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PubMed1988

In vitro studies of insulin resistance in patients with lipoatrophic diabetes. Evidence for heterogeneous postbinding defects.

We studied the binding and action of insulin in cultured fibroblasts from six patients with lipoatrophic diabetes and marked in vivo insulin resistance and from seven control subjects. The binding of insulin was not altered, which corresponds well with studies with circulating erythrocytes. Similarly, the action of the hormone on amino acid uptake (estimated by active transport of aminoisobutyric acid) was comparable in patient and control cells. Conversely, studies concerning the effect of insulin on glucose transport (estimated by facilitated diffusion of 2-deoxyglucose) or glycogen synthesis (estimated by incorporation of glucose into cellular glycogen) revealed the presence of heterogeneous alterations among the different patient cell lines. However, although the nature of the defect(s) varied among the patients, alterations in glucose metabolism were present in all cases. These data suggest the presence of primary postbinding defects in glucose cellular pathways that give rise to insulin resistance in cells from lipoatrophic diabetic patients.

Adolescent↗

PubMed1993

Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells.

Hyperglycemia has been implicated in the pathogenesis of both micro- and macrovascular complications in diabetes. Little is known, however, about glucose transporters and their regulation in the vascular system. In this study, the regulation of glucose transporters by glucose was examined in cultured BAECs and BSMCs, and in human arterial smooth muscle cells. Both BAECs and BSMCs transported glucose via the facilitated diffusion transport system. Glucose-transport activity in vascular smooth muscle cells was inversely and reversibly regulated by glucose. Exposure of BSMCs and HSMCs to high glucose decreased Vmax for 2DG and 3-O-MG uptake, whereas Km remained unchanged. The hexose-transport system of BAECs exhibited lower 2DG and 3-O-MG uptake compared with BSMCs and showed little or no adaptation to changes in ambient glucose. Northern blot analysis demonstrated that GLUT1 mRNA levels in BAECs and BSMCs were unaffected by the concentration of glucose in the medium. GLUT2-5 mRNA could not be detected by Northern blot analysis. GLUT1 protein, quantified by Western blot analysis, was more abundant in BSMCs than in BAECs and was decreased by approximately 50% when medium glucose was elevated from 1.2 to 22 mM for 24 h. The alterations in the level of GLUT1 protein correlated with the changes observed in transport activity. These observations suggest differential regulation of glucose transporter in response to glucose between smooth muscle and endothelial cells. The sites of autoregulation may involve translational control and/or the stability of the protein in the smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)

3-O-Methylglucose↗

PubMed2000

Triggering and amplifying pathways of regulation of insulin secretion by glucose.

Glucose stimulates insulin secretion by generating triggering and amplifying signals in beta-cells. The triggering pathway is well characterized. It involves the following sequence of events: entry of glucose by facilitated diffusion, metabolism of glucose by oxidative glycolysis, rise in the ATP-to-ADP ratio, closure of ATP-sensitive K+ (KATP) channels, membrane depolarization, opening of voltage-operated Ca2+ channels, Ca2+ influx, rise in cytoplasmic free Ca2+ concentration ([Ca2+]i), and activation of the exocytotic machinery. The amplifying pathway can be studied when beta-cell [Ca2+]i is elevated and clamped by a depolarization with either a high concentration of sulfonylurea or a high concentration of K+ in the presence of diazoxide (K(ATP) channels are then respectively blocked or held open). Under these conditions, glucose still increases insulin secretion in a concentration-dependent manner. This increase in secretion is highly sensitive to glucose (produced by as little as 1-6 mmol/l glucose), requires glucose metabolism, is independent of activation of protein kinases A and C, and does not seem to implicate long-chain acyl-CoAs. Changes in adenine nucleotides may be involved. The amplification consists of an increase in efficacy of Ca2+ on exocytosis of insulin granules. There exists a clear hierarchy between both pathways. The triggering pathway predominates over the amplifying pathway, which remains functionally silent as long as [Ca2+]i has not been raised by the first pathway; i.e., as long as glucose has not reached its threshold concentration. The alteration of this hierarchy by long-acting sulfonylureas or genetic inactivation of K(ATP) channels may lead to inappropriate insulin secretion at low glucose. The amplifying pathway serves to optimize the secretory response not only to glucose but also to nonglucose stimuli. It is impaired in beta-cells of animal models of type 2 diabetes, and indirect evidence suggests that it is altered in beta-cells of type 2 diabetic patients. Besides the available drugs that act on K(ATP) channels and increase the triggering signal, novel drugs that correct a deficient amplifying pathway would be useful to restore adequate insulin secretion in type 2 diabetic patients.

Adenosine Triphosphate↗

PubMed1990

Molecular physiology of glucose transporters.

Molecular cloning of cDNA encoding the human erythrocyte facilitated-diffusion glucose transporter (GT) has elucidated its structure and has permitted a careful study of its tissue distribution and of its involvement in processes such as insulin-stimulated glucose uptake by adipose cells or transformation-induced increase in glucose metabolism. An important outcome of these studies was the discovery that additional isoforms of this transporter were expressed in a tissue-specific manner; these comprise a family of structurally and functionally related molecules. Their tissue distribution, differences in kinetic properties, and differential regulation by ambient glucose and insulin levels suggest that they play specific roles in the control of glucose homeostasis. Herein, we will discuss the structure of three members of the GT family: erythroid/brain GT, liver GT, and adipose cell/muscle GT. In the light of their tissue-specific expression, kinetic parameters, and susceptibility to insulin action, we discuss their possible specific functions.

Amino Acid Sequence↗

PubMed1990

Glucose transport and glucose transporters in muscle and their metabolic regulation.

Skeletal muscle is the primary tissue responsible for insulin-dependent glucose uptake in vivo; therefore, glucose uptake by this tissue plays an important role in determining glycemia. Glucose uptake in muscle occurs by a system of facilitated diffusion involving at least two distinct glucose transporters, GLUT-1 and GLUT-4. Both bind the fungal metabolite and inhibitor of glucose transport cytochalasin B. In human skeletal muscle, both types of transporters are detected immunologically, and corresponding mRNA transcripts of both transporter forms are detected. In human skeletal muscle cells in culture, in which contamination by other tissues is ruled out, a 50,000-Mr polypeptide is photolabeled with cytochalasin B. In rat skeletal muscle, acute treatment with insulin in vivo increases glucose-transport activity and the number of specific cytochalasin B-binding sites at the plasma membrane. In mildly diabetic (streptozocin-induced) rats, the number of cytochalasin B-binding sites is decreased in total membranes, and preferentially in the plasma membrane. In response to acute insulin treatment, however, there is still recruitment of glucose transporters to the plasma membrane from an intracellular membrane store. Hence, migration of transporters does occur in this form of diabetes. In L6 muscle cells in culture, acute treatment (1 h) with insulin causes recruitment of glucose transporters to the plasma membrane, and prolonged exposure to insulin or to glucose-deprived medium causes increased expression of GLUT-1 mRNA and GLUT-1 protein. Prolonged exposure (24 h) to high glucose in the medium causes a decrease in the number of glucose transporters in the plasma membrane. Hence, in those cells the expression of the GLUT-1 glucose transporter is modulated by insulin.

Animals↗

PubMed1990

Family of glucose-transporter genes. Implications for glucose homeostasis and diabetes.

Glucose transport by facilitated diffusion is mediated by a family of tissue-specific membrane glycoproteins. At least four members of this gene family have been identified by cDNA cloning. The HepG2-type transporter is the most widely distributed of these proteins. It provides many cells with their basal glucose requirement for ATP production and the biosynthesis of sugar-containing macromolecules. The liver-type transporter is expressed in tissues from which a net release of glucose can occur and in beta-cells of pancreatic islets. A genetic defect resulting in reduced activity of this transporter could hypothetically lead to the two principal features of non-insulin-dependent diabetes mellitus, insulin resistance and relative hypoinsulinemia. The adipocyte/muscle transporter is expressed exclusively in tissues that are insulin sensitive with respect to glucose uptake. This protein is an excellent candidate for a highly specific genetic defect predisposing to insulin resistance.

Diabetes Mellitus, Type 2↗

PubMed1994

Nutrient transport by ruminal bacteria: a review.

Fermentation pathways have been elucidated for predominant ruminal bacteria, but information is limited concerning the specific transport mechanisms used by these microorganisms for C, energy, and N sources. In addition, it is possible that changes in ruminal environmental conditions could affect transport activity. Five carrier-mediated soluble nutrient transport mechanisms have been identified in bacteria: 1) facilitated diffusion, 2) shock sensitive systems, 3) proton symport, 4) Na+ symport, and the 5) phosphoenolpyruvate phosphotransferase system (PEP-PTS). Several regulatory mechanisms are also involved at the cell membrane to coordinate utilization of different sugars. Recent research has shown that predominant ruminal bacteria are capable of transporting soluble nutrients by several of the mechanisms outlined above. Megasphaera elsdenii, Selenomonas ruminantium, and Streptococcus bovis transport glucose by the PEP-PTS, and S. ruminantium and S. bovis also possess PEP-PTS activity for disaccharides. Glucose PTS activity in S. bovis was highest at a growth pH of 5.0, low glucose concentrations, and a dilution rate of .10 h-1. The cellulolytic ruminal bacterium Fibrobacter succinogenes uses a Na+ symport mechanism for glucose transport that is sensitive to low extracellular pH and ionophores. Sodium also stimulated cellobiose transport by F. succinogenes, and there is evidence for a proton symport in the transport of both arabinose and xylose by S. ruminantium. A chemical gradient of Na+ seems to play an important role in AA transport in several ruminal bacteria. Studying nutrient transport mechanisms in ruminal bacteria will lead to a better understanding of the ruminal fermentation.

Amino Acids↗

PubMed1996

Peptide regulation of intestinal glucose absorption.

Terminal hydrolysis of oligosaccharides at the small intestinal brush border yields monomeric glucose, most of which is then absorbed by the transepithelial route. This involves carrier-mediated processes requiring specialized functional proteins situated in the brush border (SGLT1) and basolateral (GLUT2) membranes. Glucose translocation at the enterocyte apical membrane is an active, Na(+)-dependent and saturable process, whereas exit from enterocytes is by facilitated diffusion and is energy-independent. Specific adaptation of glucose active transport occurs in response to changes in the proportion of glucose in the diet. The regulatory signals responsible for transport induction are imprecisely defined, although numerous protein hormones and gut regulatory proteins are implicated. Epidermal growth factor and peptide YY invoke up-regulation of jejunal active glucose transport in vivo. Recently, peptide YY has been shown to stimulate active glucose transport in mice without altering oxygen consumption of jejunal tissue. Several other peptides whose presence in tissues of the small bowel imply that they exert control over epithelial nutrient transport are considered, and the relevance of these physiological manipulations, with various regulatory peptides and hormones, to animal agriculture are discussed.

Animals↗

PubMed1990

Changes in uptake of linoleic acid and cholesterol by jejunal sacs of rats in vitro, after distal small-bowel resection.

Both linoleic acid and cholesterol uptake were studied in small-intestinal sacs of rats in vitro after distal small-bowel resection (DSBR). The relationship between linoleic acid concentration and its absorption was non-linear at low concentrations and became linear at high concentrations in the three groups of animals. These observations indicate that a concentration-dependent dual mechanism of transport is operative in linoleic acid intestinal uptake. Experiments with rotenone and ouabain suggest that a facilitated diffusion is the predominant mechanism of absorption at low concentrations, whereas at high concentrations simple diffusion is predominant. The apparent kinetic constants of linoleic acid uptake (Kd, Kt, and Vmax) increased after DSBR. The uptake of linoleic acid is, however, influenced by the simultaneous presence of linolenic acid, the inhibition constant being decreased after the surgical operation. After the surgical operation an increase of cholesterol uptake was observed, with a parallel enhancement in the apparent mass-transfer coefficient (Kd). Taken together, these results suggest that both organ growth and changes in transport function of the enterocytes appear to be involved in the adaptive response of the bowel to intestinal resection.

Animals↗

PubMed1987

Transport of vitamin C in the lens.

Mediated transport of dehydro-L-ascorbic acid (DAS) occurs in the mammalian ocular lens. At physiological pH, there is negligible cellular uptake of reduced L-ascorbate (AS). In the calf, inhibition by analogues and by cytochalasin B, and saturability with increasing concentration provide evidence of a transport-system for DAS, apparently by facilitated diffusion, since entry was independent of external Na+. The lenticular transporter for DAS evidently is interrelated with that for hexoses, as determined by kinetic studies and inhibition by analogues. Although the two ligands bind initially to separate sites, they probably permeate cellular membranes of this tissue via a common channel. Investigation of AS in the calf's lens over the range, pH 5.0-7.4, showed that uptake increased with increasing acidity in contrast to DAS and D-glucose, whose uptake decreased. This behavior of AS was attributed to back-titration of its enolic hydroxyl group to give the un-ionized moiety, which penetrated as readily as DAS under comparable able conditions, and apparently undergoes mediated transport.

2,3-Diketogulonic Acid↗

PubMed1991

Mechanisms of metal transport across liver cell plasma membranes.

The liver's pivotal role in the homeostasis of essential trace metals and detoxification of exogenous metals is attributed to its ability to efficiently extract metals from plasma, metabolize, store, and redistribute them in various forms either into bile or back into the bloodstream. Bidirectional transport across the sinusoidal plasma membrane allows the liver to control plasma concentrations and therefore availability to other tissues. In contrast, transport across the canalicular membrane is largely, but not exclusively, unidirectional and is a major excretory pathway. Although each metal has relatively distinct hepatic transport characteristics, some generalizations can be made. First, movement of metals from plasma to bile follows primarily a transcellular route. The roles of the paracellular pathway and of ductular secretion appear minimal. Second, intracellular binding proteins and in particular metallothionein play only indirect roles in transmembrane flux. The amounts of metallothionein normally secreted into plasma and bile are quite small and cannot account for total metal efflux. Third, metals traverse liver cell plasma membranes largely by facilitated diffusion, and by fluid-phase, adsorptive, and receptor-mediated endocytosis/exocytosis. There is currently no evidence for primary active transport. Because of the high rate of hepatocellular membrane turnover, metal transport via endocytic vesicles probably makes a larger contribution than previously recognized. Finally, there is significant overlap in substrate specificity on the putative membrane carriers for the essential trace metals. For example, zinc and copper share many transport characteristics and apparently compete for at least one common transport pathway. Similarly, canalicular transport of five of the metals discussed in this overview (Cu, Zn, Cd, Hg, and Pb) is linked to biliary GSH excretion. These metals may be transported as GSH complexes by the canalicular glutathione transport system(s). Unfortunately, none of the putative membrane carrier proteins have been studied at the subcellular or molecular level. Our knowledge of their biochemical properties is rudimentary and rests almost entirely on indirect evidence obtained in vivo or in intact cell systems. The challenge for the future is to isolate and characterize these putative metal carriers, and to determine how they are functionally regulated.

Biological Transport↗

PubMed1978

Phloretin-like action of bioflavonoids on sugar accumulation capability of isolated intestinal cells.

Flavanones and flavones are structural analogues of phloretin. Like phloretin they inhibit the non-Na+-dependent, facilitated diffusion transport system for sugars associated with the lateral serosal boundary of intestinal epithelial cells. The degree of inhibition varies with the extent and position of hydroxylation of the flavonoid nucleus. Flavones are more potent than corresponding flavanones. Tri- and tetrahydroxylated forms are more inhibitory than similar penta- and hexahydroxylated molecules. With one exception, none of the 18 flavonoids tested has secondary effects as metabolic inhibitors, as does phloretin. Inhibition of the passive sugar transport system with flavonoids allows the concentrative Na+-dependent sugar transport system to establish a better concentration gradient than is observed in untreated cells. The degree of gradient enhancement is proportional to the degree of inhibition of the sugar "leak." The flavonoid glycosides, which can be considered as phlorizin analogues, also inhibit the non-Na+-dependent sugar carrier, but less well than corresponding nonglycosylated agents. Only one of the glycosides inhibits the Na+-dependent transport system, and much less potently than phlorizin.

Animals↗

PubMed1991

Probing the structural basis for enzyme-substrate recognition in Cu,Zn superoxide dismutase.

A full understanding of enzyme-substrate interactions requires a detailed knowledge of their structural basis at atomic resolution. Crystallographic and biochemical data have been analyzed with coupled computational and computer graphic approaches to characterize the molecular basis for recognition of the superoxide anion substrate by Cu,Zn superoxide dismutase (SOD). Detailed analysis of the bovine SOD structure aligned with SOD sequences from 15 species provides new results concerning the significance and molecular basis for sequence conservation. Specific roles have been assigned for all 23 invariant residues and additional residues exhibiting functional equivalence. Sequence invariance is dominated by 15 residues that form the active site stereochemistry, supporting a primary biological function of superoxide dismutation. Using data from crystallographic structures and site-directed mutants, we are testing the role of individual residues in the active site channel, including (in human SOD) Glu 132, Glu 133, Lys 136, Thr 137, and Arg 143. Electrostatic calculations incorporating molecular flexibility suggest that the region of positive electrostatic potential in and over the active site channel above the Cu ion sweeps through space during molecular motion to enhance the facilitated diffusion responsible for the enzyme's rapid catalytic rate.

Amino Acid Sequence↗

PubMedDate not supplied

Effects of temperature on in vitro palmitic acid uptake by chicken and rat intestinal tissue.

The intestinal absorption of fatty acids proceeds by simple or facilitated diffusion, a mechanism which is affected by temperature. However, most studies in this field have not taken into consideration the fact that birds have higher physiological temperature than mammals, the absorption being studied at 37 degrees C in both cases. The aim of this work has been to find out whether the higher palmitic acid (PA) uptake rate in birds (chickens) compared to mammals (rats) is attributable to the differences between their body temperatures (41.5 degrees C for chickens and 37.5 degrees C for rats). PA-uptake was studied in intestinal (ileal and jejunal) tissue samples of both Hybro broiler chickens (male and female, 4 weeks-old) and Ico:OFA rats (males and females, 8 weeks-old). The intestinal tissue samples were incubated in micellar solution (0.6 mM 14C-PA; 0.3 mM monoolein; 3.4 mM sodium taurodeoxycholate) at 37.5 degrees C and 41.5 degrees C in both cases. Chicken intestinal tissue incorporated PA with higher efficiency at 41.5 degrees C than at 37.5 degrees C. In contrast, increasing the incubation temperature to 41.5 degrees C led to a decrease in PA uptake by female rat intestinal tissue whereas specimens from male rats exhibited the same absorptive efficiency. These results suggest that the incubation temperature determines to some extent the efficiency of fatty acid uptake. However the fact that the temperature caused opposite effects in rats and chickens indicates that the changes in temperature affect the intracellular processing of the fatty acids already taken up rather than the diffusion of fatty acids through the enterocyte brush-border membrane.

Animals↗

PubMed1981

Role of pyridoxal kinase in vitamin B6 uptake by Escherichia coli.

Escherichia coli KG980, a vitamin B6 auxotroph derived from wild strain K12, concentrated exogenous pyridoxal in an energy-dependent manner, and the effects of energy sources and inhibitors on pyridoxal uptake, compared with those on proline uptake indicated that the energy required was in the form of phosphate bonds and not of membrane potential. The vitamin taken up was primarily present as pyridoxal 5'-phosphate and pyridoxamine 5'-phosphate intracellularly, and energy depletion decreased the accumulation as the phosphorylated derivatives but not as unaltered pyridoxal itself. This finding suggested that the intracellular phosphorylation, which was known to require ATP, was essential for the concentrative uptake of the vitamin. The suggestion was confirmed by the following evidence. 1) Pyridoxal oxime inhibited pyridoxal uptake by decreasing the intracellular phosphorylation without affecting the entry of pyridoxal across the cell membrane. 2) A pyridoxal-kinase deficient mutant (HN1) derived from the strain KG980 showed a low ability to take up pyridoxal because of the failure to accumulate it effectively as phosphorylated derivatives. The carrier-mediated nature of pyridoxal uptake, previously suggested by saturation kinetics, was further supported by the present finding that 4'-deoxypyridoxine inhibited pyridoxal uptake competitively, decreasing the intracellular appearance of unmetabolized pyridoxal. It is therefore most likely that pyridoxal enters the cells by facilitated diffusion and is accumulated by conversion to phosphorylated derivatives. Similar results on the uptake of pyridoxine and pyridoxamine are also presented.

Escherichia coli↗

PubMed1986

Glucose-independent transport of dehydroascorbic acid in human erythrocytes.

It has been previously reported that glucose and its structural analogs inhibit dehydroascorbic acid (DHA) transport across the membranes of nonpolar cells, which led to the suggestion that the hexose transporter mediates dehydroascorbic acid transport. The present study examines the role of the erythrocyte hexose transport system in dehydroascorbic acid uptake. We have confirmed that dehydroascorbic acid may be a ligand of the hexose transport system under certain experimental conditions. However, there is an additional pathway of dehydroascorbic acid transport that is uninfluenced by external glucose. This pathway is one of facilitated diffusion, demonstrating saturation kinetics of transport, cis-inhibition, and trans-stimulation. The Km for the system is 412 microM. It is suggested that this previously undescribed sugar-independent transporter is the physiologically important route of DHA uptake in erythrocytes.

Adult↗

PubMedDate not supplied

DNA vaccines for emerging infectious diseases: what if?

A novel and powerful method for vaccine research, colloquially known as DNA vaccines, involves the deliberate introduction into tissues of a DNA plasmid carrying an antigen-coding gene that transfects cells in vivo and results in an immune response. DNA vaccines have several distinct advantages, which include ease of manipulation, use of a generic technology, simplicity of manufacture, and chemical and biological stability. In addition, DNA vaccines are a great leveler among re-searchers around the world because they provide unprecedented ease of experi-mentation. To facilitate diffusion of information, an Internet site has been established called THE DNA VACCINE WEB (URL:http://www.genweb.com/dnavax/dnavax.html). In this review, a brief survey is undertaken of the experimental models and preclinical work on DNA vaccines to contribute to a greater awareness of the possibilities for emerging infectious diseases.

Animals↗

PubMed1999

Adenosine transport in liver before and after organ preservation.

The effect of 24-h cold storage of liver on nucleoside transport was investigated. Nucleoside transport was estimated under conditions when both known types of nucleoside transport, facilitated diffusion and Na+/nucleoside cotransport, were active and when one of these transport mechanisms was inhibited. The rate of adenosine transport was not decreased after long-term cold storage of the liver. Inhibition of one of the transport systems decreased the rate of adenosine uptake before and after preservation of the liver to about the same extent. The adenosine transport rate was maintained during long-term (100 min) liver perfusion ex vivo. Slight activation of energy-dependent transport in the beginning of reperfusion and the slower recovery of this transport after the second transition from Na+-free to Na+-containing perfusion are not regarded as physiologically important because they were observed after changing the ionic content of the extracellular medium. We conclude that the nucleoside transport systems in liver are quite well preserved after 24-h cold storage of the organ.

Adenosine↗