Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucose uptake into adipose and liver cells is known to up-regulate mRNA levels for various lipogenic enzymes such as fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC). To determine whether the hexosamine biosynthesis pathway (HBP) mediates glucose regulation of mRNA expression, we treated primary cultured adipocytes for 18 h with insulin (25 ng/ml) and either glucose (20 mm) or glucosamine (2 mm). A ribonuclease protection assay was used to quantitate mRNA levels for FAS, ACC, and glycerol-3-P dehydrogenase (GPDH). Treatment with insulin and various concentrations of d-glucose increased mRNA levels for FAS (280%), ACC (93%), and GPDH (633%) in a dose-dependent manner (ED50 8-16 mm). Mannose similarly elevated mRNA levels, but galactose and fructose were only partially effective. l-glucose had no effect. Omission of glutamine from the culture medium markedly diminished the stimulatory effect of glucose on mRNA expression. Since glutamine is a crucial amide donor in hexosamine biosynthesis, we interpret these data to mean that glucose flux through the HBP is linked to regulation of lipogenesis through control of gene expression. Further evidence for hexosamine regulation was obtained using glucosamine, which is readily transported into adipocytes where it directly enters the HBP. Glucosamine was 15-30 times more potent than glucose in elevating FAS, ACC, and GPDH mRNA levels (ED50 approximately 0.5 mm). In summary: 1) GPDH, FAS, and ACC mRNA levels are upregulated by glucose; 2) glucose-induced up-regulation requires glutamine; and 3) mRNA levels for lipogenic enzymes are up-regulated by glucosamine. Hyperglycemia is the hallmark of diabetes mellitus and leads to insulin resistance, impaired glucose metabolism, and dyslipidemia. We postulate that disease pathophysiology may have a common underlying factor, excessive glucose flux through the HBP.
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PMID:Role of hexosamine biosynthesis in glucose-mediated up-regulation of lipogenic enzyme mRNA levels: effects of glucose, glutamine, and glucosamine on glycerophosphate dehydrogenase, fatty acid synthase, and acetyl-CoA carboxylase mRNA levels. 1275 50

Adipokines such as Plasminogen activator inhibitor-1 (PAI-1), interleukin (IL)-8, and tumor necrosis factor (TNF)-alpha are elevated in patients with obesity, insulin resistance, and type 2 diabetes. In the present study, we investigated whether glucose affected the production of these adipokines in human adipose tissue in vitro. Glucose (up to 35mM) increased secretion of PAI-1 (p<0.01) and IL-8 (p<0.01), but not TNF-alpha, in a dose- and time-dependent manner. Half-maximal stimulatory concentration of glucose was about 1mM. Glucosamine (5mM) decreased production of PAI-1 (p<0.05) and IL-8 (p<0.05), indicating that the hexosamine biosynthesis pathway is not involved in the glucose-induced increment in adipokine secretion. The present data demonstrate that glucose increases PAI-1 and IL-8 secretion. However, glucose concentrations above 5mM had no additional effects on adipokine secretion, suggesting that mechanisms other than diabetes/insulin resistance-related hyperglycemia may be involved in the observed elevation of these adipokines.
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PMID:Stimulation of PAI-1 and adipokines by glucose in human adipose tissue in vitro. 1455 Feb 86

Accelerated atherosclerosis is one of the major vascular complications of diabetes. Factors including hyperglycemia and hyperinsulinemia may contribute to accelerated vascular disease. Among the several mechanisms proposed to explain the link between hyperglycemia and vascular dysfunction is the hexosamine pathway, where glucose is converted to glucosamine. Although some animal experiments suggest that glucosamine may mediate insulin resistance, it is not clear whether glucosamine is the mediator of vascular complications associated with hyperglycemia. Several processes may contribute to diabetic atherosclerosis including decreased vascular heparin sulfate proteoglycans (HSPG), increased endothelial permeability and increased smooth muscle cell (SMC) proliferation. In this study, we determined the effects of glucose and glucosamine on endothelial cells and SMCs in vitro and on atherosclerosis in apoE null mice. Incubation of endothelial cells with glucosamine, but not glucose, significantly increased matrix HSPG (perlecan) containing heparin-like sequences. Increased HSPG in endothelial cells was associated with decreased protein transport across endothelial cell monolayers and decreased monocyte binding to subendothelial matrix. Glucose increased SMC proliferation, whereas glucosamine significantly inhibited SMC growth. The antiproliferative effect of glucosamine was mediated via induction of perlecan HSPG. We tested if glucosamine affects atherosclerosis development in apoE-null mice. Glucosamine significantly reduced the atherosclerotic lesion in aortic root. (P < 0.05) These data suggest that macrovascular disease associated with hyperglycemia is unlikely due to glucosamine. In fact, glucosamine by increasing HSPG showed atheroprotective effects.
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PMID:Distinct effects of glucose and glucosamine on vascular endothelial and smooth muscle cells: evidence for a protective role for glucosamine in atherosclerosis. 1620 78

In diabetic animals, enhanced production of vascular endothelial growth factor is thought to be a major contributor to the development of diabetic retinopathy. In the present study, glucosamine-treated R28 retinal neuronal cells were used as an experimental model system to explore the possible involvement of the hexosamine biosynthetic pathway in the diabetes-induced changes in mRNA translation. Glucosamine treatment enhanced vascular endothelial growth factor production subsequent to changes in phosphorylation of the alpha-subunit of eukaryotic initiation factor 2, with no change in vascular endothelial growth factor mRNA content. Possible mechanisms through which glucosamine might act to increase eukaryotic initiation factor 2alpha phosphorylation include enhanced O-linked glycosylation of protein kinase or phosphatase regulatory proteins and/or induction of oxidative stress. However, increasing global protein O-glycosylation through inhibition of O-beta-N-acetylglucosaminidase did not mimic the effect of glucosamine on eukaryotic initiation factor 2alpha phosphorylation. Likewise, attenuating glucosamine-induced oxidative stress with two different antioxidants did not reduce glucosamine-induced eukaryotic initiation factor 2alpha phosphorylation. Glucosamine treatment was also found to promote eukaryotic initiation factor 2alpha phosphorylation in wild-type mouse embryonic fibroblasts, but not in mouse embryonic fibroblasts lacking the eukaryotic initiation factor 2alpha kinase referred to as RNA-dependent protein kinase-like endoplasmic-reticulum associated kinase, implicating the kinase in the glucosamine-induced increase in eukaryotic initiation factor 2alpha phosphorylation. Overall, the results are consistent with glucosamine causing activation of RNA-dependent protein kinase-like endoplasmic-reticulum associated kinase, which phosphorylates eukaryotic initiation factor 2alpha and consequently upregulates translation of mRNAs encoding specific proteins, such as vascular endothelial growth factor.
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PMID:Glucosamine-induced phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 is mediated by the protein kinase R-like endoplasmic-reticulum associated kinase. 1632 75

Increased hexosamine biosynthesis pathway (HBP) flux and elevated levels of protein O-linked-N-acetylglucosamine (O-GlcNAc) decrease calcium influx into isolated cardiomyocytes. Increased O-GlcNAc levels also increase tolerance of cells to stress. Therefore, the goal of this study was to test the hypothesis that increasing HBP flux and protein O-GlcNAc levels in the intact heart will increase the tolerance to tissue injury resulting from the calcium paradox and ischemia. We used two strategies that have been shown to increase HBP flux in the intact heart, namely a brief period of streptozotocin-induced diabetes and acute pretreatment of the isolated perfused heart with glucosamine. Isolated perfused rat hearts were exposed to the calcium paradox or to ischemia and reperfusion. Both diabetes and glucosamine significantly improved recovery in the isolated perfused rat heart following the calcium paradox with left ventricular developed pressure (LVDP) returning to ~80% of baseline compared to 0% in controls (P<0.05), and lactate dehydrogenase release being reduced by approximately fivefold (P<0.05). In the diabetic group, azaserine, which inhibits the HBP, restored the sensitivity to the calcium paradox. Glucosamine treatment also improved functional recovery following ischemia/reperfusion (LVDP: 47+/-9% vs. 95+/-4%, P<0.05) and this was associated with a threefold increase in O-GlcNAc levels (P<0.05). Alloxan, an inhibitor of O-GlcNAc-transferase, blocked both the protection seen with glucosamine and the increase in O-GlcNAc. These data demonstrate that activation of the HBP with glucosamine may be a novel strategy for inducing cardioprotection, and that this appears to be mediated by an increase in protein O-GlcNAc levels.
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PMID:Increased hexosamine biosynthesis and protein O-GlcNAc levels associated with myocardial protection against calcium paradox and ischemia. 1633 59

Glucosamine is a popular nutritional supplement used to treat osteoarthritis. Intravenous administration of glucosamine causes insulin resistance and endothelial dysfunction. However, rigorous clinical studies evaluating the safety of oral glucosamine with respect to metabolic and cardiovascular pathophysiology are lacking. Therefore, we conducted a randomized, placebo-controlled, double-blind, crossover trial of oral glucosamine at standard doses (500 mg p.o. t.i.d.) in lean (n = 20) and obese (n = 20) subjects. Glucosamine or placebo treatment for 6 weeks was followed by a 1-week washout and crossover to the other arm. At baseline, and after each treatment period, insulin sensitivity was assessed by hyperinsulinemic-isoglycemic glucose clamp (SI(Clamp)) and endothelial function evaluated by brachial artery blood flow (BAF; Doppler ultrasound) and forearm skeletal muscle microvascular recruitment (ultrasound with microbubble contrast) before and during steady-state hyperinsulinemia. Plasma glucosamine pharmacokinetics after oral dosing were determined in each subject using a high-performance liquid chromatography method. As expected, at baseline, obese subjects had insulin resistance and endothelial dysfunction when compared with lean subjects (SI(Clamp) [median {25th-75th percentile}] = 4.3 [2.9-5.3] vs. 7.3 [5.7-11.3], P < 0.0001; insulin-stimulated changes in BAF [% over basal] = 12 [-6 to 84] vs. 39 [2-108], P < 0.04). When compared with placebo, glucosamine did not cause insulin resistance or endothelial dysfunction in lean subjects or significantly worsen these findings in obese subjects. The half-life of plasma glucosamine after oral dosing was approximately 150 min, with no significant changes in steady-state glucosamine levels detectable after 6 weeks of therapy. We conclude that oral glucosamine at standard doses for 6 weeks does not cause or significantly worsen insulin resistance or endothelial dysfunction in lean or obese subjects.
Diabetes 2006 Nov
PMID:Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects. 1706 54

Glucosamine is one of the most popular dietary supplements sold in the United States. Most clinical trials have focused on its use in osteoarthritis of the knee. The reported adverse effects have been relatively well studied and are generally uncommon and minor. No significant supplement-drug interactions involving glucosamine have been reported. The National Institutes of Health-sponsored Glucosamine/chondroitin Arthritis Intervention Trial, the largest randomized, double-blind, placebo-controlled study involving the supplement, still has not confirmed whether glucosamine is effective in the treatment of osteoarthritis. Despite conflicting results in studies, there is no clear evidence to recommend against its use. If physicians have patients who wish to try glucosamine, it would be reasonable to support a 60-day trial of glucosamine sulfate, especially in those at high risk of secondary effects from other accepted treatments. The decision to continue therapy can then be left to patients on an individual basis, while the physician monitors for possible adverse effects. Glucosamine should be used with caution in patients who have shellfish allergies or asthma, and in those taking diabetes medications or warfarin.
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PMID:Glucosamine. 1875 54

Chitosan has received much attention as a functional biopolymer for diverse applications, especially in pharmaceutics and medicine. Our recent efforts focused on the chemical and biological modification of chitosan in order to increase its solubility in aqueous solutions and absorbability in the in vivo system, thus for a better use of chitosan. This review summarizes chitosan modification and its pharmaceutical/biomedical applications based on our achievements as well as the domestic and overseas developments: (1) enzymatic preparation of low molecular weight chitosans/chitooligosaccharides with their hypocholesterolemic and immuno-modulating effects; (2) the effects of chitin, chitosan and their derivatives on blood hemostasis; and (3) synthesis of a non-toxic ion ligand--D-Glucosaminic acid from oxidation of D-Glucosamine for cancer and diabetes therapy.
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PMID:Chitosan modification and pharmaceutical/biomedical applications. 2071 18

Glucosamine (GlcN) is a widely utilized dietary supplement that is used to promote joint health. Reports that oral GlcN supplementation at usual doses adversely affects glucose metabolism in subjects with impaired glucose tolerance have raised concerns that GlcN should be contraindicated in individuals with diabetes and those at risk for developing it. This review addresses its potential, when used at typical doses, to affect glucose metabolism and insulin sensitivity in healthy individuals and those with diabetes or 'pre-diabetes'. Publicly available scientific information and data on GlcN were systematically compiled using the electronic search tool, Dialog , and reviewed with special emphasis on human studies. In long-term clinical trials, including those containing subjects with type 2 diabetes or 'pre-diabetes', GlcN produced a non-significant lowering of fasting blood glucose concentrations in all groups of subjects treated for periods of up to 3 years. Owing to limitations in study design, conclusions based on studies that report adverse affects of GlcN on insulin sensitivity and glucose tolerance in pre-diabetic subjects are suspect. However, no definitive long-term studies of GlcN use for individuals with pre-diabetes are available. Nevertheless, based on available evidence, we conclude that GlcN has no effect on fasting blood glucose levels, glucose metabolism, or insulin sensitivity at any oral dose level in healthy subjects, individuals with diabetes, or those with impaired glucose tolerance.
Diabetes Metab Res Rev 2011 Jan
PMID:A comprehensive review of oral glucosamine use and effects on glucose metabolism in normal and diabetic individuals. 2137 Mar 82

Glucosamine-6-phosphate (GlcN-6-P) synthase catalyses the first and practically irreversible step in hexosamine metabolism. The final product of this pathway, uridine 5' diphospho N-acetyl-D-glucosamine (UDP-GlcNAc), is an essential substrate for assembly of bacterial and fungal cell walls. Moreover, the enzyme is involved in phenomenon of hexosamine induced insulin resistance in type II diabetes, which makes it a potential target for antifungal, antibacterial and antidiabetic therapy. The crystal structure of the isomerase domain of GlcN-6-P synthase from human pathogenic fungus Candida albicans, in complex with UDP-GlcNAc has been solved recently but it has not revealed the molecular mechanism of inhibition taking place under UDP-GlcNAc influence, the unique feature of the eukaryotic enzyme. UDP-GlcNAc is a physiological inhibitor of GlcN-6-P synthase, binding about 1 nm away from the active site of the enzyme. In the present work, comparative molecular dynamics simulations of the free and UDP-GlcNAc-bounded structures of GlcN-6-P synthase have been performed. The aim was to complete static X-ray structural data and detect possible changes in the dynamics of the two structures. Results of the simulation studies demonstrated higher mobility of the free structure when compared to the liganded one. Several amino acid residues were identified, flexibility of which is strongly affected upon UDP-GlcNAc binding. Importantly, the most fixed residues are those related to the inhibitor binding process and to the catalytic reaction. The obtained results constitute an important step toward understanding of mechanism of GlcN-6-P synthase inhibition by UDP-GlcNAc molecule.
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PMID:Long range molecular dynamics study of regulation of eukaryotic glucosamine-6-phosphate synthase activity by UDP-GlcNAc. 2136 Jan 86


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