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PubMed2000

Lower calorie intake enhances muscle insulin action and reduces hexosamine levels.

Previous studies have demonstrated enhanced insulin sensitivity in calorie-restricted [CR, fed 60% ad libitum (AL) one time daily] compared with AL-fed rats. To evaluate the effects of reduced food intake, independent of temporal differences in consumption, we studied AL (unlimited food access)-fed and CR (fed one time daily) rats along with groups temporally matched for feeding [fed 3 meals (M) daily]: MAL and MCR, eating 100 and 60% of AL intake, respectively. Insulin-stimulated glucose transport by isolated muscle was increased in MCR and CR vs. AL and MAL; there was no significant difference for MCR vs. CR or MAL vs. AL. Intramuscular triglyceride concentration, which is inversely related to insulin sensitivity in some conditions, did not differ among groups. Muscle concentration of UDP-N-acetylhexosamines [end products of the hexosamine biosynthetic pathway (HBP)] was lower in MCR vs. MAL despite unaltered glutamine-fructose-6-phosphate aminotransferase activity (rate-limiting enzyme for HBP). These results indicate that the CR-induced increase in insulin-stimulated glucose transport in muscle is attributable to an altered amount, not timing, of food intake and is independent of lower triglyceride concentration. They further suggest that enhanced insulin action might involve changes in HBP.

3-O-Methylglucose↗
PubMed2000

Hexosamine regulation of glucose-mediated laminin synthesis in mesangial cells involves protein kinases A and C.

Hyperglycemia leads to alterations in mesangial cell function and extracellular matrix (ECM) protein accumulation. These adverse effects of glucose may be mediated by glucose metabolism through the hexosamine biosynthesis pathway (HBP). The HBP converts fructose-6-phosphate to glucosamine-6-phosphate via the rate-limiting enzyme, glutamine:fructose-6-phosphate amidotransferase (GFA). We have investigated the effects of high glucose (HG, 25 mM) and glucosamine (GlcN, 1.5 mM) on the synthesis of the ECM protein laminin in a SV-40-transformed rat kidney mesangial (MES) cell line. The roles of protein kinases C (PKC) and A (PKA) in mediating laminin accumulation were also investigated. Treatment of MES cells with HG or GlcN for 48 h increased laminin levels in cellular extracts more than twofold compared with 5 mM glucose (low glucose; LG). The presence of the GFA inhibitor diazo-oxo-norleucine (DON, 10 microM) blocked HG but not GlcN-induced laminin synthesis. HG resulted in a time-dependent increase in total PKC and PKA activities, 57+/-11.3 (P < 0.01 vs. LG) and 85+/-17.4% (P < 0.01 vs. LG), respectively. GlcN had no effect on the total PKC activity; however, both glucose and glucosamine increased membrane-associated PKC activity by twofold compared with LG. GlcN stimulated total PKA activity by 47+/-8.4% (P < 0.01 vs. LG). Similarly, membrane- associated PKA activity was also increased by HG and GlcN approximately 1.8 and 1.5-fold, respectively. HG and GlcN increased cellular cAMP levels 2.2- and 3. 4-fold, respectively. Pharmacological downregulation of PKC by long-term incubation of MES cells with 0.5 microM phorbol 12-myristate 13-acetate (PMA) or inhibition of PKA activity by 2 microM H-8 blocked the effects of HG and GlcN on laminin synthesis. These results demonstrate that glucose-induced laminin synthesis in MES cells is mediated by flux through the HBP and that this stimulation involves PKC and PKA signaling pathways.

Animals↗
PubMed2004

Activation of the hexosamine pathway leads to phosphorylation of insulin receptor substrate-1 on Ser307 and Ser612 and impairs the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin insulin biosynthetic pathway in RIN pancreatic beta-cells.

Many adverse effects of glucose were attributed to its increased routing through the hexosamine pathway (HBP). There is evidence for an autocrine role of the insulin signaling in beta-cell function. We tested the hypothesis that activation of the HBP induces defects in insulin biosynthesis by affecting the insulin-mediated protein translation signaling. Exposure of human pancreatic islets and RIN beta-cells to glucosamine resulted in reduction in glucose- and insulin-stimulated insulin biosynthesis, which in RIN beta-cells was associated with impairment in insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation at Tyr(608) and Tyr(628), which are essential for engaging phosphatidylinositol 3-kinase (PI 3-kinase). These changes were accompanied by impaired activation of PI 3-kinase, and activation of Akt/mammalian target of rapamycin/phosphorylated heat- and acid-stable protein-1/p70S6 kinase pathway. RIN beta-cells exposed to high glucose exhibited increased c-Jun N-terminal kinase (JNK) and ERK1/2 activity, which was associated with increased IRS-1 phosphorylation at serine (Ser)(307) and Ser(612), respectively, that inhibits coupling of IRS-1 to the insulin receptor and is upstream of the inhibition of IRS-1 tyrosine phosphorylation. Azaserine reverted the stimulatory effects of high glucose on JNK and ERK1/2 activity and IRS-1 phosphorylation at Ser(307) and Ser(612). Glucosamine mimicked the stimulatory effects of high glucose on JNK and ERK1/2 activity and IRS-1 phosphorylation at Ser(307) and Ser(612). Inhibition of JNK and MAPK kinase-1 activity reverted the negative effects of glucosamine on insulin-mediated protein synthesis. These results suggest that activation of the HBP accounts, in part, for glucose-induced phosphorylation at Ser(307) and Ser(612) of IRS-1 mediated by JNK and ERK1/2, respectively. These changes result in impaired coupling of IRS-1 and PI 3-kinase, and activation of the Akt/mammalian target of rapamycin/phosphorylated heat- and acid-stable protein-1/p70S6 kinase pathway.

Adaptor Proteins, Signal Transducing↗
PubMed1977

Study of the effect of oestradiol on hexosamine-containing substances and a possible receptor in the skin of male mice.

Male mice were treated with 10 microng of oestradiol for 5 days in order to study the effect of the hormone on both the distribution and the rate of synthesis of glycosaminoglycans and glycoproteins in the skin. Oestradiol exerts a very specific effect on glycosaminoglycans by increasing hyaluronic acid concentration more than 11 times. Effects on other hexosamine-containing substances were much smaller and less consistent. Although the above increase of hyaluronic acid was due mainly to an augmentation of its synthesis, the results also indicate the possibility of a blockage in the breakdown process. Despite the fact that oestrogen produces such large changes, a specific cytosol receptor of the hormone was not discerned and it was concluded that male mouse skin is not an oestrogen receptor tissue in the classical sense.

Animals↗
PubMedDate not supplied

Gastric mucosal hexosamine contents in patients with renal diseases.

Since gastric mucosal lesions are frequently encountered in patients with renal disease, we measured the gastric mucosal hexosamine (Hx) content in 51 patients with renal disease. Endoscopic examination revealed that nearly half of the patients had erosive gastritis, and that duodenal ulcers (Dus) were more common than gastric ulcers (Gus). The gastroduodenal lesions were increased in patients with advanced renal dysfunction. The relationship between Hx content and various indicators of renal function, including creatinine clearance (Ccr), serum creatinine (cr), blood urea nitrogen (BUN), and 24-h urine protein excretion, were also evaluated. The Hx content decreased in the early stage of renal dysfunction. However, it returned to normal to near normal levels in advanced renal disease and patients who underwent hemodialysis. Since the Hx content was decreased in the early stage of renal dysfunction, careful follow-up appears to be necessary in patients with renal disease.

Adolescent↗
PubMed1996

Increased hexosamine availability similarly impairs the action of insulin and IGF-1 on glucose disposal.

Prolonged glucosamine (GlcN) infusion increases the skeletal muscle hexosamine concentration and induces peripheral insulin resistance in conscious rats. IGF-1 and insulin share common steps in signal transduction, and the action of IGF-1 on carbohydrate metabolism is preserved in certain insulin-resistant states. In our study, we attempted to delineate whether increased GlcN availability also impairs the effects of IGF-1 on glucose uptake (Rd), glycolysis, and glycogen synthesis. We performed euglycemic IGF-1 (5 and 15 microg x kg(-1) x min(-1)) and insulin (3 and 18 mU mg x kg(-1) x min(-1)) clamp studies at 0-2 h and 5-7 h in conscious rats (n = 44) during saline or GlcN infusions. GlcN infusion raised plasma GlcN levels to approximately 2.0 mmol/l and skeletal muscle uridinediphospho-n-acetylglucosamine to 80-150 nmol/g (approximately three- to fivefold over basal). During physiological hyperinsulinemia (3 mU x kg(-1) x min(-1), plasma insulin approximately 50 microU/ml), GlcN infusion caused comparable decreases in Rd (15.7 +/- 1.0 [5-7 h] vs. 21.7 +/- 2.3 [0-2 h] mg x kg(-1) x min(-1); P < 0.01) and glycogen synthesis (5.4 +/- 0.5 [5-7 h] vs. 10.4 +/- 1.9 [0-2 h] mg x kg(-1) x min(-1); P < 0.005). Furthermore, GlcN markedly decreased Rd by 7.8 +/- 1.2 mg x kg(-1) x min(-1) (18.7 +/- 0.7 [5-7 h] vs. 26.5 +/- 1.3 [0-2 h] mg x kg(-1) x min(-1); P < 0.001 vs. control) during IGF-1 (5 microg x kg(-1) x min(-1)) clamp studies. This decline was associated with a 26% decrease in the steady-state concentration of skeletal muscle Glc-6-P (286 +/- 45 vs. 386 +/- 36 nmol/g; P < 0.01) and was primarily caused by impaired glycogen synthesis (6.7 +/- 0.5 [5-7 h] vs. 13.9 +/- 0.9 [0-2 h] mg x kg(-1) x min(-1); P < 0.005). The effects of GlcN infusion on glucose disposal (percentage decrease in Rd) were correlated (r2 = 0.803; P < 0.01) with the skeletal muscle concentration of UDP-GlcNAc. To investigate whether IGF-1 can overcome GlcN-induced insulin resistance, GlcN and insulin (18 mU x kg(-1) x min(-1)) were infused for 7 h during euglycemic clamps, and IGF-1 (15 microg x kg(-1) x min(-1)) was superimposed during the final 2 h. GlcN infusion induced severe impairment of insulin action on Rd (39.4 +/- 3.2 [4-5 h] vs. 49.8 +/- 3.6 [1-2 h] mg x kg(-1) x min(-1); P < 0.05), which the addition of IGF-1 failed to improve (35.9 +/- 2.3 [6-7 h] vs. 39.4 +/- 3.2 [4-5 h] mg x kg(-1) x min(-1); P > 0.1). In summary, GlcN induced severe resistance to the actions of both insulin and IGF-1 on glucose uptake and glycogen synthesis, and IGF-1 was unable to overcome GlcN-induced insulin resistance. Thus, it is likely that GlcN causes peripheral insulin resistance acting at a site common to both IGF-1 and insulin signaling pathways.

Animals↗
PubMed2001

Free fatty acids induce peripheral insulin resistance without increasing muscle hexosamine pathway product levels in rats.

To evaluate the role of the hexosamine biosynthesis pathway (HBP) in fat-induced insulin resistance, we examined whether fat-induced insulin resistance is additive to that induced by increased HBP flux via glucosamine infusion and, if so, whether such additive effects correlate with muscle HBP product levels. Prolonged hyperinsulinemic (approximately 550 pmol/l) euglycemic clamps were conducted in conscious overnight-fasted rats. After the initial 150 min to attain steady-state insulin action, rats received an additional infusion of saline, Intralipid, glucosamine, or Intralipid and glucosamine (n = 8 or 9 for each) for 330 min. At the conclusion of clamps, skeletal muscles (soleus, extensor digitorum longus, and tibialis anterior) were taken for the measurement of HBP product levels. Intralipid and glucosamine infusions decreased insulin-stimulated glucose uptake (Rd) by 38 and 28%, respectively. When the infusions were combined, insulin-stimulated Rd decreased 47%, significantly more than with Intralipid or glucosamine alone (P < 0.05). The glucosamine-induced insulin resistance was associated with four- to fivefold increases in muscle HBP product levels. In contrast, the Intralipid-induced insulin resistance was accompanied by absolutely no increase in HBP product levels in all of the muscles examined. Also, when infused with glucosamine, Intralipid decreased insulin action below that with glucosamine alone without changing HBP product levels. In a separate study, short-term (50 and 180 min) Intralipid infusion also failed to increase muscle HBP product levels. In conclusion, increased availability of plasma free fatty acids induces peripheral insulin resistance without increasing HBP product levels in skeletal muscle.

Animals↗
PubMed1975

The distribution of sulfated uronic acid and hexosamine residues in heparin and heparan sulfate.

Heparins from various sources and heparan sulfate from umbilical cords have been subjected to Smith-degradation and reaction with nitrites. These procedures were effective for providing data relating to the distribution of sulfated iduronic acid residues in the molecule. Results indicated that heparins may have, as a prominent structural feature of the molecule, non-sulfated uronic acid distributed in single sequences, much as had been shown previously for N-acetylglucosamine residues. Sulfated uronic acid, however, may occur in multiple sequences of up to 5 or 6 residues. Heparan sulfate was found to have a major proportion of its ester sulfate on iduronic acid rather than hexosamine units, thereby having sections similar to those in heparins, though in considerably lower proportion.

Amino Acids↗
PubMed1982

Studies on the in vitro incorporation of radioactivity from 1-14C-labeled D-hexosamines in the mucopolysaccharide-peptide complexes of avian tissues.

The incorporation of D-[1-14C]-labeled glucosamine (GlcN) and D-[1-14C]-labeled galactosamine (GalN) into mucopolysaccharide-peptide complex(es) (MPS-P) and the rate of 14CO2 production by tissue slices of skin, comb, liver, kidney, shell gland, and magnum from laying hens were studied during a 12 hr period. The D-[1-14C] GlcN was metabolized at a faster rate than D-[1-14C] GalN. No 14CO2 was produced by skin and comb tissues incubated with D-[1-14C]GalN for 12 hr. The amount of 14C associated with the acetone extract of the tissues, acetone-extracted tissues, and MPS-P of the tissue increased with increasing incubation time, but generally the increase was highest in the MPS-P. A comparison among the tissues indicated that the radioactivity present in CO2 and MPS-P was highest in the shell gland and lowest in comb tissue slices. The rates of incorporation of 14C-hexosamine (HexN) into MPS-P by tissue slices appeared to be in general agreement to those of intact animals.

Animals↗
PubMed2000

The effects of glucose and the hexosamine biosynthesis pathway on glycogen synthase kinase-3 and other protein kinases that regulate glycogen synthase activity.

BACKGROUND: Glycogen synthase (GS) activity is determined by its phosphorylation state. We have previously demonstrated that high glucose (HG) downregulates both basal and insulin-stimulated GS activity in rat-1 fibroblasts and that the hexosamine biosynthesis pathway (HBP) may be involved in mediating some of the effects of glucose. In this study we investigate the influence of high glucose and glucosamine (GlcN) on the activity of several kinases that phosphorylate and inactivate GS. METHODS: Glycogen synthase kinase (GSK) 3, cAMP-dependent protein kinase (PKA), protein kinase C (PKC), casein kinase (CK) 1, and phosphorylase kinase (PhK) activities were assayed in cellular extracts from control rat-1 fibroblasts and those that overexpress human cDNA for glutamine:fructose 6-phosphate amidotransferase (GFA), the rate-limiting enzyme in the HBP. RESULTS: Culturing rat-1 fibroblasts in HG (20 mmol/L) or GlcN (3-5 mmol/L) for 16-20 hours increases GSK-3 activity by 23.9 and 50%, respectively, when compared to activity at low glucose (LG, 1 mmol/L). The effects of HG on GSK-3 activity are greater in cells overexpressing GFA (38.8% increase). Insulin (1.7 nmol/L) treatment leads to a 20-25% decrease in GSK-3 activity that is not affected by HG, GlcN, or GFA overexpression. Culturing control cells in HG increases PKA and CK-1 activities by 56 and 95%, respectively, and HG diminishes insulin action on CK-1 activity. GlcN inhibits insulin action on both PKA and CK-1 activities. HG, GlcN, and GFA overexpression blunted insulin's ability to downregulate PhK activity in LG conditions. PKC activity is not significantly altered in either cell line in the above conditions. CONCLUSIONS: These results suggest that HG alters both basal and insulin-regulated activity of several kinases that phosphorylate GS, and some of the effects of glucose may be mediated by its metabolism via the HBP.

Amino Acid Sequence↗
PubMed1975

Changes in liver and gastric mucosal hexosamine synthesis after restraint.

The specific activity of L-glutamine: D-fructose-6-phosphate aminotransferase was measured in the oxyntic gland mucosa and liver of fasted, male rats after immobilization in a cold environment. Immobilization for 3 hr resulted in 100% frequency of lesion formation associated with decreased enzyme activity in oxyntic gland mucosa (70.1 plus or minus 5.9% of control) and liver 25.2 plus or minus 5.2% of control). Enzyme activity had returned to control level in the stomach 9 hr after immobilization, and in the liver 21 hr after immobilization. Immobilization for 1 1/2 hr decreased oxyntic gland mucosa enzyme activity to 21.0 plus or minus 9.8% of control, although the frequency of lesion formation was only 62.5%. Liver enzyme activity was 51.3 plus or minus 12.8% of control. Concentrations of UDP-N-acetylhexosamines, feedback inhibitors of this enzyme, were not altered in either tissue. Adrenalectomy, which increased the frequency of damage after 1 hr of immobilization, enhanced the decreases in enzyme activity in both tissues, while atropine sulfate, which decreased the frequency of damage after 3 hr of immobilization, had no significant effect on the enzyme. Thus, immobilization of rats in a cold environment decreases or alters the synthesis of hexosamine-containing compounds through a mechanism not dependent on acid secretion or adrenocorticoids. This alteration in synthesis may result not only in abnormal mucus secretion, but also in altered cell membrane structure and function.

Adrenal Cortex Hormones↗
PubMed1991

[Indices of hexosamine-containing biopolymers in experimental tooth replantation].

The experimental findings showed that the content of hexosamine-containing biopolymers, in periodontal tissue increased by 38.23 and 124% conformably over 14 days after replantation of 4 teeth of the dogs. The indices normalized in 28 days of the experiment. Investigated biochemical parameters in the root of replantation tooth, in osseus tissues of alveolus 2nd blood. Changed slightly in dynamics.

Alveolar Process↗
PubMed1979

[Human serum hexosamine. Determination in Brazilian pemphigus foliaceus].

The serum hexosamine levels of 39 patients with Pênfigo Foliáceo Brasileiro were determined. The mean value obtained, compared with the mean value found in 30 normal individuals in our laboratory, by Santos et al. (1977), shows that in this disease, the levels of serum glycosamine are higher than in the normal group. The application of Student's test (/t/) indicates a significant difference in the mean values (/t/) = 9,02 P greater than 0,001). Although little is known about the fundamental processes concerned with the increase of serum glycosamines, the authors based on the suggestions of Seibert et al. (1947) reason on the possibility that the essential lesion, i.e., the destruction of the intercellular cement (of glycoprotein nature) is an important factor in the increase of glycoproteins rich in glicosamines.

Hexosamines↗
PubMedDate not supplied

[Effect of hexosamine derivatives on mesenchymal metabolic processes of in vitro cultured fetal bone explants].

The effects of hexosamine derivatives, glucuronic acid, chondroitin sulfate, and oxyphenbutazone on growth and glycosaminoglycan metabolism of murine fetal bone explants cultured for 6 days in vitro were studied. Glucosamine hydrochloride, glucosamine hydroiodide and glucosamine sulfate (at concentrations of 100 micrograms/ml) caused a significant increase in the growth of the explants; this effect was not due to an increase in cell multiplication, as can be concluded from the DNA content of the explants, but rather to an increase in the glycosaminoglycans in the extracellular cartilage matrix. In addition, the three glucosamine salts induced an increase in the secretion of glycosaminoglycans from the surface of the explants into the culture medium. N-acetylgalactosamine, sodium glucuronide and chondroitin sulfate showed lesser or nonsignificant effects as compared to the glucosamine derivatives or the controls. Galactosamine hydrochloride (100 micrograms/ml) exerted inhibitory actions on the bone explants. Oxyphenbutazone (10 micrograms/ml), also, led to a significant inhibition of the growth and glycosaminoglycan metabolism of the explants without influencing (at this concentration) their DNA content. From the results obtained it is concluded that in the treatment of degenerative joint diseases nonsteroidal antiphlogistics acting similarly to oxyphenbutazone should be used, if at all, as cautiously as possible, whereas drugs with the type of action observed in the three glucosamine derivatives could be expected to exert a beneficial effect.

Animals↗
PubMed1981

Hexosamine metabolism during spherule formation in Physarum polycephalum.

Hexosamine metabolism in relation to the spherule-wall synthesis in Physarum polycephalum was studied by the incorporation of labeled sugar into the wall and intermediary compounds in the biosynthesis of wall polysaccharide. The incorporation of [14C]galactosamine into the wall material occurred after a lag period of about 10 h in an induction medium. Nucleotides and sugar phosphates in the acid-soluble fraction of spherulating plasmodia were analyzed by column chromatography on Dowex 1-X8 (formate). The primary labeled products formed in the spherulating plasmodia after incubation with [14C]galactosamine were galactosamine 1-phosphate, UDP-galactosamine, N-acetylhexosamine 6-phosphate and UDP-N-acetylhexosamine. Spherulation was insensitive to polyoxin D, while it was completely blocked by cycloheximide. The activity of galactokinase and galactose-1-phosphate uridyltransferase increased 4--5-fold during the spherulation.

Anti-Bacterial Agents↗
PubMedDate not supplied

Effect of bioflavonoids on the urinary excretion of hydroxyproline, hydroxylysyl glycosides and hexosamine in adjuvant arthritis.

The effects of (+)--Catechin (AC) and 0--(beta hydroxyethyl) rutosides (HR) on the urinary collagen metabolites were studied up to 49 days in rats with adjuvant-induced arthritis. The elevated levels of urinary total, non-dialysable and dialysable hydroxyproline, hydroxylysyl glycosides and total hexosamine in the arthritic animals were found to be slightly decreased in the acute phase and significantly decreased in the chronic phase of the disease due to the administration of bioflavonoids. Of the two bioflavonoids tests, CA was found to afford more protective action than HR.

Animals↗
PubMed1976

Improved continuous-flow method for detemination of total serum hexosamines.

We describe an automated determination of serum hexosamine by the Elson-Morgan reaction, together with reagent modifications that minimiz interference from amino acids and sugars present in acid hydrolysates of sera. We used a novel 15-min autoclave procedure for the acid hydrolysis of sera before analysis to facilitate the detemination as compared to the 4-h hydrolysis used in the conventional manual method. Results correlated well (r = 0.906) with those obtained by the corresponding manual method.

Autoanalysis↗
PubMed1990

Uridine diphospho sugars and related hexose phosphates in the liver of hexosamine-treated rats: identification using 31P-[1H] two-dimensional NMR with HOHAHA relay.

The effects of administration of galactosamine (GalN) and glucosamine (GlcN) on the levels of UDP-sugars and hexose monophosphates in rat livers were studied by a variety of 31P NMR methods. The flux of metabolites in the liver was monitored by in vivo NMR and showed elevated levels of UDP-sugars, and even greater increases in resonances at 4.6 ppm for GlcN treatment and at 2.0 ppm for GalN treatment. The individual compounds corresponding to these changes were identified in PCA liver extracts by 31P-[1H] two-dimensional relay spectroscopy with a HOHAHA-type 1H spin-lock. This method of transferring proton magnetization allows for nearly all of the proton chemical shifts to be observed for the hexose moiety of a UDP-sugar present in a complex mixture. The UDP-sugars in the extracts from treated rats were predominantly UDP-hexosamines. Relay spectra were also used to determine that GalN-1-P was the major component (16.0 mumol/g of liver) of the GalN-treated liver, while both alpha and beta anomers of GlcNAc-6-P were readily identified as the major hexose monophosphates in the GlcN experiment. Spectra from the 1H dimension of relay experiments conducted on extracts were nearly superimposable on relay spectra obtained under the same conditions for mixtures of standard compounds of known structure. UDP-GlcN and UDP-GalN were not commercially available, but their presence was established in the extracts after GalN treatment by obtaining relay spectra for a mixture of the compounds produced in situ enzymatically, without purification.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗