Translocation Of Transporters Research Articles

Regulation of Glucose Transporter Translocation in Health and Diabetes

To enhance glucose uptake into muscle and fat cells, insulin stimulates the translocation of GLUT4 glucose transporters from intracellular membranes to the cell surface. This response requires the intersection of insulin signaling and vesicle trafficking pathways, and it is compromised in the setting of overnutrition to cause insulin resistance. Insulin signals through AS160/Tbc1D4 and Tbc1D1 to modulate Rab GTPases and through the Rho GTPase TC10α to act on other targets. In unstimulated cells, GLUT4 is incorporated into specialized storage vesicles containing IRAP, LRP1, sortilin, and VAMP2, which are sequestered by TUG, Ubc9, and other proteins. Insulin mobilizes these vesicles directly to the plasma membrane, and it modulates the trafficking itinerary so that cargo recycles from endosomes during ongoing insulin exposure. Knowledge of how signaling and trafficking pathways are coordinated will be essential to understanding the pathogenesis of diabetes and the metabolic syndrome and may also inform a wide range of other physiologies.

Wnt Signaling Activation in Adipose Progenitors Promotes Insulin-Independent Muscle Glucose Uptake

Adipose tissues provide circulating nutrients and hormones. We present invivo mouse studies highlighting roles for Wnt signals in both aspects of metabolism. β-catenin activation in PPARγ-expressing fat progenitors (PBCA) decreased fat mass and induced fibrotic replacement of subcutaneous fat specifically. In spite of lipodystrophy, PBCA mice did not develop the expected diabetes and hepatosteatosis, but rather exhibited improved glucose metabolism and normal insulin sensitivity. Glucose uptake was increased in muscle independently of insulin, associated with cell-surface translocation of glucose transporters and AMPK activation. Exvivo assays showed these effects were likely secondary to blood-borne signals since PBCA sera or conditioned media from PBCA fat progenitors enhanced glucose uptake and activated AMPK in muscle cultures. Thus, adipose progenitor Wnt activation dissociates lipodystrophy from dysfunctional metabolism and highlights a fat-muscle endocrine axis, which may represent a potential therapy to lower blood glucose and improve metabolism.

Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats

mTOR inhibitors are currently used as immunosuppressants in transplanted patients and as promising anti-cancer agents. However, new-onset diabetes is a frequent complication occurring in patients treated with mTOR inhibitors such as rapamycin (Sirolimus). Here, we investigated the mechanisms associated with the diabetogenic effects of chronic Sirolimus administration in rats and in in vitro cell cultures. Sirolimus was administered to rats fed either a standard or high-fat diet for 21 days. Metabolic parameters were measured in vivo and in ex vivo tissues. Insulin sensitivity was assessed by glucose tolerance tests and euglycaemic hyperinsulinaemic clamps. Rapamycin effects on glucose metabolism and insulin signalling were further evaluated in cultured myotubes. Sirolimus induced a decrease in food intake and concomitant weight loss. It also induced specific fat mass loss that was independent of changes in food intake. Despite these beneficial effects, Sirolimus-treated rats were glucose intolerant, hyperinsulinaemic and hyperglycaemic, but not hyperlipidaemic. The euglycaemic hyperinsulinaemic clamp measurements showed skeletal muscle is a major site of Sirolimus-induced insulin resistance. At the molecular level, long-term Sirolimus administration attenuated glucose uptake and metabolism in skeletal muscle by preventing full insulin-induced Akt activation and altering the expression and translocation of glucose transporters to the plasma membrane. In rats fed a high-fat diet, these metabolic defects were exacerbated, although Sirolimus-treated animals were protected from diet-induced obesity. Taken together, our data demonstrate that the diabetogenic effect of chronic rapamycin administration is due to an impaired insulin action on glucose metabolism in skeletal muscles.

Exercise in type 2 diabetes: to resist or to endure?

There is now evidence that a single bout of endurance (aerobic) or resistance exercise reduces 24 h post-exercise subcutaneous glucose profiles to the same extent in insulin-resistant humans with or without type 2 diabetes. However, it remains to be determined which group would benefit most from specific exercise protocols, particularly with regard to long-term glycaemic control. Acute aerobic exercise first accelerates translocation of myocellular glucose transporters via AMP-activated protein kinase, calcium release and mitogen-activated protein kinase, but also improves insulin-dependent glucose transport/phosphorylation via distal components of insulin signalling (phosphoinositide-dependent kinase 1, TBC1 domain family, members 1 and 4, Rac1, protein kinase C). Post-exercise effects involve peroxisome-proliferator activated receptor-γ coactivator 1α and lead to ATP synthesis, which may be modulated by variants in genes such as NDUFB6. While mechanisms of acute resistance-type exercise are less clear, chronic resistance training activates the mammalian target of rapamycin/serine kinase 6 pathway, ultimately increasing protein synthesis and muscle mass. Over the long term, adherence to rather than differences in metabolic variables between specific modes of regular exercise might ultimately determine their efficacy. Taken together, studies are now needed to address the variability of individual responses to long-term resistance and endurance training in real life.

Wnt Signaling Regulates Acetylcholine Receptor Translocation and Synaptic Plasticity in the Adult Nervous System

The adult nervous system is plastic, allowing us to learn, remember, and forget. Experience-dependent plasticity occurs at synapses--the specialized points of contact between neurons where signaling occurs. However, the mechanisms that regulate the strength of synaptic signaling are not well understood. Here, we define a Wnt-signaling pathway that modifies synaptic strength in the adult nervous system by regulating the translocation of one class of acetylcholine receptors (AChRs) to synapses. In Caenorhabditis elegans, we show that mutations in CWN-2 (Wnt ligand), LIN-17 (Frizzled), CAM-1 (Ror receptor tyrosine kinase), or the downstream effector DSH-1 (disheveled) result in similar subsynaptic accumulations of ACR-16/α7 AChRs, a consequent reduction in synaptic current, and predictable behavioral defects. Photoconversion experiments revealed defective translocation of ACR-16/α7 to synapses in Wnt-signaling mutants. Using optogenetic nerve stimulation, we demonstrate activity-dependent synaptic plasticity and its dependence on ACR-16/α7 translocation mediated by Wnt signaling via LIN-17/CAM-1 heteromeric receptors.

The effect of hyperglycemia and hypoglycemia on glucose transport and expression of glucose transporters in human lymphocytes B and T: An in vitro study

Glucose transport in lymphocytes is regulated by many agents. It is interesting if only changing glucose concentrations in environment involves the impact on glucose uptake.The aims of this study were to investigate the impact of changing glucose concentrations in medium on deoxy-d-glucose uptake and what these conditions impact on the percent of cells with expression of chosen glucose transporters in human lymphocytes B and T.Isolated lymphocytes B and T obtained from healthy subject were cultivated in different concentrations of glucose. The experiments were carried out using tritium labeled deoxy-d-glucose and flow cytometry.In comparison to normoglycemia, hyperglycemia impairs the uptake of deoxy-d-glucose more than hypoglycemia. Lymphocytes B manifest significantly lower uptake of deoxy-d-glucose than lymphocytes T. Lymphocytes incubated in hyperglycemic and hypoglycemic medium show lower percent cells with expression of GLUT 1 and GLUT 3, and higher percent cells with expression of GLUT 4. The incubation of lymphocytes in hyperglycemic and hypoglycemic medium does not stimulate translocation of glucose transporters 3 and 4 to plasma membrane.Study shows that a change in concentration of glucose in incubation environment influence intracellular expression of glucose transporters in a significant part of lymphocytes B and T.

Obestatin as a regulator of adipocyte metabolism and adipogenesis

The role of obestatin, a 23-amino-acid peptide encoded by the ghrelin gene, on the control of the metabolism of pre-adipocyte and adipocytes as well as on adipogenesis was determined. For in vitro assays, pre-adipocyte and adipocyte 3T3-L1 cells were used to assess the obestatin effect on cell metabolism and adipogenesis based on the regulation of the key enzymatic nodes, Akt and AMPK and their downstream targets. For in vivo assays, white adipose tissue (WAT) was obtained from male rats under continuous subcutaneous infusion of obestatin. Obestatin activated Akt and its downstream targets, GSK3α/β, mTOR and S6K1, in 3T3-L1 adipocyte cells. Simultaneously, obestatin inactivated AMPK in this cell model. In keeping with this, ACC phosphorylation was also decreased. This fact was confirmed in vivo in white adipose tissue (omental, subcutaneous and gonadal) obtained from male rats under continuous sc infusion of obestatin (24 and 72 hrs). The relevance of obestatin as regulator of adipocyte metabolism was supported by AS160 phosphorylation, GLUT4 translocation and augment of glucose uptake in 3T3-L1 adipocyte cells. In contrast, obestatin failed to modify translocation of fatty acid transporters, FATP1, FATP4 and FAT/CD36, to plasma membrane. Obestatin treatment in combination with IBMX and DEX showed to regulate the expression of C/EBPα, C/EBPβ, C/EBPδ and PPARγ promoting adipogenesis. Remarkable, preproghrelin expression, and thus obestatin expression, increased during adipogenesis being sustained throughout terminal differentiation. Neutralization of endogenous obestatin secreted by 3T3-L1 cells by anti-obestatin antibody decreased adipocyte differentiation. Furthermore, knockdown experiments by preproghrelin siRNA supported that obestatin contributes to adipogenesis. In summary, obestatin promotes adipogenesis in an autocrine/paracrine manner, being a regulator of adipocyte metabolism. These data point to a putative role in the pathogenesis of metabolic syndrome.

Glycemic Control in the Intensive Care Unit and during the Postoperative Period

Glycemic Control in the Intensive Care Unit and during the Postoperative Period

Action of Metformin on the Insulin-Signaling Pathway and on Glucose Transport in Human Granulosa Cells

Abstract Context: Hyperinsulinemia in polycystic ovary syndrome is widely treated with the insulin sensitizer metformin, which, in addition to its systemic effects, directly affects the ovarian insulin-stimulated steroidogenesis pathway. Objective: Our aim was to investigate the interaction of metformin with the other insulin-stimulated ovarian pathway, namely that leading to glucose uptake. Design: Human granulosa-luteal cells were cultured with metformin (10−7m), insulin (10 ng/ml) or metformin and insulin (Met + Ins) combined. Insulin receptor (IR) involvement was assessed by culture with an (anti)-insulin receptor (IR) antibody. Main Outcome Measures: The effect of metformin on insulin-receptor substrate proteins 1 and 2 (IRS-1 and -2) mRNA and protein expression was determined. The KGN granulosa-cell line was used to investigate the effect of insulin and metformin on Akt activation and glucose transporter-4 (Glut-4) expression. Glut-4 translocation from the cytosol to the membrane was determined in cytoplasmic and membrane-enriched fractions of protein lysates. Results: IRS-1 mRNA and protein increased with all treatments. In contrast, basal IRS-2 mRNA levels were barely detectable, but transcription was up-regulated by metformin. The anti-IR antibody reduced treatment-stimulated IRS-1 to basal levels and IRS-2 expression to an even greater extent than IRS-1, showing greater dependence on the IR than IRS-1. Metformin in the presence of insulin activated Akt and this was dependent on phosphoinositide-3 kinase, as was translocation of Glut-4 to the membrane. Metformin was able to substantially enhance the insulin-stimulated translocation of Glut-4 transporters from the cytosol to the membrane. Conclusion: This net increase in Glut-4 transporters in the plasma membrane has the potential to increase glucose uptake and metabolism by granulosa cells of the insulin-resistant polycystic ovary, thereby facilitating follicle growth.

Action of Metformin on the Insulin-Signaling Pathway and on Glucose Transport in Human Granulosa Cells

Hyperinsulinemia in polycystic ovary syndrome is widely treated with the insulin sensitizer metformin, which, in addition to its systemic effects, directly affects the ovarian insulin-stimulated steroidogenesis pathway. Our aim was to investigate the interaction of metformin with the other insulin-stimulated ovarian pathway, namely that leading to glucose uptake. Human granulosa-luteal cells were cultured with metformin (10(-7) M), insulin (10 ng/ml) or metformin and insulin (met + ins) combined. Insulin receptor (IR) involvement was assessed by culture with an (anti)-insulin receptor (IR) antibody. The effect of metformin on insulin-receptor substrate proteins 1 and 2 (IRS-1 and -2) mRNA and protein expression was determined. The KGN granulosa-cell line was used to investigate the effect of insulin and metformin on Akt activation and glucose transporter-4 (Glut-4) expression. Glut-4 translocation from the cytosol to the membrane was determined in cytoplasmic and membrane-enriched fractions of protein lysates. IRS-1 mRNA and protein increased with all treatments. In contrast, basal IRS-2 mRNA levels were barely detectable, but transcription was up-regulated by metformin. The anti-IR antibody reduced treatment-stimulated IRS-1 to basal levels and IRS-2 expression to an even greater extent than IRS-1, showing greater dependence on the IR than IRS-1. Metformin in the presence of insulin activated Akt and this was dependent on phosphoinositide-3 kinase, as was translocation of Glut-4 to the membrane. Metformin was able to substantially enhance the insulin-stimulated translocation of Glut-4 transporters from the cytosol to the membrane. This net increase in Glut-4 transporters in the plasma membrane has the potential to increase glucose uptake and metabolism by granulosa cells of the insulin-resistant polycystic ovary, thereby facilitating follicle growth.

Rab11b and its effector Rip11 regulate the acidosis‐induced traffic of V‐ATPase in salivary ducts

Redistribution of acid-base transporters is a crucial regulatory mechanism for many types of cells to cope with extracellular pH changes. In epithelial cells, however, translocation of acid-base transporters ultimately leads to changes in vectorial transport of H+ and HCO3-. We have previously shown that the bicarbonate-secreting epithelium of salivary ducts responds to changes of systemic acid-base balance by adaptive redistribution of H+ and HCO3- transporters, thereby influencing the ionic composition and buffering capacity of saliva. However, the specific proteins involved in regulated vesicular traffic of acid-base transporters are largely unknown. In the present study we have investigated the impact of Rab11 family members on the acidosis-induced trafficking of the vacuolar-type H+-ATPase (V-ATPase) in salivary duct cells in vitro using the human submandibular cell line of ductal origin HSG as an experimental model. The results show that Rab11b is expressed in salivary ducts and exhibits a significantly higher co-localization with V-ATPase than Rab11a and Rab25. We also show that Rab11 but not Rab25 interacts with the ε subunit of V-ATPase. Extracellular acidosis up-regulates Rab11b expression and protein abundance in HSG cells and causes translocation of the V-ATPase from intracellular pools toward the plasma membrane. Loss-of-function experiments using specific siRNA either against Rab11b or against its effector Rip11 prevent acidosis-induced V-ATPase translocation. These data introduce Rab11b as a crucial regulator and Rip11 as mediator of acidosis-induced V-ATPase traffic in duct cells of submandibular gland.

Of mice and men: filling gaps in the TBC1D1 story

Of mice and men: filling gaps in the TBC1D1 story

Selectivity mechanism of the nuclear pore complex characterized by single cargo tracking

The Nuclear Pore Complex (NPC) mediates all exchange between the cytoplasm and the nucleus. Small molecules can passively diffuse through the NPC, while larger cargos require transport receptors to translocate1. How the NPC facilitates the translocation of transport receptor/cargo complexes remains unclear. Here, we track single protein-functionalized Quantum Dot (QD) cargos as they translocate the NPC. Import proceeds by successive sub-steps comprising cargo capture, filtering and translocation, and release into the nucleus. The majority of QDs are rejected at one of these steps and return to the cytoplasm including very large cargos that abort at a size-selective barrier. Cargo movement in the central channel is subdiffusive and cargos that can bind more transport receptors diffuse more freely. Without Ran, cargos still explore the entire NPC, but have a markedly reduced probability of exit into the nucleus, suggesting that NPC entry and exit steps are not equivalent and that the pore is functionally asymmetric to importing cargos. The overall selectivity of the NPC appears to arise from the cumulative action of multiple reversible sub-steps and a final irreversible exit step.

The antidiabetic effect of W9, a medicinal plant from the pharmacopea of the Cree of the Eastern James Bay region in Canada

W9 is a Boreal forest plant identified among species used by the Cree of Eeyou Istchee of northern Quebec to treat symptoms of diabetes. In a previous study, the ethanol extract of W9 enhanced glucose uptake in C2C12 muscle cells via stimulation of AMP-activated protein kinase (AMPK) pathway. In this study, we investigated the effect of this product on the translocation of insulin-sensitive GLUT4 transporters in skeletal muscle cells in culture. Treatment of L6 myotubes with W9 for 18h significantly increased glucose uptake and GLUT4 translocation to the cell membrane. W9 increased phosphorylation of AMPK and P38 MAPK with no indication of increased phosphorylation of Akt. To validate the effect of W9 in vivo, the extract (1% in drinking water) was administered to KKAy diabetic mice for 10 days. Glycemia and fluid intakes were significantly reduced by W9. Moreover, W9-treatment increased skeletal muscle GLUT4 content, stimulated ACC phosphorylation and increased hepatic levels of PPAR-α of KKAy mice. Administration of W9 to normal C57BL/6 had no effect on glycemia. The results of the present study expand the understanding of the molecular mechanisms underlying the antidiabetic potential of W9.

Amino acids influence the glucose uptake through GLUT4 in CHO-K1 cells under high glucose conditions

According to studies earlier, amino acids have proven to be antidiabetic, antiglycating, and anticataractogenic. The present study was to explore whether amino acids as mixtures could enhance glucose uptake in CHO-K1 cells specifically. The cells in F-12K1 serum-free medium were exposed to normal (7 mM) and high glucose (12, 17 and 27 mM) in the presence and absence of amino acids mixture (AAM) in varying concentration (2.5, 5 and 10 mM). The mixture 5 and 10 mM AAM increased the 2-deoxyglucose (2DG) uptake at all glucose concentration significantly. There was also a significant increase in the GLUT4 (glucose transporter) translocation as revealed by flow cytometer. Addition of a mixture of amino acids was found to improve cell viability, which got altered by high glucose in the CHO-K1 cells. Amino acids as mixture had a beneficial effect in improving the net utilization of glucose as an additive effect with insulin.

Abstract 5244: Preclinical, real-time assessment of early pharmacodynamic effects for the IGF-1R/IR inhibitor OSI-906 by [18F]-FDG-PET

Abstract The insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) are transmembrane receptor tyrosine kinases that serve as key regulators of the IGF signaling axis. Activation of IGF-1R and IR results in proliferative and antiapoptotic effects via the ERK and PI3K/AKT pathways. Activated IGF-1R and IR also directly affect glucose metabolism by decreasing gluconeogenesis, increasing glycogen formation and increasing translocation of GLUT transporters, thereby increasing overall glucose uptake in tissues. Dysregulated IGF-1R/IR signaling has been implicated in many human cancers and has been implicated in resistance to anticancer therapies including cytotoxic chemotherapy, hormonal agents and radiation therapy. IGF-1R/IR overexpression has been demonstrated in several tumor types including breast, prostate, lung, ovarian and colon cancers. Moreover, increased activation and overexpression of IGF-1R/IR is associated with an increased propensity for invasion and metastasis correlating with poor survival. Consequently, IGF-1R and IR have been identified as attractive targets for the generation of novel anticancer agents. OSI-906 is a potent and selective dual inhibitor of IGF-1R/IR and is currently in clinical development. The radiotracer [18F]-FDG is used clinically to stage disease or monitor treatment response by virtue of measuring glucose uptake as a surrogate for metabolic activity in tumors. Since IGF-1R and IR signaling directly affect glucose metabolism we evaluated the utility of [18F]-FDG-PET as a potential means to non-invasively monitor pharmacodynamic (PD) effects for OSI-906. In vitro the IGF-1R/IR positive cell line, H292, responded rapidly to OSI-906 treatment by significantly reducing uptake of 3H-glucose. Radiotracer uptake was inhibited in a dose dependent manner and occurred within minutes of drug treatment correlating with inhibition of the IGF-1R/IR pathways and other downstream signaling events. In vivo xenografts bearing the same cell line demonstrated significantly reduced uptake of [18F]-FDG at 2 and 4 hours post treatment which correlated with substantial (>80%) target inhibition of both phospho-IGF1-R and phospho-IR in the tumor lysates. Western blot analysis of in vivo tumor lysates confirmed significant inhibition of phospho-AKT and other markers associated with altered glycolysis. In contrast, in the IGF-1R/IR-negative H441 xenograft model no significant change in uptake of [18F]-FDG was observed over the same time course. Our data indicate that [18F]-FDG-PET may serve as a rapid, non-invasive PD marker for OSI-906 in the clinical setting where accurate assessment of PD effects is often limited by the lack of readily accessible tumor samples. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5244.

Insulinotropic effect of cinnamaldehyde on transcriptional regulation of pyruvate kinase, phosphoenolpyruvate carboxykinase, and GLUT4 translocation in experimental diabetic rats

Diabetes mellitus is a chronic metabolic disorder affecting about 6% of population worldwide with its complications and is rapidly reaching epidemic scale. Cinnamomum zeylanicum is widely used in alternative system of medicine for treatment of diabetes. In the present study, we have performed bioassay guided fractionation of chloroform extract of C. zeylaniucm and identified cinnamaldehyde (CND) as an active principle against diabetes. In continuation to it, a detailed study was undertaken to elucidate its mode of antidiabetic action in STZ induced diabetic rats. Oral administration of CND (20 mg/kg bw) to diabetic rats for 2 months showed significant improvement ( p < 0.001) in muscle and hepatic glycogen content. In vitro incubation of pancreatic islets with CND enhanced the insulin release compared to glibenclamide. The insulinotropic effect of CND was found to increase the glucose uptake through glucose transporter (GLUT4) translocation in peripheral tissues. The treatment also showed a significant improvement in altered enzyme activities of pyruvate kinase (PK) and phosphoenolpyruvate carboxykinase (PEPCK) and their mRNA expression levels. Furthermore, the median lethal dose (LD 50) of CND could not be obtained even at 20 times (0.4 g/kg bw) of its effective dose. With the high margin of safety of CND, it can be developed as a potential therapeutic candidate for the treatment of diabetes.

Regulation of V‐ATPase traffic in submandibular gland through Rab GTPases

Redistribution of acid‐base transporters is a crucial regulatory mechanism for many cells to cope with extracellular pH changes. Moreover, in epithelial cells, translocation of acid‐base transporters ultimately leads to changes in vectorial transport of H+ and HCO3−. However, the specific proteins involved in regulated vesicular traffic of acid‐base transporters in epithelial cells are largely unknown. In the present study we have investigated the impact of members of the Rab family of small GTPases on the acidosis‐induced trafficking of the vacuolar‐type H+‐ATPase (V‐ATPase) in salivary duct cells in vitro using the human submandibular cell line of ductal origin HSG as an experimental model. We demonstrate distinct subpopulations of intracellular V‐ATPase pools in HSG cells. We also show differential co‐localization of V‐ATPase with Rab family members. Extracellular acidosis causes translocation of the V‐ATPase from the Golgi apparatus toward the plasma membrane, a process mediated by PKA and Src kinases. Loss‐of‐function experiments using specific siRNA against distinct Rab family members prevent acidosis‐induced V‐ATPase translocation. The data introduce members of the Rab family as crucial regulators of acidosis‐induced V‐ATPase traffic in duct cells of submandibular gland. Funded by the Deutsche Forschungsgemeinschaft.

SNAT2 and LAT1 transporter abundance is developmentally regulated in skeletal muscle of neonatal pigs

Previously we demonstrated that the insulin‐ and amino acid–induced activation of the mammalian target of rapamycin complex 1 (mTORC1) is developmentally regulated in neonatal pigs. Recent studies have indicated an important role of the System A transporters (SNAT2 and SLC1A5) and the L transporter (LAT1) in intracellular accumulation of essential amino acids, such as leucine, and in mTORC1 activation. This study aimed to determine the effects of age and the post‐prandial rise in insulin and amino acids on the abundance and activation of SNAT2, SLC1A5 and LAT1. Overnight fasted 6‐ and 26‐day‐old pigs were infused for 2 h with saline, insulin, or amino acids to achieve fed levels. The abundance of SNAT2 and LAT1, but not SLC1A5, was significantly higher in muscle of 6‐ than in 26‐d‐old pigs. The activation of SNAT2, determined by transporter translocation to the plasma membrane, was unaffected by 2 hr infusion of amino acids or insulin. To determine the acute effects of feeding, SNAT2 activation was determined 0, 30, and 60 min after a complete meal. Feeding had no effect on SNAT2 activation at any time point suggesting that SNAT2 activation in vivo may be short‐lived. In conclusion, the elevated abundance of SNAT2 and LAT1 is likely to play a significant role in the enhanced amino acid‐induced activation of mTORC1 in neonatal pigs (Supported by NIH grants AR‐44474 and USDA/ARS 6250510000‐33).

Improved Insulin Sensitivity After Exercise: Focus on Insulin Signaling

After a single bout of exercise, the ability of insulin to stimulate glucose uptake is markedly improved locally in the previously active muscles. This makes exercise a potent stimulus counteracting insulin resistance characterizing type 2 diabetes (T2D). It is believed that at least part of the mechanism relates to an improved ability of insulin to stimulate translocation of glucose transporters (GLUT4) to the muscle membrane after exercise. How this is accomplished is still unclear; however, an obvious possibility is that exercise interacts with the insulin signaling pathway to GLUT4 translocation allowing for a more potent insulin response. Parallel to unraveling of the insulin signaling cascade, this has been investigated within the past 25 years. Reviewing existing studies clearly indicates that improved insulin action can occur independent of interactions with proximal insulin signaling. In contrast, more recent observations indicate that interactions exist at the distal signaling level of AS160 and atypical protein kinase C (aPKC). Although the functional interpretation is lacking, these novel observations may present a breakthrough in understanding the beneficial interplay between exercise and insulin action.