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Previous work suggests that normal GLUT4 content is sufficient for increases in muscle glucose uptake (MGU) during exercise because GLUT4 overexpression does not increase exercise-stimulated MGU. Instead of glucose transport, glucose phosphorylation is a primary limitation of exercise-stimulated MGU. It was hypothesized that a partial ablation of GLUT4 would not impair exercise-stimulated MGU when glucose phosphorylation capacity is normal but would do so when glucose phosphorylation capacity was increased. Thus, C57BL/6J mice with hexokinase II (HKII) overexpression (HK(Tg)), a GLUT4 partial knock-out (G4(+/-)), or both (HK(Tg) + G4(+/-)) and wild-type (WT) littermates were implanted with carotid artery and jugular vein catheters for sampling and infusions at 4 months of age. After a 7-day recovery, 5-h fasted mice remained sedentary or ran on a treadmill at 0.6 mph for 30 min (n = 9-12 per group) and received a bolus of 2-deoxy[3H]glucose to provide an index of MGU (Rg). Arterial blood glucose and plasma insulin concentrations were similar in WT, G4(+/-), HKTg, and HKTg + G4(+/-) mice. Sedentary Rg values were the same in all genotypes in all muscles studied, confirming that glucose transport is a significant barrier to basal glucose uptake. Gastrocnemius and soleus Rg were greater in exercising compared with sedentary mice in all genotypes. During exercise, G4(+/-) mice had a marked increase in blood glucose that was corrected by the addition of HK II overexpression. Exercise Rg (micromol/100g/min) was not different between WT and G4(+/-) mice in the gastrocnemius (24 +/- 5 versus 21 +/- 2) or the soleus (54 +/- 6 versus 70 +/- 7). In contrast, the enhanced exercise Rg observed in HKTg mice compared with that in WT mice was absent in HKTg + G4(+/-) mice in both the gastrocnemius (39 +/- 7 versus 22 +/- 6) and the soleus (98 +/- 13 versus 65 +/- 13). Thus, glucose transport is not a significant barrier to exercise-stimulated MGU despite a 50% reduction in GLUT4 content when glucose phosphorylation capacity is normal. However, when glucose phosphorylation capacity is increased by HK II overexpression, GLUT4 availability becomes a marked limitation to exercise-stimulated MGU.

Previous work suggests that normal GLUT4 content is sufficient for increases in muscle glucose uptake (MGU) during hyperinsulinemia, because glucose phosphorylation is the more formidable barrier to insulin-stimulated MGU. It was hypothesized that a partial ablation of GLUT4 would not impair insulin-stimulated MGU when glucose phosphorylation capacity is normal but would do so when glucose phosphorylation capacity is increased. Thus, chow-fed C57BL/6J mice with a GLUT4 partial knockout (GLUT4(+/-)), hexokinase II overexpression (HK(Tg)), or both (HK(Tg) + GLUT4(+/-)) and wild-type littermates were studied. Carotid artery and jugular vein catheters were implanted for sampling and infusions at 4 months of age. After a 5-d recovery, 5-h fasted mice (n = 8-11/group) underwent a 120-min saline infusion or insulin clamp (4 mU/kg.min insulin with glucose maintained at 165 mg/dl) and received a 2-deoxy[(3)H]glucose bolus to provide an index of MGU (R(g)) for the soleus, gastrocnemius, and superficial vastus lateralis. Basal R(g) from all muscles studied from saline-infused mice were not changed by any of the genetic modifications. HK(Tg) mice had augmented insulin-stimulated R(g) in all muscles studied compared with remaining genotypes. Insulin-stimulated R(g) was not impaired in any of the muscles studied from GLUT4(+/-) mice. However, the enhanced insulin-stimulated R(g) created by HK overexpression was ablated in HK(Tg) + GLUT4(+/-) mice. Thus, a 50% reduction of normal GLUT4 content in the presence of normal HK activity does not impair insulin-stimulated MGU. However, when the glucose phosphorylation barrier is lowered by HK overexpression, GLUT4 availability becomes a limitation to insulin-stimulated MGU.

Phospholipids extracted from "ghosts" of human erythrocytes or from other sources carry substantial quantities of glucose or other monosaccharides from the dry state into highly nonpolar solvents. Various characteristics of this weak association phenomenon show suggestive parallels with known properties of the mediated sugar-transfer system in the membrane of the intact red cell.

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Sevoflurane, which is widely used in paediatric anaesthesia, induces neural apoptosis in the developing brain and cognitive impairment in young mammals. Glucose hypometabolism is the key pathophysiological modulator of cognitive dysfunction. However, the effects and mechanism of sevoflurane on cerebral glucose metabolism after its use as an anaesthetic and its complete elimination are still unknown. We therefore investigated the influence of sevoflurane on neuronal glucose transporter isoform 3 (GLUT3) expression, glucose metabolism and apoptosis in vivo and in vitro and on neurocognitive function in young mice 24 h after the third exposure to sevoflurane. Postnatal day 14 (P14) mice and neural cells were exposed to 3% sevoflurane 2 h daily for three days. We found that sevoflurane anaesthesia decreased GLUT3 gene and protein expression in the hippocampus and temporal lobe, consistent with a decrease in glucose metabolism in the hippocampus and temporal lobe observed by [18F] fluorodeoxyglucose positron emission tomography (18F-FDG PET). Moreover, sevoflurane anaesthesia increased the number of TUNEL-positive cells and the levels of Bax, cleaved caspase 3 and cleaved PARP and reduced Bcl-2 levels in the hippocampus and temporal lobe. Young mice exposed to sevoflurane multiple times also showed learning and memory impairment. In addition, sevoflurane inhibited GLUT3 expression in primary hippocampal neurons and PC12 cells. GLUT3 overexpression in cultured neurons ameliorated the sevoflurane-induced decrease in glucose utilization and increase in the apoptosis rate. These data indicate that GLUT3 deficiency may contribute to sevoflurane-induced learning and memory deficits in young mice. [ABSTRACT FROM AUTHOR]

Background: Skeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor β (TGF‐β) superfamily, including activin A, which causes atrophy. TGF‐β superfamily ligands also negatively regulate insulin‐sensitive proteins, but whether this pathway contributes to insulin action remains to be determined. Methods: To elucidate if TGF‐β superfamily ligands regulate insulin action, we used an adeno‐associated virus gene editing approach to overexpress an activin A inhibitor, follistatin (Fst288), in mouse muscle of lean and diet‐induced obese mice. We determined basal and insulin‐stimulated 2‐deoxy‐glucose uptake using isotopic tracers in vivo. Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans, we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux‐en‐Y gastric bypass (RYGB). Results: Fst288 muscle overexpression markedly increased in vivo insulin‐stimulated (but not basal) glucose uptake (+75%, P < 0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, pyruvate dehydrogenase‐E1α, and p70S6K, while decreasing TBC1D1 signaling (P < 0.05). Fst288 increased both basal and insulin‐stimulated protein synthesis, but no correlation was observed between the Fst288‐driven hypertrophy and the increase in insulin‐stimulated glucose uptake. Importantly, Fst288 completely normalized muscle glucose uptake in insulin‐resistant diet‐induced obese mice. RYGB surgery doubled circulating Fst and reduced activin A (−24%, P < 0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations. Conclusions: We here present evidence that Fst is a potent regulator of insulin action in muscle, and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4, pyruvate dehydrogenase‐E1α, and PAK1 as Fst targets. Circulating Fst more than doubled post‐RYGB surgery, a treatment that markedly improved insulin sensitivity, suggesting a role for Fst in regulating glycaemic control. These findings demonstrate the therapeutic potential of inhibiting TGF‐β superfamily ligands to improve insulin action and Fst's relevance to muscle wasting‐associated insulin‐resistant conditions in mice and humans. [ABSTRACT FROM AUTHOR]

Muscle is a heterogeneous tissue composed of multiple fiber types. Earlier research revealed fiber type-selective postexercise effects on insulin-stimulated glucose uptake (ISGU) from insulin-resistant rats (increased for type IIA, IIB, IIBX, and IIX, but not type I). In whole muscle from insulin-resistant rats, the exercise increase in ISGU is accompanied by an exercise increase in insulin-stimulated AS160 phosphorylation (pAS160), an ISGU-regulating protein. We hypothesized that, in insulin-resistant muscle, the fiber type-selective exercise effects on ISGU would correspond to the fiber type-selective exercise effects on pAS160. Rats were fed a 2-wk high-fat diet (HFD) and remained sedentary (SED) or exercised before epitrochlearis muscles were dissected either immediately postexercise (IPEX) or at 3 h postexercise (3hPEX) using an exercise protocol that previously revealed fiber type-selective effects on ISGU. 3hPEX muscles and SED controls were incubated ± 100μU/mL insulin. Individual myofibers were isolated and pooled on the basis of myosin heavy chain (MHC) expression, and key phosphoproteins were measured. Myofiber glycogen and MHC expression were evaluated in muscles from other SED, IPEX, and 3hPEX rats. Insulin-stimulated pAktSer473 and pAktThr308 were unaltered by exercise in all fiber types. Insulin-stimulated pAS160 was greater for 3hPEX vs. SED on at least one phosphosite (Ser588, Thr642, and/or Ser704) in type IIA, IIBX, and IIB fibers, but not in type I or IIX fibers. Both IPEX and 3hPEX glycogen were decreased versus SED in all fiber types. These results provided evidence that fiber type-specific pAS160 in insulin-resistant muscle may play a role in the previously reported fiber type-specific elevation in ISGU in some, but not all, fiber types. [ABSTRACT FROM AUTHOR]

Earlier research using muscle tissue demonstrated that postexercise elevation in insulin-stimulated glucose uptake (ISGU) occurs concomitant with greater insulin-stimulated Akt substrate of 160 kDa (AS160) phosphorylation (pAS160) on sites that regulate ISGU. Because skeletal muscle is a heterogeneous tissue, we previously isolated myofibers from rat epitrochlearis to assess fiber type-selective ISGU. Exercise induced greater ISGU in type I, IIA, IIB, and IIBX but not IIX fibers. This study tested if exercise effects on pAS160 correspond with previously published fiber type-selective exercise effects on ISGU. Rats were studied immediately postexercise (IPEX) or 3.5 h postexercise (3.5hPEX) with time-matched sedentary controls. Myofibers dissected from the IPEX experiment were analyzed for fiber type (myosin heavy chain isoform expression) and key phosphoproteins. Isolated muscles from the 3.5hPEX experiment were incubated with or without insulin. Myofibers (3.5hPEX) were analyzed for fiber type, key phosphoproteins, and GLUT4 protein abundance. We hypothesized that insulin-stimulated pAS160 at 3.5hPEX would exceed sedentary controls only in fiber types characterized by greater ISGU postexercise. Values for phosphorylation of AMP-activated kinase substrates (acetyl CoA carboxylaseSer79 and AS160Ser704) from IPEX muscles exceeded sedentary values in each fiber type, suggesting exercise recruitment of all fiber types. Values for pAS160Thr642 and pAS160Ser704 from insulin-stimulated muscles 3.5hPEX exceeded sedentary values for type I, IIA, IIB, and IIBX but not IIX fibers. GLUT4 abundance was unaltered 3.5hPEX in any fiber type. These results advanced understanding of exercise-induced insulin sensitization by providing compelling support for the hypothesis that enhanced insulin-stimulated phosphorylation of AS160 is linked to elevated ISGU postexercise at a fiber type-specific level independent of altered GLUT4 expression. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction and Type 2 diabetes are associated with perturbed circadian rhythms. However, exercise appears to ameliorate circadian disturbances, as it can phase-shift or reset the internal clock system. Evidence is emerging that exercise at a distinct time of day can correct misalignments of the circadian clock and influence energy metabolism. This suggests that timing of exercise training can be important for the prevention and management of metabolic dysfunction. In this study, obese, high-fat diet-fed mice were subjected to voluntary wheel running (VWR) at two different periods of the day to determine the effects of time-of-day-restricted VWR on basal and insulin-stimulated glucose disposal. VWR in the late dark phase reduced body weight gain compared with VWR in the beginning of the dark phase. Conversely, time-of-day-restricted VWR did not influence insulin action and glucose disposal, since skeletal muscle and adipose tissue glucose uptake and insulin signaling remained unaffected. Protein abundance of the core clock proteins, brain-muscle arnt-like 1 (BMAL1), and circadian locomotor output control kaput (CLOCK), were increased in skeletal muscle after VWR, independent of whether mice had access to running wheels in the early or late dark phase. Collectively, we provide evidence that VWR in the late dark phase ameliorates diet-induced obesity without altering insulin action or glucose homeostasis. [ABSTRACT FROM AUTHOR]

Adipose tissue (AT) expands under obesogenic conditions. Yet, when the growth exceeds a certain limit, AT becomes dysfunctional and surplus lipids start depositing ectopically. Polymerase I and transcription release factor (PTRF) has been proposed as a mechanism leading to a dysfunctional AT by decreasing the adipogenic potential of human adipocyte precursors. However, whether or not PTRF can be secreted by the adipocytes into the bloodstream is not yet known. For this work, PTRF presence was investigated in plasma. We also produced a recombinant PTRF (rPTRF) and examined its impact on the functional interactions between the adipocyte and the hepatocyte in vitro. We demonstrated that PTRF can be found in human plasma, and is at least in part, carried by exosomes. In vitro treatment with rPTRF increased the hypertrophy and senescence of 3T3-L1 adipocytes. In turn, those rPTRF-treated adipocytes increased lipid accumulation in hepatocytes. Lastly, we found a positive correlation between circulating PTRF and the concentration of PTRF in the visceral fat depot. All these findings point toward the presence of an enlarged and dysfunctional visceral adipose tissue which secretes PTRF. This circulating PTRF behaves as an adipokine and may partially contribute to the well-known detrimental effects of visceral fat accumulation. [ABSTRACT FROM AUTHOR]

Key points: The actin cytoskeleton regulating GTPase, Rac1, is a novel player in insulin-stimulated glucose uptake in muscle in vivo. High‐fat diet (HFD) exacerbates muscle insulin resistance in Rac1 muscle knockout (mKO) mice. Muscle Rac1 KO protects against HFD‐induced insulin resistance in fat tissue indicating tissue cross‐talk. A fatty diet markedly reduces insulin clearance in mice. Abstract: Insulin resistance and perturbations in glucose metabolism underpin common lifestyle diseases such as type 2 diabetes and obesity. Insulin resistance in muscle is characterized by compromised activity of the GTPase, Ras‐related C3 Botulinum toxin substrate 1 (Rac1), yet the role of Rac1 in insulin‐stimulated glucose uptake in vivo and diet‐induced insulin resistance is unknown. Inducible muscle‐specific Rac1 knockout (Rac1 mKO) and wild type (WT) littermate mice were either fed a chow or a 60% high‐fat diet (HFD). Insulin‐stimulated 2‐deoxy‐glucose uptake, intracellular signalling, protein expression, substrate utilization, and glucose and insulin tolerance were assessed. In chow‐fed mice, in vivo insulin‐stimulated glucose uptake was reduced in triceps, soleus and gastrocnemius muscles from Rac1 mKO mice. HFD‐induced whole body insulin resistance was exacerbated by the lack of muscle Rac1 and glucose uptake was reduced in all muscles, except for soleus. Muscle Akt (also known as protein kinase B) signalling was unaffected by diet or genotype. In adipose tissue, Rac1 mKO mice were protected from HFD‐induced insulin resistance (with respect to both glucose uptake and phosphorylated‐Akt), rendering their whole body glucose tolerance comparable to WT mice on HFD. Our findings show that lack of Rac1 exacerbates HFD‐induced insulin resistance in skeletal muscle. Whole body glucose tolerance, however, was largely unaffected in Rac1 mKO mice, likely due to improved insulin‐stimulated glucose uptake in adipose tissue. We conclude that lack of Rac1 in the context of obesity is detrimental to insulin‐stimulated muscle glucose uptake in muscle independently of Akt signalling. [ABSTRACT FROM AUTHOR]

Exercise bypasses insulin resistance to increase glucose uptake in skeletal muscle and therefore represents an important alternative to stimulate glucose uptake in insulin-resistant muscle. Both Rac1 and AMPK have been shown to partly regulate contraction-stimulated muscle glucose uptake, but whether those two signaling pathways jointly account for the entire signal to glucose transport is unknown. We therefore studied the ability of contraction and exercise to stimulate glucose transport in isolated muscles with AMPK loss of function combined with either pharmacological inhibition or genetic deletion of Rac1.Muscle-specific knockout (mKO) of Rac1, a kinase-dead α2 AMPK (α2KD), and double knockout (KO) of β1 and β2 AMPK subunits (β1β2 KO) each partially decreased contraction-stimulated glucose transport in mouse soleus and extensor digitorum longus (EDL) muscle. Interestingly, when pharmacological Rac1 inhibition was combined with either AMPK β1β2 KO or α2KD, contraction-stimulated glucose transport was almost completely inhibited. Importantly, α2KD+Rac1 mKO double-transgenic mice also displayed severely impaired contraction-stimulated glucose transport, whereas exercise-stimulated glucose uptake in vivo was only partially reduced by Rac1 mKO with no additive effect of α2KD. It is concluded that Rac1 and AMPK together account for almost the entire ex vivo contraction response in muscle glucose transport, whereas only Rac1, but not α2 AMPK, regulates muscle glucose uptake during submaximal exercise in vivo. [ABSTRACT FROM AUTHOR]

Culture-based approaches are used to monitor, e.g., drinking water or bathing water quality and to investigate species diversity and antibiotic resistance levels in environmental samples. For health risk assessment, it is important to know whether the growing cultures display the actual abundance of, e.g., clinically relevant antibiotic resistance phenotypes such as vancomycin-resistant Enterococcus faecium/ Enterococcus faecalis (VRE) or methicillin-resistant Staphylococcus aureus. In addition, it is important to know whether sub-inhibitory antibiotic concentrations, which are present in surface waters, favor the growth of antibiotic-resistant strains. Therefore, clinically relevant bacteria were isolated from different water sources and the growth behavior of 58 Escherichia coli, 71 Enterococcus, and 120 Staphylococcus isolates, belonging to different species and revealing different antibiotic resistance patterns, was studied with respect to 'environmental' antibiotic concentrations. The finding that VRE could only be detected after specific enrichment can be explained by their slow growth compared to non-resistant strains. Interpreting their absence in standardized culture-based methods as nonexistent might be a fallacy. Sub-inhibitory antibiotic concentrations that were detected in sewage and receiving river water did not specifically promote antibiotic-resistant strains. Generally, those antibiotics that influenced cell metabolism directly led to slightly reduced growth rates and less than maximal optical densities after 48 h of incubation. [ABSTRACT FROM AUTHOR]

Key point Exercise increases skeletal muscle energy turnover and one of the important substrates for the working muscle is glucose taken up from the blood., The GTPase Rac1 can be activated by muscle contraction and has been found to be necessary for insulin-stimulated glucose uptake, although its role in exercise-stimulated glucose uptake is unknown., We show that Rac1 regulates the translocation of the glucose transporter GLUT4 to the plasma membrane in skeletal muscle during exercise., We find that Rac1 knockout mice display significantly reduced glucose uptake in skeletal muscle during exercise., Abstract Exercise increases skeletal muscle energy turnover and one of the important substrates for the working muscle is glucose taken up from the blood. Despite extensive efforts, the signalling mechanisms vital for glucose uptake during exercise are not yet fully understood, although the GTPase Rac1 is a candidate molecule. The present study investigated the role of Rac1 in muscle glucose uptake and substrate utilization during treadmill exercise in mice in vivo. Exercise-induced uptake of radiolabelled 2-deoxyglucose at 65% of maximum running capacity was blocked in soleus muscle and decreased by 80% and 60% in gastrocnemius and tibialis anterior muscles, respectively, in muscle-specific inducible Rac1 knockout (mKO) mice compared to wild-type littermates. By developing an assay to quantify endogenous GLUT4 translocation, we observed that GLUT4 content at the sarcolemma in response to exercise was reduced in Rac1 mKO muscle. Our findings implicate Rac1 as a regulatory element critical for controlling glucose uptake during exercise via regulation of GLUT4 translocation. [ABSTRACT FROM AUTHOR]

Chronic muscle loading (overload) induces skeletal muscles to undergo hypertrophy and to increase glucose uptake. Although AMP-activated protein kinase (AMPK) reportedly serves as a negative regulator of hypertrophy and a positive regulator of glucose uptake, its role in overload-induced skeletal muscle hypertrophy and glucose uptake is unclear. This study aimed to determine whether AMPK regulates overload-induced hypertrophy and glucose uptake in skeletal muscles. To this end, skeletal muscle overload was induced through unilateral synergist ablations in wild-type (WT) and transgenic mice, expressing the dominant-negative mutation of AMPK (AMPK-DN). After 14 days, parameters, including muscle fiber cross-sectional area (CSA), glycogen level, and in vivo [ 3 H]-2-deoxy-D-glucose uptake, were assessed. No significant difference was observed in body weight or blood glucose level between the WT and AMPK-DN mice. However, the 14-day muscle overload activated the AMPK pathway in WT mice skeletal muscle, whereas this response was impaired in the AMPK-DN mice. Despite a normal CSA gain in each fiber type, the AMPK-DN mice demonstrated a significant impairment of overload-induced muscle glucose uptake and glycogenesis, compared to WT mice. Moreover, 14-day overload-induced changes in GLUT4 and HKII expression levels were reduced in AMPK-DN mice, compared to WT mice. This study demonstrated that AMPK activation is indispensable for overload-induced muscle glucose uptake and glycogenesis; however, it is dispensable for the induction of hypertrophy in AMPK-DN mice. Furthermore, the AMPK/GLUT4 and HKII axes may regulate overload-induced muscle glucose uptake and glycogenesis., (© 2021 Federation of American Societies for Experimental Biology.)

In most vertebrates, uptake and oxidation of circulating sugars by locomotor muscles rises with increasing exercise intensity. However, uptake rate by muscle plateaus at moderate aerobic exercise intensities and intracellular fuels dominate at oxygen consumption rates of 50 % of maximum or more. Further, uptake and oxidation of circulating fructose by muscle is negligible. In contrast, hummingbirds and nectar bats are capable of fueling expensive hovering flight exclusively, or nearly completely, with dietary sugar. In addition, hummingbirds and nectar bats appear capable of fueling hovering flight completely with fructose. Three crucial steps are believed to be rate limiting to muscle uptake of circulating glucose or fructose in vertebrates: (1) delivery to muscle; (2) transport into muscle through glucose transporter proteins (GLUTs); and (3) phosphorylation of glucose by hexokinase (HK) within the muscle. In this review, we summarize what is known about the functional upregulation of exogenous sugar flux at each of these steps in hummingbirds and nectar bats. High cardiac output, capillary density, and blood sugar levels in hummingbirds and bats enhance sugar delivery to muscles (step 1). Hummingbird and nectar bat flight muscle fibers have relatively small cross-sectional areas and thus relatively high surface areas across which transport can occur (step 2). Maximum HK activities in each species are enough for carbohydrate flux through glycolysis to satisfy 100 % of hovering oxidative demand (step 3). However, qualitative patterns of GLUT expression in the muscle (step 2) raise more questions than they answer regarding sugar transport in hummingbirds and suggest major differences in the regulation of sugar flux compared to nectar bats. Behavioral and physiological similarities among hummingbirds, nectar bats, and other vertebrates suggest enhanced capacities for exogenous fuel use during exercise may be more wide spread than previously appreciated. Further, how the capacity for uptake and phosphorylation of circulating fructose is enhanced remains a tantalizing unknown. [ABSTRACT FROM AUTHOR]

Dynamic positron emission tomography (PET) imaging was performed using sequential tracer injections ([15O]H2O, [11C]3-O-methylglucose [3-OMG], and [18F]fluorodeoxyglucose [FDG]) to quantify, respectively, skeletal muscle tissue perfusion (glucose delivery), kinetics of bidirectional glucose transport, and glucose phosphorylation to interrogate the individual contribution and interaction among these steps in muscle insulin resistance (IR) in type 2 diabetes (T2D). PET imaging was performed in normal weight nondiabetic subjects (NW) (n = 5), obese nondiabetic subjects (OB) (n = 6), and obese subjects with T2D (n = 7) during fasting conditions and separately during a 6-h euglycemic insulin infusion at 40 mU·m-2·min-1. Tissue tracer activities were derived specifically within the soleus muscle with PET images and magnetic resonance imaging. During fasting, NW, OB, and T2D subjects had similar [11C]3-OMG and [18F]FDG uptake despite group differences for tissue perfusion. During insulin-stimulated conditions, IR was clearly evident in T2D (P < 0.01), and [18F]FDG uptake by muscle was inversely correlated with systemic IR (P < 0.001). The increase in insulin-stimulated glucose transport was less (P < 0.01) in T2D (twofold) than in NW (sevenfold) or OB (sixfold) subjects. The fractional phosphorylation of [18F]FDG during insulin infusion was also significantly lower in T2D (P < 0.01). Dynamic triple-tracer PET imaging indicates that skeletal muscle IR in T2D involves a severe impairment of glucose transport and additional impairment in the efficiency of glucose phosphorylation. [ABSTRACT FROM AUTHOR]

Glucose is an important fuel for contracting muscle, and normal glucose metabolism is vital for health. Glucose enters the muscle cell via facilitated diffusion through the GLUT4 glucose transporter which translocates from intracellular storage depots to the plasma membrane and T-tubules upon muscle contraction. Here we discuss the current understanding of how exercise-induced muscle glucose uptake is regulated. We briefly discuss the role of glucose supply and metabolism and concentrate on GLUT4 translocation and the molecular signaling that sets this in motion during muscle contractions. Contraction-induced molecular signaling is complex and involves a variety of signaling molecules including AMPK, Ca2+, and NOS in the proximal part of the signaling cascade as well as GTPases, Rab, and SNARE proteins and cytoskeletal components in the distal part. While acute regulation of muscle glucose uptake relies on GLUT4 translocation, glucose uptake also depends on muscle GLUT4 expression which is increased following exercise. AMPK and CaMKII are key signaling kinases that appear to regulate GLUT4 expression via the HDAC4/5-MEF2 axis and MEF2-GEF interactions resulting in nuclear export of HDAC4/5 in turn leading to histone hyperacetylation on the GLUT4 promoter and increased GLUT4 transcription. Exercise training is the most potent stimulus to increase skeletal muscle GLUT4 expression, an effect that may partly contribute to improved insulin action and glucose disposal and enhanced muscle glycogen storage following exercise training in health and disease. [ABSTRACT FROM AUTHOR]

Strategies to amplify whole-body glucose disposal are key therapies to treat type 2 diabetes. Mice that over-express glucose transporter 4 (Glut4) in skeletal muscle, heart, and adipose tissue (G4Tg) exhibit increased fasting glucose disposal and thus lowered blood glucose. Intriguingly, G4Tg mice also exhibit improved insulin-stimulated suppression of endogenous glucose production even though Glut4 is not present in the liver. It is unclear, however, if hepatic gluco-regulation is altered in G4Tg mice in the basal, non-insulin-stimulated state. The current studies were performed to examine fasting hepatic glucose metabolism in G4Tg mice and to determine whether gluco-regulatory adaptations exist in the non-insulinstimulated condition. To test this question, phloridzin-glucose clamps were used to match blood glucose and pancreatic hormone levels while tracer dilution techniques were used to measure glucose flux. These techniques were performed in chronically-catheterized, conscious, and un-stressed 5h-fasted G4Tg and wild-type (WT) littermates. Results show reduced blood glucose, hepatic glycogen content, and hepatic glucokinase (GK) activity/expression as well as higher endogenous glucose production, glucose disposal, arterial glucagon, and hepatic glucose-6-phosphatase (G6Pase) activity/expression in G4Tg mice versus WT controls. Clamping blood glucose for 90 min at ∼115 mg/dLin G4Tg and WT mice normalized nearly all variables. Notably, however, net hepatic glycogen synthetic rates were disproportionately elevated compared to changes in blood glucose. In conclusion, these studies demonstrate that basal improvements in glucose tolerance due to increased uptake in extra-hepatic sites provoke important gluco-regulatory adaptations in the liver. Although changes in blood glucose underlie the majority of these adaptations, net hepatic glycogen synthesis is sensitized. These data emphasize that anti-diabetic therapies that target skeletal muscle, heart, and/or adipose tissue likely positively impact the liver. [ABSTRACT FROM AUTHOR]

We examined the acquisition of initial mental graphemic representations (MGRs) by 46 kindergarten children (mean age = 5 years, 9 months) at risk for literacy development because of low socioeconomic status. Using a storybook context, we exposed children to novel nonwords that varied in their phonotactic and orthotactic probabilities and then assessed the children's development of initial MGRs through spelling and reading recognition tasks. The children developed some initial MGRs but less than past reports of children from middle socioeconomic status backgrounds. Children with more advanced word recognition abilities developed more initial MGRs than their peers with less advanced word recognition skills. Like previous reports, the words' linguistic properties affected initial MGR acquisition and MGR acquisition ability predicted reading and spelling achievement above other known predictors. The results speak to the importance of increasing the print and orthographic knowledge of children at-risk for adequate literacy development. [ABSTRACT FROM PUBLISHER]

The highly oxygenated hydrocarbon triethylene glycol dimethyl ether or triglyme (CHO-(CHO-)CH) was found to efficiently reduce NO under lean conditions over Ag/AlO, but gave a low NO conversion over Cu-ZSM-5. Furthermore, triglyme showed an extraordinary promoting effect when added together with propene as reducing agent for NO over Ag/AlO at low temperature. This is most likely due to that triglyme promotes the activation of propene. Graphical Abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

ims/hypothesis: Aldosterone concentrations increase in obesity and predict the onset of diabetes. We investigated the effects of aldosterone on glucose homeostasis and insulin secretion in vivo and in vitro. Methods: We assessed insulin sensitivity and insulin secretion in aldosterone synthase-deficient ( As [also known as Cyp11b2]) and wild-type mice using euglycaemic-hyperinsulinaemic and hyperglycaemic clamps, respectively. We also conducted studies during high sodium intake to normalise renin activity and potassium concentration in As mice. We subsequently assessed the effect of aldosterone on insulin secretion in vitro in the presence or absence of mineralocorticoid receptor antagonists in isolated C57BL/6J islets and in the MIN6 beta cell line. Results: Fasting glucose concentrations were reduced in As mice compared with wild-type. During hyperglycaemic clamps, insulin and C-peptide concentrations increased to a greater extent in As than in wild-type mice. This was not attributable to differences in potassium or angiotensin II, as glucose-stimulated insulin secretion was enhanced in As mice even during high sodium intake. There was no difference in insulin sensitivity between As and wild-type mice in euglycaemic-hyperinsulinaemic clamp studies. In islet and MIN6 beta cell studies, aldosterone inhibited glucose- and isobutylmethylxanthine-stimulated insulin secretion, an effect that was not blocked by mineralocorticoid receptor antagonism, but was prevented by the superoxide dismutase mimetic tempol. Conclusions/interpretation: We demonstrated that aldosterone deficiency or excess modulates insulin secretion in vivo and in vitro via reactive oxygen species and in a manner that is independent of mineralocorticoid receptors. These findings provide insight into the mechanism of glucose intolerance in conditions of relative aldosterone excess. [ABSTRACT FROM AUTHOR]

The article discusses a review on the role of membrane fatty acid transporters in cellular lipid metabolism. It states that specific fatty acid transporters transfer from intracellular stores to the plasma membrane to help in fatty acid uptake. Furthermore, the regulatory mechanism made by the fatty acid transporters is important to clear lipids from the circulation and helps in providing substrates when the metabolic demands of organs and tissues are increased by contractile activity.

In skeletal muscle, contractions increase glucose uptake due to a translocation of GLUT4 glucose transporters from intracellular storage sites to the surface membrane. Vesicle-associated membrane proteins (VAMPs) are believed to play an important role in docking and fusion of the GLUT4 transporters at the surface membrane. However, knowledge about which VAMP isoforms colocalize with GLUT4 vesicles in mature skeletal muscle and whether they translocate during muscle contractions is incomplete. The aim of the present study was to further identify VAMP isoforms, which are associated with GLUT4 vesicles and examine which VAMP isoforms translocate to surface membranes in skeletal muscles undergoing contractions. VAMP2, VAMP3, VAMP5, and VAMP7 were enriched in immunoprecipitated GLUT4 vesicles. In response to 20 mm of in situ contractions, there was a redistribution of GLUT4 (+64 ± 13%), transferrin receptor (TfR; +75 ± 22%), and insulin-regulated aminopeptidase (IRAP; +70 ± 13%) to fractions enriched in heavy membranes away from low-density membranes (-32 ± 7%; -18 ± 12%; -33 ± 9%; respectively), when compared with the resting contralateral muscle. Similarly, there was a redistribution of VAMP2 (+240 ± 40%), VAMP5 (+79 ± 9%), and VAMP7 (+79 ± 29%), but not VAMP3, to fractions enriched in heavy membranes away from low-density membranes (-49 ± 10%, -54 ± 9%, -14 ± 11%, respectively) in contracted vs. resting muscle. In summary, VAMP2, VAMP3, VAMP5, and VAMP7 coimmunoprecipitate with intracellular GLUT4 vesicles in muscle, and VAMP2, VAMPS, VAMP7, but not VAMP3, translocate to the cell surface membranes similar to GLUT4, TfR, and IRAP in response to muscle contractions. These findings suggest that VAMP2, VAMP5, and VAMP7 may be involved in translocation of GLUT4 during muscle contractions. [ABSTRACT FROM AUTHOR]

This study evaluated whether improved insulin-stimulated glucose uptake in recovery from acute exercise coincides with reduced malonyl-CoA (MCoA) content in human muscle. Furthermore, we investigated whether a high-fat diet [65 energy-% (Fat)] would alter the content of MCoA and insulin action compared with a high-carbohydrate diet [65 energy-% (CHO)]. After 4 days of isocaloric diet on two occasions (Fat/CHO), 12 male subjects performed I h of one-legged knee extensor exercise (~80% peak workload). Four hours after exercise, insulin-stimulated glucose uptake was determined in both legs during a euglycemic-hyperinsulinemic clamp. Muscle biopsies were obtained in both legs before and after the clamp. Four hours after exercise, insulin-stimulated glucose uptake was improved (--70%, P < 0.001) independent of diet com- position and despite normal insulin-stimulated regulation of insulin receptor substrate- 1-associated phosphatidylinositol 3-kinase, Akt, GSK-3, and glycogen synthase. Interestingly, exercise resulted in a sustained reduction (~20%, P < 0.05) in MCoA content 4 h after exercise that correlated (r = 0.65, P < 0.001) with improved insulin- stimulated glucose uptake. Four days of Fat diet resulted in an increased content of intramyocellular triacylglycerol (P < 0.01) but did not influence muscle MCoA content or whole body insulin- stimulated glucose uptake. However, at the muscular level proximal insulin signaling and insulin-stimulated glucose uptake appeared to be compromised, although to a minor extent, by the Fat diet. Collectively, this study indicates that reduced muscle MCoA content in recovery from exercise may be part of the adaptive response leading to improved insulin action on glucose uptake after exercise in human muscle. [ABSTRACT FROM AUTHOR]

Four grams of glucose circulates in the blood of a person weighing 70 kg. This glucose is critical for normal function in many cell types. In accordance with the importance of these 4 g of glucose, a sophisticated control system is in place to maintain blood glucose constant. Our focus has been on the mechanisms by which the flux of glucose from liver to blood and from blood to skeletal muscle is regulated. The body has a remarkable capacity to satisfy the nutritional need for glucose, while still maintaining blood glucose homeostasis. The essential role of glucagon and insulin and the importance of distributed control of glucose fluxes are highlighted in this review. With regard to the latter, studies are presented that show how regulation of muscle glucose uptake is regulated by glucose delivery to muscle, glucose transport into muscle, and glucose phosphorylation within muscle. Four grams of glucose circulates in the blood of a person weighing 70 kg. This glucose is critical for normal function in many cell types. In accordance with the importance of these 4 g of glucose, a sophisticated control system is in place to maintain blood glucose constant. Our focus has been on the mechanisms by which the flux of glucose from liver to blood and from blood to skeletal muscle is regulated. The body has a remarkable capacity to satisfy the nutritional need for glucose, while still maintaining blood glucose homeostasis. The essential role of glucagon and insulin and the importance of distributed control of glucose fluxes are highlighted in this review. With regard to the latter, studies are presented that show how regulation of muscle glucose uptake is regulated by glucose delivery to muscle, glucose transport into muscle, and glucose phosphorylation within muscle. [ABSTRACT FROM AUTHOR]

Homozygous deletion of the gene of the neuronal glucose transporter GLUT3 (Slc2a3) in mice results in embryonic lethality, whereas heterozygotes (Slc2a3+/-) are viable. Here, we describe the characterization of heterozygous mice with regard to neuronal function, glucose homeostasis, and, since GLUT3 might be a component of the neuronal glucose-sensing mechanism, food intake and energy balance. Levels of GLUT3 mRNA and protein in brain were reduced by 50% in Slc2a3+/- mice. Electrographic features examined by electroencephalographic recordings give evidence for slightly but significantly enhanced cerebrocortical activity in Slc2a3+/- mice. In addition, Slc2a3+/- mice were slightly more sensitive to an acoustic startle stimulus (elevated startle amplitude and reduced prepulse inhibition). However, systemic behavioral testing revealed no other functional abnormalities, e.g., in coordination, reflexes, motor abilities, anxiety, learning, and memory. Furthermore, no differences in body weight, blood glucose, and insulin levels were detected between wild-type and Slc2a3+/- littermates. Food intake as monitored randomly or after intracerebroventricular administration of 2-deoxyglucose or D-glucose, or food choice for carbohydrates/fat was not affected in S1c2a3+/- mice. Taken together, our data indicate that, in contrast to Slc2a1, a single allele of Slc2a3 is sufficient for maintenance of neuronal energy supply, motor abilities, learning and memory, and feeding behavior. [ABSTRACT FROM AUTHOR]

Abstract  It had been suggested that chronic exposure to Schistosoma mansoni prevents the onset of Th1-mediated diseases such as diabetes mellitus. The present study was carried out on four groups of mice: (1) control group, (2) group infected with S. mansoni, (3) group injected with streptozotocin to induce diabetes, and (4) group infected and then 3 months postinfection injected with streptozotocin. No differences were detected between the infected non-diabetic and infected diabetic groups regarding worm burden, tissue egg count, and oogram. At the same time, results showed a reducing effect of S. mansoni infection on the rate of glucose uptake by the diaphragm with reduction in glycogen content of soleus muscle. This an important issue since skeletal muscle is the primary site for insulin-stimulated glucose disposal. In conclusion, because of the detected depressed peripheral glucose uptake by the diaphragm, the protecting effect of helminths infection in diabetes should be reconsidered, to be able to devise therapeutic strategies for the treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To characterize differences in whole-body glucose metabolism between commonly used inbred mouse strains. RESEARCH DESIGN AND METHODS--Hyperinsulinemic-euglycemic (∼8.5 mmol/l) and -hypoglycemic (∼3.0 mmol/l) clamps were done in catheterized, 5-h-fasted mice to assess insulin action and hypoglycemic counter-regulatory responsiveness. Hyperglycemic clamps (∼15 mmol/l) were done to assess insulin secretion and compared with results in perifused islets. RESULTS--Insulin action and hypoglycemic counter-regulatory and insulin secretory phenotypes varied considerably in four inbred mouse strains. In vivo insulin secretion was greatest in 129X1/Sv mice, but the counter-regulatory response to hypoglycemia was blunted. FVB/N mice in vivo showed no increase in glucose-stimulated insulin secretion, relative hepatic insulin resistance, and the highest counter-regulatory response to hypoglycemia. In DBA/2 mice, insulin action was lowest among the strains, and islets isolated had the greatest glucose-stimulated insulin secretion in vitro. In C57BL/6 mice, in vivo physiological responses to hyperinsulinemia at euglycemia and hypoglycemia were intermediate relative to other strains. Insulin secretion by C57BL/6 mice was similar to that in other strains in contrast to the blunted glucose-stimulated insulin secretion from isolated islets. CONCLUSIONS--Strain-dependent differences exist in four inbred mouse strains frequently used for genetic manipulation and study of glucose metabolism. These results are important for selecting inbred mice to study glucose metabolism and for interpreting and designing experiments. Diabetes 57:1790-1799, 2008 [ABSTRACT FROM AUTHOR]

OBJECTIVE--Muscle glucose uptake (MGU) is regulated by glucose delivery to, transport into, and phosphorylation within muscle. The aim of this study was to determine the role of limitations in glucose phosphorylation in the control of MGU during either physiological insulin stimulation (4 mU ⋅ kg-1 ⋅ min-1) or exercise with chow or high-fat feeding. RESEARCH DESIGN AND METHODS--C57BL/6J mice with (HK+/-) and without (WT) a 50% hexokinase (HK) II deletion were fed chow or high-fat diets and studied at 4 months of age during a 120-min insulin clamp or 30 min of treadmill exercise (n = 8-10 mice/group). 2-deoxy[³H]glucose was used to measure Rg, an index of MGU. RESULTS--Body weight and fasting arterial glucose were increased by high-fat feeding and partial HK II knockout (HK+/-). Both high-fat feeding and partial HK II knockout independently created fasting hyperinsulinemia, a response that was increased synergistically with combined high-fat feeding and HK II knockout. Whole-body insulin action was suppressed by ∼25% with either high-fat feeding or partial HK II knockout alone but by >50% when the two were combined. Insulin-stimulated Rg was modestly impaired by high-fat feeding and partial HK II knockout independently (∼15-20%) but markedly reduced by the two together (∼40-500%). Exercise-stimulated Rg was reduced by ∼50% with high-fat feeding and partial HK II knockout alone and was not attenuated further by combining the two. CONCLUSIONS--In summary, impairments in whole-body metabolism and MGU due to high-fat feeding and partial HK II knockout combined during insulin stimulation are additive. In contrast, combining high-fat feeding and partial HK II knockout during exercise causes no greater impairment in MGU than the two manipulations independently. This suggests that MGU is impaired during exercise by high-fat feeding due to, in large part, a limitation in glucose phosphorylation. Together, these studies show that the high-fat-fed mouse is characterized by defects at multiple steps of the MGU system that are precipitated by different physiological conditions. Diabetes 56:2476-2484, 2007 [ABSTRACT FROM AUTHOR]

Regular endurance exercise has profound benefits on overall health, including the prevention of obesity, cardiovascular disease, and diabetes. The objective of this study was to determine whether AMP-activated protein kinase (AMPK) mediates commonly observed adaptive responses to exercise training in skeletal muscle. Six weeks of voluntary wheel running induced a significant (P < 0.05) fiber type IIb to IIa/x shift in triceps muscle of wild-type mice. Despite similar wheel running capacities, this training-induced shift was reduced by ∼40% in transgenic mice expressing a muscle-specific AMPKα2 inactive subunit. Sedentary mice carrying an AMPK-activating mutation (γ1TG) showed a 2.6-fold increase in type IIa/x fibers but no further increase with training. To determine whether AMPK is involved in concomitant metabolic adaptations to training, we measured markers of mitochondria (citrate synthase and succinate dehydrogenase) and glucose uptake capacity (GLUT4 and hexokinase II). Mitochondrial markers increased similarly in wild-type and AMPKα2-inactive mice. Sedentary γ1TG mice showed a ∼25% increase in citrate synthase activity but no further increase with training. GLUT4 protein expression was not different in either line of transgenic mice compared with wild-type mice and tended to increase with training, although this increase was not statistically significant. Training induced a ∼65% increase in hexokinase II protein in wild-type mice but not in AMPKα2-inactive mice. Hexokinase II was significantly elevated in sedentary γ1TG mice, without an additional increase with training. AMPK is not necessary for exercise training-induced increases in mitochondrial markers, but it is essential for fiber type IIb to IIa/x transformation and increases in hexokinase II protein. Diabetes 56:2062-2069, 2007 [ABSTRACT FROM AUTHOR]

The absence of GLUT4 severely impairs basal glucose uptake in vivo, but does not alter glucose homeostasis or circulating insulin. Glucose uptake in isolated contracting skeletal muscle (MGU) is also impaired by the absence of GLUT4, and onset of muscle fatigue is hastened. Whether the body can compensate and preserve glucose homeostasis during exercise, as it does in the basal state, is unknown. One aim was to test the effectiveness of glucoregulatory compensation for the absence of GLUT4 in vivo. The absence of GLUT4 was also used to further define the role of hexokinase (HK) II, which catalyses glucose phosphorylation after it is transported in the cell. HK II increases MGU during exercise, as well as exercise endurance. In the absence of GLUT4, HK II expression will not affect MGU. A second aim was to test whether, in the absence of GLUT4, HK II retains its ability to increase exercise endurance. Wild-type (WT), GLUT4 null (GLUT4−/−), and GLUT4 null overexpressing HK II (GLUT4−/−HKTg) mice were studied using a catheterized mouse model that allows blood sampling and isotope infusions during treadmill exercise. The impaired capacity of working muscle to take up glucose in GLUT4−/− is partially offset by an exaggerated increase in the glucagon: insulin ratio, increased liver glucose production, hyperglycaemia, and a greater capillary density in order to increase the delivery of glucose to the exercising muscle of GLUT4−/−. Hearts of GLUT4−/− also exhibited a compensatory increase in HK II expression and a paradoxical increase in glucose uptake. Exercise tolerance was reduced in GLUT4−/− compared to WT. As expected, MGU in GLUT4−/−HKTg was the same as in GLUT4−/−. However, HK II overexpression retained its ability to increase exercise endurance. In conclusion, unlike the basal state where glucose homeostasis is preserved, hyperglycaemia results during exercise in GLUT4−/− due to a robust stimulation of liver glucose release in the face of severe impairments in MGU. Finally, studies in GLUT4−/−HKTg show that HK II improves exercise tolerance, independent of its effects on MGU. [ABSTRACT FROM AUTHOR]

Fatty acid translocase (FAT)/CD36 is involved in regulating the uptake of long-chain fatty acids into muscle cells. However, the contribution of FAT/CD36 to fatty acid metabolism remains unknown. We examined the role of FAT/CD36 on fatty acid metabolism in perfused muscles (soleus and red and white gastrocnemius) of wild-type (WT) and FAT/CD36 null (KO) mice. In general, in muscles of KO mice, 1) insulin sensitivity and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AlCAR) sensitivity were normal, 2) key enzymes involved in fatty acid oxidation were altered minimally or not at all, and 3) except for an increase in soleus muscle FATP1 and FATP4, these fatty acid transporters were not altered in red and white gastrocnemius muscles, whereas plasma membrane-bound fatty acid binding protein was not altered in any muscle. In KO muscles perfused under basal conditions (i.e., no insulin, no AICAR), rates of hindquarter fatty acid oxidation were reduced by 26%. Similarly, in oxidative but not glycolytic muscles, the basal rates of triacylglycerol esterification were reduced by 40%. When muscles were perfused with insulin, the net increase in fatty acid esterification was threefold greater in the oxidative muscles of WT mice compared with the oxidative muscles in KO mice. With AICAR-stimulation, the net increase in fatty acid oxidation by hindquarter muscles was 3.7-fold greater in WT compared with KO mice. In conclusion, the present studies demonstrate that FAT/CD36 has a critical role in regulating fatty acid esterification and oxidation, particularly during stimulation with insulin or AICAR. [ABSTRACT FROM AUTHOR]

Hexokinase is responsible for glucose phosphorylation, a process fundamental to regulating glucose uptake. In some tissues, hexokinase translocates to the mitochondria, thereby increasing its efficiency and decreasing its susceptibility to product inhibition. It may also decrease free radical formation in the mitochondria and prevent apoptosis. Whether hexokinase translocation occurs in the heart is controversial; here, using immunogold labeling for the first time, we provide evidence for this process. Rat hearts (6 groups, n = 6/group), perfused with either glucose- or glucose + oleate (0.4 mmol/l)-containing buffer, were exposed to 30-mm insulin stimulation, ischemia, or control perfusion. Hexokinase I (HK I) and hexokinase II (HK II) distributions were then determined. In glucose-perfused hearts, HK 1-mitochondrial binding increased from 0.41 ± 0.04 golds/mm in control hearts to 0.71 ± 0.10 golds/mm after insulin and to 1.54 ± 0.38 golds/mm after ischemia (P < 0.05). Similarly, HK II-mitochondrial binding increased from 0.16 ± 0.02 to 0.53 ± 0.08 golds/mm with insulin and 0.44 ± 0.07 golds/mm after ischemia (P < 0.05). Under basal conditions, the fraction of HK I that was mitochondrial bound was five times greater than for HK II; insulin and ischemia caused a fourfold increase in HK II binding but only a doubling in HK I binding. Oleate decreased hexokinase-mitochondrial binding and abolished insulin-mediated translocation of HK I. Our data show that mitochondrial-hexokinase binding increases under insulin or ischemic stimulation and that this translocation is modified by oleate. These events are isoform specific, suggesting that HK I and HK II are independently regulated and implying that they perform different roles in cardiac glucose regulation. [ABSTRACT FROM AUTHOR]

The article argues that glucose phosphorylation is a significant barrier to muscle glucose uptake (MGU) by the working muscle. According to the authors, working muscle becomes freely permeable to glucose and therefore offers no barrier to MGU under these conditions, however, it is still difficult to know whether exercise increases the capacity of the muscle to phosphorylate glucose.

Abstract  While Nazism is almost universally recognized as a great evil, control of science and medicine by the totalitarian Nazi state might be viewed as increasing efficiency. Scientific methods are applied to semiquantitatively analyze the effects of Nazism on medical progress in gastroenterology to document its pernicious effects, and to honor outstanding gastroenterologists persecuted or murdered by the Nazis. This is a retrospective, quasi-case-controlled study. To disprove the null hypothesis that Nazism was efficient, retarded progress in gastroenterology is demonstrated by (1) enumerating the loss to Nazi Germany from 1933 to 1944 due to violent death, incarceration, or forced exile of key researchers in gastroenterology, defined by authorship of at least one book or 10 articles in peer-reviewed journals or other outstanding scholarship; (2) demonstrating a statistically significantly greater loss in Nazi Germany than in non-Nazi (Weimar German Republic from 1921 to 1932) or anti-Nazi (democratic America from 1933 to 1944) control groups; and (3) demonstrating that each loss was directly due to Nazism (murder, incarceration, or exile due to documented threat of violence/death or revocation of medical license). Sources of error in analyzing events from 70 years ago are described. Nazi Germany and Nazi-occupied Europe gained 0 and lost 53 key gastroenterology researchers, including 32 lost due to forced exile, 11 murdered by the Nazis, 5 lost due to suicide under threat of violence, 3 in hiding from the Gestapo, and 2 for other reasons. Fifty-two of the gastroenterologists were persecuted solely because they were Jewish or of Jewish descent and one because he was a Christian anti-Nazi Polish patriot. Particularly severe losses occurred in endoscopy. The loss in Nazi Germany from 1933 to 1944 was significantly greater than that in non-Nazi Germany and Austria from 1921 to 1932 (53 versus 4; odds ratio = 25.27; 95% CI: 9.01–70.48; P < 0.0001) and was significantly greater than that in anti-Nazi America from 1933 to 1944 (53 versus 0; odds ratio > 104.0; 95% CI: 17.62–608.95; P < 0.0001). Lost physicians in Nazi Germany (with reasons for loss) included Ismar Boas, the father of modern gastroenterology (suicide after medical license revoked); Hans Popper, the father of hepatopathology (fled impending arrest); Rudolph Nissen, the father of antireflux surgery (fled after job dismissal); Rudolph Schindler, the father of semiflexible endoscopy (fled after incarceration); Heinrich Lamm, the first to experimentally demonstrate fiberoptic transmission and the first to suggest its applicability for gastroscopy (fled after medical license revoked); Hermann Strauss, a pioneer in rigid sigmoidoscopy (suicide in a concentration camp); A.A.H. van den Bergh, who discovered the van den Bergh reaction to differentiate indirect from direct bilirubin (died in hiding in Nazi-occupied Holland); and Kurt Isselbacher, subsequently the Chief of Gastroenterology at Harvard Medical School (fled in childhood after a grandfather murdered by Nazis). All four refugee physicians who were reexposed to Nazi domination, after a regime change in their country of refuge, fled again or committed suicide. The Nazi damage to German and Austrian gastroenterology was immense, e.g., 13 of 14 major international discoveries in diagnostic gastroscopy were made by Germans or Austrians before the Third Reich, versus only 1 of 8 subsequently (odds ratio = 91; 95% [ABSTRACT FROM AUTHOR]

Insulin-mediated glucose clearance (GC) is diminished in type 2 diabetes. Skeletal muscle has been estimated to account for essentially all of the impairment. Such estimations were based on leg muscle and extrapolated to whole body muscle mass. However, skeletal muscle is not a uniform tissue and insulin resistance may not be evenly distributed. We measured basal and insulin-mediated (1 pmol min−1 kg−1) GC simultaneously in the arm and leg in type 2 diabetes patients (TYPE 2) and controls (CON) (n= 6 for both). During the clamp arterio-venous glucose extraction was higher in CONversusTYPE 2 in the arm (6.9± 1.0versus4.7± 0.8%; mean±s.e.m.;P= 0.029), but not in the leg (4.2± 0.8versus3.1± 0.6%). Blood flow was not different between CON and TYPE 2 but was higher (P<0.05) in armversusleg (CON: 74± 8versus56± 5; TYPE 2: 87± 9versus43± 6 ml min−1 kg−1 muscle, respectively). At basal, CON had 84% higher arm GC (P= 0.012) and 87% higher leg GC (P= 0.016) compared with TYPE 2. During clamp, the difference between CON and TYPE 2 in arm GC was diminished to 54% but maintained at 80% in the leg. In conclusion, this study shows that glucose clearance is higher in arm than leg muscles, regardless of insulin resistance, which may indicate better preserved insulin sensitivity in arm than leg muscle in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Suppose $ \bar{M} $ is a compact connected odd-dimensional manifold with boundary, whose interior M comes with a complete hyperbolic metric of finite volume. We will show that the $ L^2 $ -topological torsion of $ \bar{M} $ and the $ L^2 $ -analytic torsion of the Riemannian manifold M are equal. In particular, the $ L^2 $ -topological torsion of $ \bar{M} $ is proportional to the hyperbolic volume of M, with a constant of proportionality which depends only on the dimension and which is known to be nonzero in odd dimensions [HS]. In dimension 3 this proves the conjecture [Lü2, Conjecture 2.3] or [LLü, Conjecture 7.7] which gives a complete calculation of the $ L^2 $ -topological torsion of compact $ L^2 $ -acyclic 3-manifolds which admit a geometric JSJT-decomposition.¶In an appendix we give a counterexample to an extension of the Cheeger-Müller theorem to manifolds with boundary: if the metric is not a product near the boundary, in general analytic and topological torsion are not equal, even if the Euler characteristic of the boundary vanishes. [ABSTRACT FROM AUTHOR]

Twelve patients in shock, defined as being present if the mean arterial blood pressure was less than 60 mm Hg, pulmonary arterial occlusion pressure was 15 mm Hg or greater, urine output was 20 ml or less for 2 consecutive hours, and there was clinical evidence of poor peripheral perfusion, underwent a comparative therapeutic trial with dopamine at 200 micrograms . min-1 and 400 micrograms . min-1 (2.5-5.5 micrograms . kg-1 . min-1), dobutamine 250 micrograms . min-1 and 500 micrograms . min-1 (3.5-7 micrograms . kg-1 . min-1) and isoproterenol 2 micrograms . min-1 and 4 micrograms . min-1 (0.025-0.055 micrograms . kg-1 . min-1). Isoproterenol at 2 micrograms . min-1, produced a significant increase in pulse rate, cardiac output, left ventricular stroke work index and decrease in mean pulmonary blood pressure and pulmonary arterial occlusion pressure and at 4 micrograms . min-1 a significant increase in stroke volume, mixed venous oxygen tension and decrease in right atrial pressure and systemic vascular resistance was also observed. Dopamine at 200 micrograms . min-1 produced a significant increase in cardiac output, pulmonary arterial occlusion pressure and mixed venous oxygen tension and at 400 micrograms . min-1 a significant increase in pulse rate, mean arterial blood pressure mean pulmonary blood pressure, right ventricular stroke work index, right atrial pressure and pulmonary arterial occlusion pressure and decrease in arterial oxygen tension was also observed.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]