things that we know on Earth and we need to create life with.
Archeological studies will help creat life on the Mars Planet.


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|05 Mar 2012
"Account Unknown"
Firstly apologies as I know this has been raised before. I did a search but the threads I found didn't give any answers that made sense to me.
When I look at the permissions for a text document I find among the list of accounts the following:-
"Account Unknown(S-1 -5-21 -5372119434272335595-134997445-1000)"
When I open the User Accounts in Control panel there is no such account shown, nor is it shown if I look in Local Users and Groups in Computer Management.
Could someone explain, preferably in simple terms, what this entry is, whether it is desirable to get rid of it and if so how?
Thanks for any help.
|My System Specs
|05 Mar 2012
Windows 7 x64
It appears to be a temporary permission, the SID or security identifier number checks out so I do not believe it to be malicious though if that was your concern.
|My System Specs
|05 Mar 2012
Its probably a user account that has been removed or recently deleted.
The long number is a SID (Security Identifier) number. You can remove it via the security tab in the properties (Right click on the file and select properties, click security).
|My System Specs
|05 Mar 2012
Thanks for your responses. Yes, my primary concern was that it might have been created by malware in order to gain access to my system. A secondary worry was that if it was legitimately created by the system then deleting it might make the file inaccessible.
Dave, I haven't created or deleted any user accounts since installing the OS. I did do a re-install of the OS since the original installation, but this was after changing partition sizes and reformatting the partitions so was a clean install.
I think I'll try removing it and see what happens.
|My System Specs
|05 Mar 2012
Is it a file you have copied from another PC? Sometimes they retain the permissions.
Do a Malware scan just to be sure but I wouldnt worry about it too much.
|My System Specs
|05 Mar 2012
Hi Dave,
That's an interesting question. When I upgraded from XP I copied all my user files to an external drive then copied them back onto the new system. Maybe that could be the explanation? If so then presumably this would apply to every file.
Interestingly when I removed the Account Unknown from the list of permissions ALL the permissions were removed and I then had to individually add back the ones I wanted.
|My System Specs
|05 Mar 2012
Hi Gwaihir,
Yes it could explain the permissions from an old user. It shouldn't have removed the other permissions as well but as long as you can gaion access to it then again dont worry too much unless its causing you a problem.
Do a virus scan anyway - Just to be safe .
|My System Specs
|05 Mar 2012
Hi Dave,
No, no access problems after deleting it. I've checked a few other files and they all have it so it looks like you've nailed it.
Far too many files to change so I'll just leave alone as long as it's not malicious. I have Avast free anti-virus and will try a scan.
I'll think I'll mark this thread as solved now. Many thanks for your help.
|My System Specs
|09 Sep 2013
Windows 7 Home Premium 64-bit
There were multiple account unknown on mine, and one cannot be removed, was not originally an admin, but has full control, what do I do?
The attached picture shows you cannot remove the selected account from the permissions:
|My System Specs
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2004 Mazda Mazdaspeed MX-5 Miata - Consumer Review
Average Consumer Rating
Total Reviews
Base Convertible (1.8L 4-cyl. Turbo 6-speed Manual)
Build Quality
Reliability Value
Build Quality
Reliability Value
Beauty and the beast
By slaker on
Vehicle2004 Mazda Mazdaspeed MX-5 Miata 2dr Roadster (1.8 4cyl Turbo 6M)
ReviewThe MS miata is a real work of art.The
style can't be beat at any price. This
car has the ability to put a smile on
your face moving or standing still. The
transmission needed to be broken in, for
the first 1000 miles I was wondering if
this new beefed up trany was ever going
to shift smoothly like my loved
1990,then like magic, the trany went
from stiff and bulky,(actually missing
gears or refusing to go in altogether,
Revlimiter was used many times because
the shift was too slow in engaging.) to
smooth and precise the way miata's have
always been.The handling is razor sharp
this little car hauls a$$. The cockpit
fits like a glove(it's great to be
average). Finally I can get over my 1990.
Best FeaturesLooks, the Red may be better looking but the gray is more masculine. Handling, shifting,over all "oneness" defines this car. Value, I paid under 24 with the leather and fabric top. Speaking of the top, excellent design. ZOOM ZOOM ZOOM.
Worst FeaturesHey mazda give us more rev. 6500rpm is just getting into the beef, another grand would do, you know the engine can handle it. Cup holders are useless when trying to shift. The dead pedal is made for a size 6.The gas mileage is only fair, around 20 mpg. but over all a well thought out SPORTS CAR
Recommend (0) (0)
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Days Inn Sevenoaks Clacket Lane
Select your stay dates to check availability at Days Inn Sevenoaks Clacket Lane
Days Inn Sevenoaks Clacket Lane
About the Hotel
Property Location
With a stay at Days Inn Sevenoaks Clacket Lane in Westerham, you'll be close to Titsey Place and Gardens and Chartwell. This hotel is within close proximity of Squerryes House and Quebec House.
Stay in one of 58 guestrooms featuring flat-screen televisions. Complimentary wireless Internet access keeps you connected, and digital programming is available for your entertainment. Bathrooms have shower/tub combinations and hair dryers. Conveniences include desks and coffee/tea makers, and you can also request cribs/infant beds (complimentary).
Rec, Spa, Premium Amenities
Make use of convenient amenities, which include complimentary wireless Internet access and gift shops/newsstands.
You can enjoy a meal at a restaurant serving the guests of Days Inn Sevenoaks Clacket Lane, or find a snack in a coffee shop/café.
Business, Other Amenities
Free self parking is available onsite.
Hotel Facilities
- Free RV, bus, truck parking
- Breakfast available (surcharge)
- Free self parking
- Smoke-free property
- Total number of rooms - 58
- Number of buildings/towers - 1
- Restaurant
- 24-hour front desk
- Coffee shop or café
- Gift shops or newsstand
- Free WiFi
- Number of floors - 2
Room Facilities
- Coffee/tea maker
- Digital TV service
- Private bathroom
- Connecting/adjoining rooms available
- Free WiFi
- Desk
- Shower/tub combination
- Free cribs/infant beds
- Hair dryer
- Flat-panel TV
Hotel Policy
Know Before You Go
- The property has connecting/adjoining rooms, which are subject to availability and can be requested by contacting the property using the number on the booking confirmation.
The following fees and deposits are charged by the property at time of service, check-in, or check-out.
- Fee for full breakfast: GBP 7.50 per person (approximately)
- Pet fee: GBP 10.00 per pet, per stay
The above list may not be comprehensive. Fees and deposits may not include tax and are subject to change.Show all hotel policy Show less hotel policy


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