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PubMed1996

Reversible insulin resistance in non-insulin-dependent diabetes mellitus.

Insulin resistance is a major component of non-insulin-dependent diabetes mellitus (NIDDM). While a genetic contribution is likely, as yet none of several proposed candidate genes have been incriminated in the typically obese patient with NIDDM to explain their insulin resistance. Accordingly, this review focuses on some recent advances in understanding three acquired factors contributing to insulin resistance: visceral obesity, glucotoxicity and lipotoxicity. Newer computerized tomography scans allow quantitation of fat accumulating in visceral organs including the mesentery and omentum. This visceral fat relates much more to the insulin resistance syndrome than does subcutaneous fat. Moreover, exercise, as performed by active Sumo wrestlers, is associated with low visceral fat, absent hyperglycemia and absent dyslipidemia despite massive subcutaneous obesity. It remains to be seen whether exercise programs more moderate than Sumo wrestling will also mobilize visceral fat. A new metabolic pathway has recently been described whereby hexosamines are formed by an increased flux of glucose into fat and muscle. These hexosamine products appear to explain how glucotoxicity results in insulin resistance. They act as a negative feedback system to limit further glucose transport by insulin target tissue during hyperglycemia. Lipotoxicity has previously been implicated in insulin resistance by its inhibitory effect on glucose uptake by muscle because of the Randle-fatty acid cycle. Recently the role of elevated fatty acids in producing "hepatic" resistance to insulin in NIDDM has also been documented, but the site of insulin resistance may be the fat cell rather than the hepatocyte. Therapy consists mainly of hygienic measures, including caloric restriction and exercise, which can reverse all three of these acquired forms of insulin resistance. In addition, pharmacologic measures to reduce hyperglycemia can reduce the glucotoxicity and lipotoxicity. The use of insulin-sparing antihyperglycemia drugs may be particularly useful in the insulin-resistant patient to avoid weight gain while correcting the hyperglycemia.

Diabetes Mellitus, Type 2↗
PubMed1980

Oligosaccharide moieties of glycoprotein hormones: bovine lutropin resists enzymatic deglycosylation because of terminal O-sulfated N-acetylhexosamines.

The oligosaccharides of the bovine pituitary gonadotropin lutropin are N-linked to asparagine residues. These carbohydrates are unusual in that, although they contain the mannose, N-acetylglucosamine, and fucose typical of N-linked oligosaccharides, they also contain one residue of N-acetylgalactosamine but insignificant amounts of sialic acid or galactose. These oligosaccharides exhibit complete resistance to several exoglycosidases. This is in contrast to the ready release of peripheral sugars from human chorionic gonadotropin, a placenta hormone which has oligosaccharides of the complex type with terminal sialic acid and galactose residues. Stability of the lutropin hexosamines to periodate oxidation and reduction (Smith degradation) together with other data show that one residue of N-acetylgalactosamine and one of N-acetylglucosamine are peripheral to two periodate-sensitive mannose residues. The insensitivity to periodate of these two terminal amino sugars is found to result from a sulfate group covalently linked to each; sulfation of these hexosamines is also the most probable reason for the resistance to enzymatic deglycosylation. The alpha subunits of bovine thyrotropin and human pituitary lutropin also contain sulfate, in contrast to human chorionic gonadotropin. The results indicate that sulfating enzymes are present in the pituitary and that sulfation of peripheral sialic acids in the placental gonadotropin. The data lead to a partial structure for the oligosaccharides of bovine LH as follows: (formula see text).

Acetylgalactosamine↗
PubMed1998

Mass spectrometric evidence for the enzymatic mechanism of the depolymerization of heparin-like glycosaminoglycans by heparinase II.

Heparin-like glycosaminoglycans, acidic complex polysaccharides present on cell surfaces and in the extracellular matrix, regulate important physiological processes such as anticoagulation and angiogenesis. Heparin-like glycosaminoglycan degrading enzymes or heparinases are powerful tools that have enabled the elucidation of important biological properties of heparin-like glycosaminoglycans in vitro and in vivo. With an overall goal of developing an approach to sequence heparin-like glycosaminoglycans using the heparinases, we recently have elaborated a mass spectrometry methodology to elucidate the mechanism of depolymerization of heparin-like glycosaminoglycans by heparinase I. In this study, we investigate the mechanism of depolymerization of heparin-like glycosaminoglycans by heparinase II, which possesses the broadest known substrate specificity of the heparinases. We show here that heparinase II cleaves heparin-like glycosaminoglycans endolytically in a nonrandom manner. In addition, we show that heparinase II has two distinct active sites and provide evidence that one of the active sites is heparinase I-like, cleaving at hexosamine-sulfated iduronate linkages, whereas the other is presumably heparinase III-like, cleaving at hexosamine-glucuronate linkages. Elucidation of the mechanism of depolymerization of heparin-like glycosaminoglycans by the heparinases and mutant heparinases could pave the way to the development of much needed methods to sequence heparin-like glycosaminoglycans.

Binding Sites↗
PubMed1998

Glucosamine-induced insulin resistance in 3T3-L1 adipocytes is caused by depletion of intracellular ATP.

Glucosamine, which enters the hexosamine pathway downstream of the rate-limiting step, has been routinely used to mimic the insulin resistance caused by high glucose and insulin. We investigated the effect of glucosamine on insulin-stimulated glucose transport in 3T3-L1 adipocytes. The Delta-insulin (insulin-stimulated minus basal) value for 2-deoxyglucose uptake was dramatically inhibited with increasing concentrations of glucosamine with an ED50 of 1.95 mM. Subcellular fractionation experiments demonstrated that reduction in insulin-stimulated 2-deoxyglucose uptake by glucosamine was due to an inhibition of translocation of both Glut 1 and Glut 4 from the low density microsomes (LDM) to the plasma membrane. Analysis of the insulin signaling cascade revealed that glucosamine impaired insulin receptor autophosphorylation, insulin receptor substrate (IRS-1) phosphorylation, IRS-1-associated PI 3-kinase activity in the LDM, and AKT-1 activation by insulin. Measurement of intracellular ATP demonstrated that the effects of glucosamine were highly correlated with its ability to reduce ATP levels. Reduction of intracellular ATP using azide inhibited Glut 1 and Glut 4 translocation from the LDM to the plasma membrane, insulin receptor autophosphorylation, and IRS-1 tyrosine phosphorylation. Additionally, both the reduction in intracellular ATP and the effects on insulin action caused by glucosamine could be prevented by the addition of inosine, which served as an alternative energy source in the medium. We conclude that direct administration of glucosamine can rapidly lower cellular ATP levels and affect insulin action in fat cells by mechanisms independent of increased intracellular UDP-N-acetylhexosamines and that increased metabolism of glucose via the hexosamine pathway may not represent the mechanism of glucose toxicity in fat cells.

3T3 Cells↗
PubMed2000

Phosphorylation of human glutamine:fructose-6-phosphate amidotransferase by cAMP-dependent protein kinase at serine 205 blocks the enzyme activity.

Glutamine:fructose-6-phosphate amidotransferase (GFAT) is the rate-limiting enzyme in glucosamine synthesis. Prior studies from our laboratory indicated that activation of adenylate cyclase was associated with depletion of O-GlcNAc modification. This finding and evidence that human GFAT (hGFAT) might be regulated by cAMP-dependent protein kinase (PKA) led us to investigate the role of PKA in hGFAT function. We confirmed that adenylate cyclase activation by forskolin results in diminished O-GlcNAc modification of several cellular proteins which can be overcome by exposure of the cells to glucosamine but not glucose, suggesting the PKA activation results in depletion of UDP-GlcNAc for O-glycosylation. To determine if GFAT is indeed regulated by PKA, we expressed the active form of the enzyme using a vaccinia virus expression system and showed that the activity of the enzyme was to decrease to undetectable levels by PKA phosphorylation. We mapped the PKA phosphorylation sites with the aid of matrix-assisted laser desorption ionization mass spectroscopy and showed that the protein was stoichiometrically phosphorylated at serine 205 and also phosphorylated, to a lesser extent at serine 235. Mutagenesis studies indicated that the phosphorylation of serine 205 by PKA was necessary for the observed inhibition of enzyme activity while serine 235 phosphorylation played no observable role. The activity of GFAT is down-regulated by cAMP, thus placing regulation on the hexosamine pathway that is in concert with the energy requirements of the organism. During starvation, hormones acting through adenylate cyclase could direct the flux of glucose metabolism into energy production rather than into synthetic pathways that require hexosamines.

Colforsin↗
PubMed2001

Development of glucose-induced insulin resistance in muscle requires protein synthesis.

Muscles and fat cells develop insulin resistance when exposed to high concentrations of glucose and insulin. We used an isolated muscle preparation incubated with high levels of glucose and insulin to further evaluate how glucose-induced insulin resistance (GIIR) is mediated. Incubation with 2 milliunits/ml insulin and 36 mm glucose for 5 h resulted in an approximately 50% decrease in insulin-stimulated muscle glucose transport. The decrease in insulin responsiveness of glucose transport induced by glucose was not due to impaired insulin signaling, as insulin-stimulated phosphatidylinositol 3-kinase activity and protein kinase B phosphorylation were not reduced. It has been hypothesized that entry of glucose into the hexosamine biosynthetic pathway with accumulation of UDP-N-acetylhexosamines (UDP-HexNAcs) mediates GIIR. However, inhibition of the rate-limiting enzyme GFAT (glutamine:fructose-6-phosphate amidotransferase) did not protect against GIIR despite a marked reduction of UDP-HexNAcs. The mRNA synthesis inhibitor actinomycin D and the protein synthesis inhibitor cycloheximide both completely protected against GIIR despite the massive increases in UDP-HexNAcs and glycogen that resulted from increased glucose entry. Activation of AMP-activated protein kinase also protected against GIIR. These results provide evidence that GIIR can occur in muscle without increased accumulation of hexosamine pathway end products, that neither high glycogen concentration nor impaired insulin signaling is responsible for GIIR, and that synthesis of a protein with a short half-life mediates GIIR. They also suggest that dephosphorylation of a transcription factor may be involved in the induction of GIIR.

Animals↗
PubMed2006

Acceptor specificity of the Pasteurella hyaluronan and chondroitin synthases and production of chimeric glycosaminoglycans.

The hyaluronan (HA) synthase, PmHAS, and the chondroitin synthase, PmCS, from the Gram-negative bacterium Pasteurella multocida polymerize the glycosaminoglycan (GAG) sugar chains HA or chondroitin, respectively. The recombinant Escherichia coli-derived enzymes were shown previously to elongate exogenously supplied oligosaccharides of their cognate GAG (e.g. HA elongated by PmHAS). Here we show that oligosaccharides and polysaccharides of certain noncognate GAGs (including sulfated and iduronic acid-containing forms) are elongated by PmHAS (e.g. chondroitin elongated by PmHAS) or PmCS. Various acceptors were tested in assays where the synthase extended the molecule with either a single monosaccharide or a long chain (approximately 10(2-4) sugars). Certain GAGs were very poor acceptors in comparison to the cognate molecules, but elongated products were detected nonetheless. Overall, these findings suggest that for the interaction between the acceptor and the enzyme (a) the orientation of the hydroxyl at the C-4 position of the hexosamine is not critical, (b) the conformation of C-5 of the hexuronic acid (glucuronic versus iduronic) is not crucial, and (c) additional negative sulfate groups are well tolerated in certain cases, such as on C-6 of the hexosamine, but others, including C-4 sulfates, were not or were poorly tolerated. In vivo, the bacterial enzymes only process unsulfated polymers; thus it is not expected that the PmCS and PmHAS catalysts would exhibit such relative relaxed sugar specificity by acting on a variety of animal-derived sulfated or epimerized GAGs. However, this feature allows the chemoenzymatic synthesis of a variety of chimeric GAG polymers, including mimics of proteoglycan complexes.

Carbohydrates↗
PubMed1963

The composition and structure of bacterial spores.

The composition of the insoluble "integuments" and soluble "contents" fractions of spores of four Bacillus species of widely differing heat resistance were compared. Electron microscopy of thin sections was also used to determine and compare the morphological structures in the integument preparations. The soluble fractions of the thermophiles, B. coagulans and B. stearothermophilus, had a higher content of hexose and dipicolinic acid. The hexose content of both fractions of the four species was related to heat resistance. Integument fractions consisted chiefly of protein together with variable amounts of the mucopeptide constituents, alpha, epsilon-diaminopimelic acid (DAP) and hexosamine. In the thermophiles the DAP and hexosamine were found chiefly in the insoluble integuments fractions, while in B. cereus and B. subtilis most of this material was soluble. Integument preparations, containing mainly protein with little mucopeptide, consisted chiefly of outer and inner spore coats, while preparations having more mucopeptide contained also residual cortical material and a cortical membrane (possibly the germ cell wall). The results suggest that spore integuments consist of mainly proteinaceous outer and inner coats together with variable amounts of residual cortex and cortical membrane which contain the mucopeptide material.

Amino Acids↗
PubMed1962

Variation in the group-specific carbohydrate of group C hemolytic Streptococci.

Certain strains of Group C hemolytic streptococci, termed Group C-intermediate, contain a group-specific carbohydrate antigen which gives a precipitin cross-reaction with A-variant antiserum. The carbohydrate antigens of these strains have a rhamnose:hexosamine ratio ranging from 2.4 to 2.6 whereas the ratio of typical Group C strains varies between 1.1 and 1.7. N-acetylgalactosamine, the major hexosamine in all of these strains is the principle determinant of Group C specificity. The high concentration of rhamnose in the C-intermediate carbohydrate suggests that a portion of the rhamnose oligosaccharide side chains are devoid of terminal N-acetylgalactosamine and thus react with Group A-variant antiserum. This view is supported by the fact that the induced variant enzyme, which destroys A-variant carbohydrate reactivity with the liberation of rhamnose oligosaccharides, has a similar action upon the Group C-intermediate carbohydrate. C-intermediate carbohydrate, after treatment with variant enzyme which removed approximately 25 per cent of the rhamnose, does not react with A-variant antisera.

Carbohydrate Metabolism↗
PubMed1966

Studies on the immunochemistry of streptococcal mucopeptide.

Streptococcal mucopeptide, solubilized by either ultrasonic treatment or lysozyme, gave a precipitin reaction with rabbit antimucopeptide serum. A haptenic inhibitor of this reaction, which was composed of alanine, glutamic acid, and lysine in a mole ratio of 4:1:1, was isolated from a Streptomyces albus enzymes digest of Group D cell walls by ion exchange chromatography. When selected antisera were employed, greater than 90% inhibition of the mucopeptide quantitative precipitin reaction was achieved with 2 mg/ml of this inhibitor, whereas a hexosamine fraction with minimal concentrations of amino acid residues was inactive in this respect. These results suggest that the peptide moiety is an antigenic determinant of mucopeptide. Preliminary results indicate that the hexosamine polymer of the mucopeptide is a secondary antigenic determinant.

Antigen-Antibody Reactions↗
PubMed1968

Immunochemical studies on the cross-reactivity between streptococcal and staphylococcal mucopeptide.

Particulate mucopeptides of Group A-variant streptococci and Staphylococcus aureus, solubilized by ultrasonic treatment, give a precipitin reaction with the sera of rabbits immunized with Group A-variant streptococci. gamma-G globulin antibodies have been recovered from these sera which react with the mucopeptides but not with the Group A-variant carbohydrate. The immunochemical basis for the cross-reactivity between the streptococcal and staphylococcal mucopeptides was investigated in detail. Three chemically different fractions have been isolated from enzymatic digests of staphylococcal mucopeptide and were employed as haptenic inhibitors of the precipitin reaction. A fraction consisting of the peptide moiety of mucopeptide was the strongest inhibitor, whereas the hexosamine-rich fraction was less effective. The third fraction, rich in glycine, was least effective. It is suggested that the immunologic cross-reactivity between streptococcal and staphylococcal mucopeptide is due to the fact that these two substances contain chemically similar tetrapeptides. The hexosamine polymer which is identical for both mucopeptides may also contribute to their cross-reactivity.

Amino Acids↗
PubMed1950

Immuno-chemical studies on blood groups; the preparation of blood group A and B substances and an inactive substance from individual horse stomachs and of blood group B substance from human saliva.

Blood group substances have been isolated from the saliva of human beings of blood group B and from the linings of individual horse stomachs. The properties of the human B substances are similar to those of hog and human blood group substances previously isolated. The horse substances showed lower hexosamine and reducing sugar and higher total and non-hexosamine nitrogen than do the materials from the other species. Materials isolated from individual horse stomachs possess either A or B activity or both. Certain stomachs yielded products of identical analytical composition but with neither blood group A, B, or O activity as measured by their ability to inhibit isoagglutination. Fucose has been identified as a constituent of the horse blood group substances.

Animals↗
PubMed2004

The potential beneficial effect of glycine on the carbohydrate moieties of glycoproteins in an experimental model of alcohol-induced hepatotoxicity.

Glycine is known to have a protective role against alcohol-induced liver damage. The aim of our study was to evaluate the effect of glycine on liver and brain glycoproteins in alcohol-fed rats. Administering ethanol (7.9 g/kg of body of weight) every day to Wistar rats for 60 days resulted in significantly elevated levels of liver and brain hexosamine, fucose, and sialic acid and significantly reduced levels of total hexoses as compared with those of the control rats. Simultaneous glycine supplementation (0.6 g/kg of body weight) during the last 30 days of the experiment to rats given alcohol normalized the levels of hexosamine, fucose, and sialic acid and elevated the levels of total hexoses in the liver and brain significantly as compared with unsupplemented alcohol-treated rats. Microscopic examination of alcohol-fed rat liver showed inflammatory cell infiltrates and fatty changes, which were reversed on treatment with glycine. Similarly, alcohol-treated rat brain demonstrated edema, which was markedly reduced on treatment with glycine. Thus glycine administration plays a significant role in reducing the toxicity of ethanol.

Animals↗
PubMed1999

Incorporation of 15N from ammonium into the N-linked oligosaccharides of an immunoadhesin glycoprotein expressed in Chinese hamster ovary cells.

Elevated ammonium concentrations in the medium of cultivated cells have been shown to increase the intracellular levels of uridine-5'-diphospho-N-acetylglucosamine (UDP-GlcNAc) and uridine-5'-diphospho-N-acetylgalactosamine (UDP-GalNAc; Ryll et al., 1994). These sugar nucleotides are substrates for glycosyltransferases in the glycosylation pathway. In our experiments, recombinant Chinese hamster ovary cells producing an immunoadhesin glycoprotein (GP1-IgG) have been cultivated under controlled cell culture conditions in the presence of different ammonium concentrations.15N-Labeled ammonium chloride (15NH4Cl) was added exogenously to the cell culture media to determine if ammonium was incorporated into UDP-GlcNAc and cytidine-5'-monophospho-N-acetylneuraminic acid (CMP-NANA) pools, and subsequently incorporated into GP1-IgG as N-linked glycans. The intracellular pools of UDP-activated hexosamines (UDP-GNAc) were followed during the time course of the experiment. To assess the extent of15NH4+incorporation into the glycans of GP1-IgG, the glycoprotein was first purified to homogeneity by protein A chromatography. Enzymatically released N-glycans were then analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. N-Glycans synthesized in the presence of15NH4Cl revealed an N-glycan-dependent increase in mass-to-charge of 2.5-4.8 Da. These results indicate that 60-70% of the total nitrogen containing monosaccharides had incorporated15N. Presumably,15NH4+was incorporated into GlcNAc and N-acetylneuraminic acid as proposed earlier (Ryll et al., 1994). This might be a universal and previously not described reaction in mammalian cells when exposed to nonphysiological but in cell culture commonly found concentrations of ammonium. The data presented here are of significance for glycoprotein production in mammalian cell culture, since it has been shown previously that elevated levels of UDP-activated hexosamines affect N-glycan characteristics such as branching and degree of amino sugar incorporation. In addition, our results demonstrate that isotope labeling in combination with MALDI-TOF-MS can be used as an alternate tool to radioactive labeling of sugar substrates in metabolic studies.

Animals↗
PubMed1982

A simple method for the determination of glucosamine and galactosamine using cellulose acetate electrophoresis.

A new electrophoretic method is presented for the determination of glucosamine and galactosamine. The technique is quite simple and rapid, it involves cellulose acetate electrophoresis in borate buffer (200 V, 15 min) and silver nitrate staining. Hexosamine samples of 0.36-1.80 micrograms were separated and stained within 30 min. This method was applied for the hexosamine analysis of glycosaminoglycans.

Animals↗
PubMed1986

Immunohistochemical study of islet amyloid in diabetes mellitus.

Amyloid was isolated from islets of amyloidotic pancreata of monkey and human beings by solubilization of non-amyloid materials from the pancreas and digestion of contaminating collagen and elastin. The resulting pellet was estimated to be greater than 90% pure islet amyloid. Antibodies specific for monkey islet amyloid and for monkey and human liver amyloid A (AA) were raised in rabbits. Immunohistochemical reaction using the peroxidase antiperoxidase method demonstrated that amyloidotic pancreas reacted with both anti-AA and anti-islet amyloid antibodies. Although the antibodies are specific toward antigens, they cross-react with tissues from human and monkeys. The immunochemical results suggest the possibility that more than one kind of amyloid is associated with islet amyloidosis, but that a significant portion of the islet amyloid is related to AA. Preliminary chemical analysis indicated that islet amyloid is enriched with hexosamines while AA contains both hexosamines and hexoses. Establishment of the islet amyloid composition(s) can give insight into its source and its role in diabetes in Macaca nigra and human beings.

Amyloid↗
PubMed1988

Immunobiological properties of lipopolysaccharides isolated from Fusobacterium nucleatum and F. necrophorum.

Lipopolysaccharides (LPSs) were isolated from Fusobacterium nucleatum ATCC 10953 and F. necrophorum ATCC 25286 by the hot phenol/water procedure. F. nucleatum LPS was composed of 16% (w/w) carbohydrate, 10% (w/w) hexosamine and 40% (w/w) fatty acid, while F. necrophorum LPS was composed of 26% (w/w) carbohydrate, 12% (w/w) hexosamine and 28% (w/w) fatty acid. These LPS preparations induced mitogenic responses in spleen cells of BALB/c, BALB/c (nu/nu) and C3H/HeN mice, and these responses were suppressed by the addition of polymyxin B. The preparations also induced the polyclonal responses of C3H/HeN spleen cells. In addition, enhanced glucose utilization and interleukin-1 production by murine peritoneal macrophages were demonstrated. Neither spleen cells nor macrophages from the 'LPS-nonresponsive' C3H/HeJ mouse were activated by LPSs from the Fusobacterium species.

Animals↗
PubMed1999

Characterization of glycolipids from Meiothermus spp.

Thin-layer chromatographic analysis of the polar lipids of Meiothermus strains revealed two glycolipid bands with similar chromatographic mobility to the major glycolipid of Thermus strains. In this study the glycolipids from the type strains of Meiothermus ruber, Meiothermus chliarophilus, Meiothermus silvanus and Meiothermus cerbereus were characterized using GC, GC/MS, fast atom bombardment MS and chemical methods. All strains contained dihexosyl-(N-acyl)hexosaminylglucosyl diacylglycerols, related in structure to the major glycolipid of Thermus strains but varying in their fatty acylation pattern. The detection of two glycolipid bands by TLC in Meiothermus spp. was attributable to the invariable presence of 2-hydroxyacyl groups N-linked to the hexosamine of the polar head group which cause the glycolipids to be more strongly retained on silica TLC plates than 3-hydroxy or non-hydroxylated N-acyl glycolipids of similar structure that are also present. M. silvanus contained, in addition to these glyceroglycolipids, several glycolipids which were linked to acylated branched octadecanediols rather than to glycerol. The presence of glycolipids containing 2-hydroxyacyl groups N-linked to hexosamine appears to be a stable phenotypic marker that distinguishes the genus Meiothermus from the genus Thermus.

Carbohydrates↗