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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes is a major independent risk factor for cardiovascular disease and stroke; however, the molecular and cellular mechanisms by which diabetes contributes to the development of vascular disease are not fully understood. Our previous studies demonstrated that endoplasmic reticulum (ER) stress-inducing agents, including homocysteine, promote lipid accumulation and activate inflammatory pathways-the hallmark features of atherosclerosis. We hypothesize that the accumulation of intracellular glucosamine observed in diabetes may also promote atherogenesis via a mechanism that involves ER stress. In support of this theory, we demonstrate that glucosamine can induce ER stress in cell types relevant to the development of atherosclerosis, including human aortic smooth muscle cells, monocytes, and hepatocytes. Furthermore, we show that glucosamine-induced ER stress dysregulates lipid metabolism, leading to the accumulation of cholesterol in cultured cells. To examine the relevance of the ER stress pathway in vivo, we used a streptozotocin-induced hyperglycemic apolipoprotein E-deficient mouse model of atherosclerosis. Using molecular biological and histological techniques, we show that hyperglycemia is associated with tissue-specific ER stress, hepatic steatosis, and accelerated atherosclerosis. This novel mechanism may not only explain how diabetes and hyperglycemia promote atherosclerosis, but also provide a potential new target for therapeutic intervention.
Diabetes 2006 Jan
PMID:Glucosamine-induced endoplasmic reticulum dysfunction is associated with accelerated atherosclerosis in a hyperglycemic mouse model. 1638 Apr 81

The dysregulation of the metabolism of glycosaminoglycan and protein components of extracellular matrix (ECM) is a typical feature of diabetic complications. High glucose-induced enrichment of ECM with hyaluronan (HA) not only affects tissue structural integrity, but influences cell metabolic response due to the variety of effects depending on the HA polymer molecular weight. TSP-1-dependent activation of TGFbeta1 axis is known to mediate numerous matrix disorders in diabetes, but its role concerning HA has not been studied so far. In this work we demonstrated that 30 mM D-glucose increased the incorporation of [(3)H]glucosamine in high-molecular-weight (> 2000 kDa) HA of medium and matrix compartments of human mesangial cultures. Simultaneously, the synthesis of HA with lower molecular weight and HA degradation were not altered. The cause of the increased high-molecular-weight HA synthesis consisted in the up-regulation of hyaluronan synthase (HAS) 2 mRNA without alterations of the expression of HAS3, which generates HA of lower molecular weight. D-Glucose at 30 mM also stimulated the production of transforming growth factor beta1 (TGFbeta1), the excessive activation of which was determined by the up-regulation of thrombospondin-1 (TSP-1). The blockage of TGFbeta1 action either by neutralizing anti-TGFbeta1 antibodies or by quenching the TGFbeta1 activation (with TSP-1-derived synthetic GGWSHW peptide) abolished the effect of high glucose on HAS2 mRNA expression and normalized the synthesis of HA. Exogenous human TGFbeta1 had the same effect on HAS2 expression and HA synthesis as high glucose treatment. Therefore, we supposed that TSP-1-dependent TGFbeta1 activation is involved in the observed high glucose effect on HA metabolism. Since high-molecular-weight HA polymers, unlike middle- and low-molecular weight HA oligosaccharides, are known to possess anti-inflammatory and anti-fibrotic functions, we suppose that the enrichment of mesangial matrix with high-molecular-weight HA may represent an endogenous mechanism to limit renal injury in diabetes.
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PMID:Elevated level of ambient glucose stimulates the synthesis of high-molecular-weight hyaluronic acid by human mesangial cells. The involvement of transforming growth factor beta1 and its activation by thrombospondin-1. 1673 56

Recent decades have seen a significant increase in the incidence of diabetes mellitus. The number of individuals with diabetes is projected to reach 300 million by the year 2025. Diabetes is a leading cause of blindness, renal failure, lower limb amputation, and an independent risk factor for atherosclerotic cardiovascular disease (CVD)--a leading cause of death in Western society. Understanding the molecular and cellular mechanisms by which diabetes mellitus promotes atherosclerosis is essential to developing methods to treat and prevent diabetes-associated CVD. This review summarizes our current knowledge of the mechanisms by which diabetes may promote atherogenesis and specifically focuses on a novel pathway linking these 2 conditions. We hypothesize that the accumulation of intracellular glucosamine observed in conditions of chronic hyperglycaemia may promote atherogenesis via a mechanism involving dysregulated protein folding, activation of endoplasmic reticulum (ER) stress, and increased glycogen synthase kinase (GSK)-3 activity. The identification of this novel mechanism provides a promising hypothesis and multiple new targets for potential therapeutic intervention in the treatment of diabetes mellitus and accelerated atherosclerosis.
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PMID:Mechanisms linking diabetes mellitus to the development of atherosclerosis: a role for endoplasmic reticulum stress and glycogen synthase kinase-3. 1684 89

We have previously shown that one of the potential mediators of the deleterious effects of high glucose on extracellular matrix protein (ECM) expression in renal mesangial cells is its metabolic flux through the hexosamine biosynthesis pathway (HBP). Here, we investigate further whether the hexosamines induce oxidative stress, cell-cycle arrest and ECM expression using SV-40-transformed rat mesangial (MES) cells and whether the anti-oxidant alpha-lipoic acid will reverse some of these effects. Culturing renal MES cells with high glucose (HG, 25 mM) or glucosamine (GlcN, 1.5 mM) for 48 h stimulates laminin gamma1 subunit expression significantly approximately 1.5 +/- 0.2- and 1.9 +/- 0.3-fold, respectively, when compared to low glucose (LG, 5 mM). Similarly, HG and GlcN increase the level of G0/G1 cell-cycle progression factor cyclin D1 significantly approximately 1.7 +/- 0.2- and 1.4 +/- 0.04-fold, respectively, versus LG (p < 0.01 for both). Azaserine, an inhibitor of glutamine:fruc-6-PO(4) amidotransferase (GFAT) in the HBP, blocks the HG-induced expression of laminin gamma1 and cyclin D1, but not GlcN's effect because it exerts its metabolic function distal to GFAT. HG and GlcN also elevate reactive oxygen species (ROS) generation, pro-apoptotic caspase-3 activity, and lead to mesangial cell death as revealed by TUNEL and Live/Dead assays. FACS analysis of cell-cycle progression shows that the cells are arrested at G1 phase; however, they undergo cell growth and hypertrophy as the RNA/DNA ratio is significantly (p < 0.05) increased in HG or GlcN-treated cells relative to LG. The anti-oxidant alpha-lipoic acid (150 microM) reverses ROS generation and mesangial cell death induced by HG and GlcN. Alpha-lipoic acid also reduces HG and GlcN-induced laminin gamma1 and cyclin D1 expression in MES cells. In addition, induction of diabetes in rats by streptozotocin (STZ) increases both laminin gamma1 and cyclin D1 expression in the renal cortex and treatment of the diabetic rats with alpha-lipoic acid (400 mg kg(-1) body weight) reduces the level of both proteins significantly (p < 0.05) when compared to untreated diabetic rats. These results support the hypothesis that the hexosamine pathway mediates mesangial cell oxidative stress, ECM expression and apoptosis. Anti-oxidant alpha-lipoic acid reverses the effects of high glucose, hexosamine and diabetes on oxidative stress and ECM expression in mesangial cells and rat kidney.
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PMID:Hexosamine induction of oxidative stress, hypertrophy and laminin expression in renal mesangial cells: effect of the anti-oxidant alpha-lipoic acid. 1689 52

There is growing recognition that the O-linked attachment of N-acetyl-glucosamine (O-GlcNAc) on serine and threonine residues of nuclear and cytoplasmic proteins is a highly dynamic post-translational modification that plays a key role in signal transduction pathways. Numerous proteins have been identified as targets of O-GlcNAc modifications including kinases, phosphatases, transcription factors, metabolic enzymes, chaperons, and cytoskeletal proteins. Modulation of O-GlcNAc levels has been shown to modify DNA binding, enzyme activity, protein-protein interactions, the half-life of proteins, and subcellular localization. The level of O-GlcNAc is regulated in part by the metabolism of glucose via the hexosamine biosynthesis pathway (HBP), and the metabolic abnormalities associated with insulin resistance and diabetes, such as hyperglycemia, hyperlipidemia, and hyperinsulinemia, are all associated with increased flux through the HBP and elevated O-GlcNAc levels. Increased HBP flux and O-GlcNAc levels have been implicated in the impaired relaxation of isolated cardiomyocytes, blunted response to angiotensin II and phenylephrine, hyperglycemia-induced cardiomyocyte apoptosis, and endothelial and vascular cell dysfunction. In contrast to these adverse effects, recent studies have also shown that O-GlcNAc levels increase in response to acute stress and that this is associated with increased cell survival. Thus, while the relationship between O-GlcNAc levels and cellular function is complex and not well-understood, it is clear that these pathways play a critical role in the regulation of cell function and survival in the cardiovascular system and may be implicated in the adverse effects of metabolic disease on the heart.
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PMID:Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system. 1697 Sep 29

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

beta-O-N-Acetyl-d-glucosamine (O-GlcNAc) is a dynamic carbohydrate modification that is involved in cell signaling and has been implicated in a variety of disease states, including Alzheimer's and type-II diabetes. Despite the importance of this modification, little is known about the spatial and temporal localization of O-GlcNAc during signaling. This is due to the lack of methods for the study of O-GlcNAc in living cell systems. Herein we report the first genetically encoded FRET-based sensor for the detection of O-GlcNAc dynamics in live mammalian cells.
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PMID:A cellular FRET-based sensor for beta-O-GlcNAc, a dynamic carbohydrate modification involved in signaling. 1710 62

Dysregulated sphingolipid metabolism causes neuronal cell death and is associated with insulin resistance and diseases. Thus, we hypothesized that diabetes-induced changes in retinal sphingolipid metabolism may contribute to neuronal pathologies in diabetic retinopathy. ESI-MS/MS was used to measure ceramide content and ceramide metabolites in whole retinas after 2, 4, and 8 weeks of streptozotocin-induced diabetes. After 4 and 8 weeks of diabetes, a approximately 30% decrease in total ceramide content was observed, concomitant with a significant approximately 30% increase in glucosylceramide levels in fed diabetic rats compared with their age-matched controls. Acute insulin therapy as well as a short-term lowering of glucose via fasting did not affect the increase in glucosylceramide composition. To assess the putative biological consequences of the increase in glucosylceramide composition, R28 retinal neurons were treated with glucosylceramide synthase inhibitors. Inhibiting glycosphingolipid metabolism increased insulin sensitivity in retinal neurons. Glycosphingolipid inhibitors augmented insulin-stimulated p70 S6kinase activity in the presence of inhibitory concentrations of high glucose or glucosamine. Inhibition of glycosphingolipid synthesis also suppressed glucosamine- and interleukin-1beta-induced death. Consistent with these inhibitor studies, pharmacological accumulation of glycosphingolipids increased activation of the endoplasmic reticulum stress response, a putative modulator of insulin resistance and neuronal apoptosis. It is speculated that an increase in glucosylceramide, and possibly higher-order glycosphingolipids, could contribute to the pathogenesis of diabetic retinopathy by contributing to local insulin resistance, resulting in neuronal cell death. Thus, dysfunctional glycosphingolipid metabolism may contribute to metabolic stress in diabetes, and therapeutic strategies to restore normal sphingolipid metabolism may be a viable approach for treatment of diabetic retinopathy.
Diabetes 2006 Dec
PMID:Diabetes alters sphingolipid metabolism in the retina: a potential mechanism of cell death in diabetic retinopathy. 1713 May 6

Despite theoretical risks based on animal models given high intravenous doses, glucosamine/chondroitin (1500 mg/1200 mg daily) does not adversely affect short-term glycemic control for patients whose diabetes is well-controlled, or for those without diabetes or glucose intolerance (SOR: A, consistent, good-quality patient-oriented evidence). Some preliminary evidence suggests that glucosamine may worsen glucose intolerance for patients with untreated or undiagnosed glucose intolerance or diabetes (SOR: C, extrapolation from disease-oriented evidence). Long-term effects are unknown; however, no compelling theoretical or incidental data suggest that long-term results should be different (SOR: C, expert opinion). Further studies are required to clarify the effects of glucosamine on patients with poorly controlled diabetes or glucose intolerance.
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PMID:Clinical inquiries: Do glucosamine and chondroitin worsen blood sugar control in diabetes? 1747 62

Peroxisome proliferator activator receptor-gamma coactivator 1 (PGC-1) is a major candidate gene for diabetes-related metabolic phenotypes, contributing to decreased expression of nuclear-encoded mitochondrial genes in muscle and adipose tissue. We have demonstrated that muscle expression of PGC-1alpha and -beta is reduced in both genetic (Lep(ob)/Lep(ob)) and acquired obesity (high fat diet). In C57BL6 mice, muscle PGC-1alpha expression decreased by 43% (p < 0.02) after 1 week of a high fat diet and persisted more than 11 weeks. In contrast, PGC-1alpha reductions were not sustained in obesity-resistant A/J mice. To identify mediators of obesity-linked reductions in PGC-1, we tested the effects of cellular nutrients in C2C12 myotubes. Although overnight exposure to high insulin, glucose, glucosamine, or amino acids had no effect, saturated fatty acids potently reduced PGC-1alpha and -beta mRNA expression. Palmitate decreased PGC-1alpha and -beta expression by 38% (p = 0.01) and 53% (p = 0.006); stearate similarly decreased expression of PGC-1alpha and -beta by 22% (p = 0.02) and 39% (p = 0.02). These effects were mediated at a transcriptional level, as indicated by an 11-fold reduction of PGC-1alpha promoter activity by palmitate and reversal of effects by histone deacetylase inhibition. Palmitate also (a) reduced expression of tricarboxylic acid cycle and oxidative phosphorylation mitochondrial genes and (b) reduced oxygen consumption. These effects were reversed by overexpression of PGC-1alpha or -beta, indicating PGC-1 dependence. Palmitate effects also required p38 MAPK, as demonstrated by 1) palmitate-induced increase in p38 MAPK phosphorylation, 2) reversal of palmitate effects on PGC-1 and mitochondrial gene expression by p38 MAPK inhibitors, and 3) reversal of palmitate effects by small interfering RNA-mediated decreases in p38alpha MAPK. These data indicate that obesity and saturated fatty acids decrease PGC-1 and mitochondrial gene expression and function via p38 MAPK-dependent transcriptional pathways.
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PMID:Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation. 1741 3


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