Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nephropathy is a serious microvascular complication of diabetes mellitus which is preceded by a period of microalbuminura. Increased loss of proteoglycan (PG) from glomerular basement (GBM) has been postulated to alter glomerular charge selectivity which contributes to urinary loss of albumin. In this study we measured the excretion of urinary glycosaminoglycans (GAG), the degradation products of PG, in 82 non-insulin-dependent (NIDDM) (Type 2) diabetic and 34 non-diabetic subjects. We found that diabetic subjects had a significantly higher GAG urinary excretion rate compared to non-diabetic subjects (12.54 +/- 5.67 vs 8.80 +/- 3.99 micrograms glucuronic acid min-1, p = 0.0001). Categorizing for albuminuric status shows that the diabetic normo-, micro- and macroalbuminuric groups have a higher GAG excretion rate than non-diabetic subjects. Heparan sulphate (HS) GAG urinary excretion was measured in 25 samples from diabetic subjects and 18 non-diabetic subjects. Diabetic subjects excreted more HS GAG than controls both as a rate or as a percentage of total GAG (3.70 +/- 1.94 vs 2.38 +/- 1.48 micrograms glucosamine min-1, p = 0.02; 31.6% +/- 12.5 vs 23.1% +/- 10.4, p = 0.02). Categorizing for albuminuric status shows that micro- and macro-albuminuric groups have a significantly higher HS GAG excretion rate than non-diabetic subjects. We conclude that, as in IDDM, excretion of GAG and HS GAG is higher in NIDDM and may precede the development of microalbuminuria.
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PMID:Urinary glycosaminoglycan excretion in NIDDM subjects: its relationship to albuminura. 886 53

Hyperglycemia can lead directly to a secondary state of insulin resistance or can worsen a preexisting insulin-resistant state. Troglitazone is an orally active hypoglycemic agent that has been shown to ameliorate insulin resistance and hyperinsulinemia in both diabetic animal models and NIDDM subjects. To determine whether this drug could prevent the development of hyperglycemia-induced insulin resistance and to investigate the mechanism by which this might occur, we studied troglitazone's effect on insulin action in rats made hyperglycemic or infused with glucosamine. Normal male SD rats were fed regular powdered diet with or without troglitazone as a food admixture (0.2%). After 2 weeks, rats were made hyperglycemic with glucose (52 mg x kg(-1) x min[-1]) and somatostatin (0.8 microg x kg(-1) x min[-1]) infusion or were infused with glucosamine (6.5 mg x kg(-1) x min[-1]) for 6.5 h. In vivo insulin action was measured by the hyperinsulinemic-euglycemic clamp technique at a submaximal (24 pmol x kg(-1) x min[-1]) or maximal (240 pmol x kg(-1) x min[-1]) insulin infusion rate. The infusion of glucose and somatostatin caused a pronounced rise in the plasma glucose concentration (19.8 +/- 0.6 mmol/l) compared with saline-infused animals (8.0 +/- 0.2 mmol/l; P < 0.001). Hyperglycemia resulted in insulin resistance, as evidenced by a marked reduction in the submaximal glucose disposal rate (GDR) (78 +/- 7 vs. 135 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) and maximal GDR (141 +/- 9 vs. 237 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) compared with the control group. Troglitazone treatment largely prevented the hyperglycemia-induced decline in submaximal (116 +/- 7 micromol x kg(-1) x min[-1]) and maximal GDR (209 +/- 9 micromol x kg(-1) x min(-1); P < 0.05). Glucosamine infusion also resulted in a marked reduction in the submaximal GDR (85 +/- 3 vs. 135 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) and maximal GDR (137 +/- 14 vs. 237 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) compared with the control group. In contrast to the results in the hyperglycemic animals, troglitazone treatment had no effect on glucosamine-induced insulin resistance. In summary, 1) in normal rats, experimental hyperglycemia, as well as glucosamine infusion, led to a marked state of peripheral and hepatic insulin resistance; 2) troglitazone treatment prevented the hyperglycemia-induced, but not the glucosamine-induced, insulin resistance; and 3) either troglitazone acts at one or more sites proximal to the entry of glucosamine into the hexosamine pathway, or the increased flux of glucose-derived products through the hexosamine pathway is not a major mechanism for the hyperglycemia-induced defect in insulin action in these animals.
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PMID:Troglitazone prevents hyperglycemia-induced but not glucosamine-induced insulin resistance. 951 45

Streptozotocin has been widely used to create animal models of diabetes. Structurally, streptozotocin resembles N-acetylglucosamine, with a nitrosourea group corresponding to the acetate present in N-acetylglucosamine. Streptozotocin has recently been shown to inhibit O-GlcNAc-selective N-acetyl-beta-d-glucosaminidase, which removes O-linked N-acetylglucosamine from proteins. Compared to other cells, beta-cells express much more of the enzyme O-GlcNAc transferase, which catalyzes addition of O-linked N-acetylglucosamine to proteins. This suggests why beta-cells might be particularly sensitive to streptozotocin. In this report, we demonstrate that both streptozotocin and glucose stimulate O-glycosylation of a 135 kD beta-cell protein. Only the effect of glucose, however, was blocked by inhibition of fructose-6-phosphate amidotransferase, suggesting that glucose acts through the glucosamine pathway to provide UDP-N-acetylglucosamine for p135 O-glycosylation. The fact that both glucose and streptozotocin stimulate p135 O-glycosylation provides a possible mechanism by which hyperglycemia may cause streptozotocin-like effects in beta-cells and thus contribute to the development of type 2 diabetes.
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PMID:Glucose and streptozotocin stimulate p135 O-glycosylation in pancreatic islets. 1062 69

The pancreatic beta cell can respond in the long term to hyperglycemia both with an increased capacity for insulin production and, in susceptible individuals, with apoptosis. When glucose-induced apoptosis offsets the increasing beta cell capacity, type 2 diabetes results. Here, we tested the idea that the pathway of glucose metabolism that leads to the modification of intracellular proteins with the O-linked monosaccharide N-acetylglucosamine (O-GlcNAc) is involved in the glucose-induced apoptosis. This idea is based on two recent observations. First, the beta cell expresses much more O-GlcNAc transferase than any other known cell, and second, that the beta cell-specific toxin, streptozotocin (STZ), itself a GlcNAc analog, specifically blocks the enzyme that cleaves O-GlcNAc from intracellular proteins. As a consequence, we now show that hyperglycemia leads to the rapid and reversible accumulation of O-GlcNAc specifically in beta cells in vivo. Animals pretreated with STZ also accumulate O-GlcNAc in their beta cells when hyperglycemic, but this change is sustained upon re-establishment of euglycemia. In concert with the idea that STZ toxicity results from the sustained accumulation of O-GlcNAc after a hyperglycemic episode, we established a low-dose STZ protocol in which the beta cells' toxicity of STZ was manifest only after glucose or glucosamine administration. Transgenic mice with impaired beta cell glucosamine synthesis treated with this protocol are resistant to the diabetogenic effect of STZ plus glucose yet succumb to STZ plus glucosamine. This study provides a causal link between apoptosis in beta cells and glucose metabolism through glucosamine to O-GlcNAc, implicating this pathway of glucose metabolism with beta cell glucose toxicity.
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PMID:Glucose stimulates protein modification by O-linked GlcNAc in pancreatic beta cells: linkage of O-linked GlcNAc to beta cell death. 1071

Elevated plasma angiotensinogen (AGT) levels have been demonstrated in insulin-resistant states such as obesity and type 2 diabetes mellitus (DM2), conditions that are directly correlated to hypertension. We examined whether hyperinsulinemia or hyperglycemia may modulate fat and liver AGT gene expression and whether obesity and insulin resistance are associated with abnormal AGT regulation. In addition, because the hexosamine biosynthetic pathway is considered to function as a biochemical sensor of intracellular nutrient availability, we hypothesized that activation of this pathway would acutely mediate in vivo the induction of AGT gene expression in fat and liver. We studied chronically catheterized lean (approximately 300 g) and obese (approximately 450 g) Sprague-Dawley rats in four clamp studies (n = 3/group), creating physiological hyperinsulinemia (approximately 60 microU/ml, by an insulin clamp), hyperglycemia (approximately 18 mM, by a pancreatic clamp using somatostatin to prevent endogenous insulin secretion), or euglycemia with glucosamine infusion (GlcN; 30 micromol. kg(-1). min(-1)) and equivalent saline infusions (as a control). Although insulin infusion suppressed AGT gene expression in fat and liver of lean rats, the obese rats demonstrated resistance to this effect of insulin. In contrast, hyperglycemia at basal insulin levels activated AGT gene expression in fat and liver by approximately threefold in both lean and obese rats (P < 0.001). Finally, GlcN infusion simulated the effects of hyperglycemia on fat and liver AGT gene expression (2-fold increase, P < 0.001). Our results support the hypothesis that physiological nutrient "pulses" may acutely induce AGT gene expression in both adipose tissue and liver through the activation of the hexosamine biosynthetic pathway. Resistance to the suppressive effect of insulin on AGT expression in obese rats may potentiate the effect of nutrients on AGT gene expression. We propose that increased AGT gene expression and possibly its production may provide another link between obesity/insulin resistance and hypertension.
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PMID:Hyperglycemia modulates angiotensinogen gene expression. 1150 94

This review summarizes the state of knowledge on D-glucosamine-6P synthesis catalyzed by glucosamine-6P synthase. The mechanisms of L-glutamine hydrolysis, ammonia transfer and fructose-6P conversion into D-glucosamine-6P are analyzed with the E. coli enzyme in light of recent X-ray structures. With 92 references this paper covers the literature up to June 2001 and emphasizes the potential implication of the mammalian glucosamine-6P synthase in type 2 diabetes.
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PMID:From Lobry de Bruyn to enzyme-catalyzed ammonia channelling: molecular studies of D-glucosamine-6P synthase. 1190 40

Chronic lipid exposure is implicated in beta-cell dysfunction in type 2 diabetes. We therefore used oligonucleotide arrays to define global alterations in gene expression in MIN6 cells after 48-h pretreatment with oleate or palmitate. Altogether, 126 genes were altered > or =1.9-fold by palmitate, 62 by oleate, and 46 by both lipids. Importantly, nine of the palmitate-regulated genes are known to be correspondingly changed in models of type 2 diabetes. A tendency toward beta-cell de-differentiation was also apparent with palmitate: pyruvate carboxylase and mitochondrial glycerol 3-phosphate dehydrogenase were downregulated, whereas lactate dehydrogenase and fructose 1,6-bisphosphatases were induced. Increases in the latter (also seen with oleate), along with glucosamine-phosphate N-acetyl transferase, imply upregulation of the hexosamine biosynthesis pathway in palmitate-treated cells. However, palmitate also increased expression of calcyclin and 25-kDa synaptosomal-associated protein (SNAP25), which control distal secretory processes. Consistent with these findings, secretory responses to noncarbohydrate stimuli, especially palmitate itself, were upregulated in palmitate-treated cells (much less so with oleate). Indeed, glucose-stimulated secretion was slightly sensitized by chronic palmitate exposure but inhibited by oleate treatment, whereas both lipids enhanced basal secretion. Oleate and palmitate also induced expression of chemokines (MCP-1 and GRO1 oncogene) and genes of the acute phase response (serum amyloid A3). Increases in transcriptional modulators such as ATF3, CCAAT/enhancer binding protein-beta (C/EBPbeta), C/EBPdelta, and c-fos were also seen. The results highlight links between regulated gene expression and phenotypic alterations in palmitate versus oleate-pretreated beta-cells.
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PMID:Expression profiling of palmitate- and oleate-regulated genes provides novel insights into the effects of chronic lipid exposure on pancreatic beta-cell function. 2194

Type 2 diabetes mellitus results from a complex interaction between nutritional excess and multiple genes. Whereas pancreatic beta-cells normally respond to glucose challenge by rapid insulin release (first phase insulin secretion), there is a loss of this acute response in virtually all of the type 2 diabetes patients with significant fasting hyperglycemia. Our previous studies demonstrated that irreversible intracellular accumulation of a glucose metabolite, protein O-linked N-acetylglucosamine modification (O-GlcNAc), is associated with pancreatic beta-cell apoptosis. In the present study, we show that streptozotocin (STZ), a non-competitive chemical blocker of O-GlcNAcase, induces an insulin secretory defect in isolated rat islet cells. In contrast, transgenic mice with down-regulated glucose to glucosamine metabolism in beta-cells exhibited an enhanced insulin secretion capacity. Interestingly, the STZ blockade of O-GlcNAcase activity is also associated with a growth hormone secretory defect and impairment of intracellular secretory vesicle trafficking. These results provide evidence for the roles of O-GlcNAc in the insulin secretion and possible involvement of O-GlcNAc in general glucose-regulated hormone secretion pathways.
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PMID:Streptozotocin, an O-GlcNAcase inhibitor, blunts insulin and growth hormone secretion. 1224 36

Many studies suggest that insulin resistance develops and/or is maintained by an increased flux of glucose through the hexosamine biosynthesis pathway. This pathway may attenuate insulin-stimulated glucose uptake by activating protein kinase C (PKC). Therefore, we investigated whether the concentrations of the major hexosamine metabolites, uridine diphosphate- N-acetyl-glucosamine (UDP-GlcNAc) and uridine diphosphate- N-acetyl-galactosamine (UDP-GalNAc), and the expression levels of PKC isoforms were affected in Zucker Diabetic Fatty (ZDF) rats, an animal model widely used to study type 2 diabetes mellitus. At the age of 6 wk, control and ZDF rats were normoglycemic. Whereas control rats remained normoglycemic, the ZDF rats became hyperglycemic. The amount of UDP-GlcNAc and UDP-GalNAc in muscle tissue of ZDF rats was similar at 6, 12, 18, and 24 wk of age. Moreover, the concentration of both hexosamines did not differ among ZDF, phlorizin-treated ZDF, and control rats. Western blot analysis revealed that PKCalpha, delta, epsilon, andzeta, but not PKCbeta and gamma, were expressed in muscle and fat tissues from 6- and 24-wk-old control and ZDF rats. In addition, we did not observe changes in the expression levels of the PKC isoforms following prolonged hyperglycemia. Taken together, these findings indicate that the amounts of several metabolites from the hexosamine biosynthesis pathway and PKC isoforms, both hypothesized to be important in the development and/or maintenance of the insulin-resistant state of muscle and fat tissue, are not different in ZDF compared with nondiabetic rats.
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PMID:Exploring levels of hexosamine biosynthesis pathway intermediates and protein kinase C isoforms in muscle and fat tissue of Zucker Diabetic Fatty rats. 1272 3

Recent epidemiological studies suggest that alcohol consumption is one of the risk factors leading to type 2 diabetes, but the direct effect of ethanol on beta-cell gene expression is not known. Here, using cDNA RDA method, we isolated 43 ethanol-induced genes in pancreatic beta-cells, and confirmed their differential expression by Northern blot or semi-quantitative RT-PCR. These genes were further categorized by the functional criteria based on the published data; Translation, Transcription, Metabolism, Signal transduction, Transport, Structure, Cytoskeleton, Regulation, or Putative/Unknown genes. The effects of each gene on beta-cell function need to be further investigated, however, the present data strongly suggest that these genes might be related to the metabolic alterations caused by ethanol as indicated in earlier study. In particular, RPS3 gene expression was increased by ethanol, glucosamine, and cytokines, implying that ethanol might decrease the metabolic activity by oxidative stress in beta-cells. Therefore, cloning of these genes in full-length and the detailed studies of each gene on beta-cell functions might provide clues on the pathophysiology of type 2 diabetes caused by alcohol.
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PMID:Isolation of ethanol-induced genes in pancreatic beta-cells by representational difference analysis (RDA). 1503 69


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