Effects of diabetes and hyperglycemia on the hexosamine synthesis pathway in rat muscle and liver

Robinson, Katherine A.; Weinstein, Mara; Lindenmayer, George E.; Buse, Maria G.

doi:10.2337/diabetes.44.12.1438

Cited by 82 publications

(118 citation statements)

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“…Glycosylation of the transcription factor Sp1 by UDP-GlcNAc leads to increased transcription of acetyl-CoA carboxylase, the rate-limiting enzyme for fatty acid synthesis [30], and a switch to hepatic lipogenesis [4]. Although, in agreement with Robinson et al [7], we did not find an increase of hepatic UDP-GlcNAc in diabetic control subjects, the basal hepatic levels of UDP-GlcNAc may be permissive for de novo lipogenesis with concurrent signalling via sterol regulatory element binding protein-1c and carbohydrate response element binding protein [31]. Suppression of UDP-GlcNAc then decreases Sp1 glycosylation and represses lipogenic enzyme expression.…”

Section: Discussionsupporting

confidence: 78%

“…HDL cholesterol was determined by the L-Type HDL-C assay test kit (Wako, Osaka, Japan). Hepatic UDP-N-acetylglucosamine (UDP-GlcNAc, nmol/g wet weight) was determined by anion exchange HPLC with spectrophotometric detection [7] and FAS activity was determined spectrophotometrically by measuring the malonyl-CoA-and acetyl-CoA-dependent oxidation of NADPH as described [8].…”

Section: Plasma Cholesterol Hdl Cholesterol Triglycerides Udp-n-acmentioning

confidence: 99%

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High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats

et al. 2004

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Aims/hypothesis. Cardiovascular disease in diabetes is linked to increased risk of atherosclerosis, increased levels of triglyceride-rich lipoproteins and enhanced hepatic lipogenesis. The hepatic hexosamine pathway has been implicated in signalling for de novo lipogenesis by the liver. In this study, we assessed if decrease of flux through the hexosamine pathway induced by high-dose thiamine therapy counters diabetic dyslipidaemia. Methods. The model of diabetes used was the streptozotocin-induced diabetic rat with maintenance insulin therapy. Normal control and diabetic rats were studied for 24 weeks with and without oral high-dose therapy (7 and 70 mg/kg) with thiamine and benfotiamine. Plasma total cholesterol, HDL cholesterol and triglycerides were determined at 6-week intervals and hepatic metabolites and transketolase activity after death of the rats at 24 weeks.Results. We found that thiamine therapy (70 mg/kg) prevented diabetes-induced increases in plasma cholesterol and triglycerides in diabetic rats but did not reverse the diabetes-induced decrease of HDL. This was achieved by prevention of thiamine depletion and decreased transketolase activity in the liver of diabetic rats. There was a concomitant decrease in hepatic UDP-N-acetylglucosamine and fatty acid synthase activity. Thiamine also normalised food intake of diabetic rats. A lower dose of thiamine (7 mg/kg) and the thiamine monophosphate prodrug benfotiamine (7 and 70 mg/kg) were ineffective. Conclusions/interpretation. High-dose thiamine therapy prevented diabetic dyslipidaemia in experimental diabetes probably by suppression of food intake and hexosamine pathway signalling but other factors may also be involved. Benfotiamine was ineffective.Keywords Cholesterol · Dyslipidaemia · Glycation · Hexosamine · Streptozotocin · Thiamine · Triglycerides Abbreviations: 1,3-bis-PG, 1,3-bisphosphoglycerate · ACC, acetyl-CoA carboxylase · CEL, N ε -(1-carboxyethyl)lysine · CML, N ε -carboxymethyl-lysine · CTEP, cholesteryl ester transfer protein · DAG, diacylglycerol · DHAP, dihydroxyacetonephosphate · F-1,6-bis-P, fructose-1,6-bis-phosphate · FAS, fatty acid synthase · FL, N ε -fructosyl-

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Section: Discussionsupporting

confidence: 78%

Section: Plasma Cholesterol Hdl Cholesterol Triglycerides Udp-n-acmentioning

confidence: 99%

High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats

et al. 2004

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“…Enhanced flux through the hexosamine biosynthesis pathway has been implicated as a contributor to the pathogenesis of insulin resistance (17)(18)(19)(20)(21)56) and, more recently, to the pathogenesis of diabetic nephropathy (25). These effects on cell function may involve alterations in gene expression.…”

Section: Discussionmentioning

confidence: 99%

Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells.

2000

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Increased flux through the hexosamine biosynthetic pathway is associated with altered gene expression. To investigate the underlying mechanisms, we treated glomerular mesangial cells with glucosamine and studied the regulation of the plasminogen activator inhibitor (PAI)-1 gene. Incubating mesangial cells with 2 mmol/l glucosamine for 4 days resulted in a 3.1 ± 0.4-fold increase in PAI-1 mRNA levels (P < 0.01) and a 33 ± 9-fold increase in the activity of a transiently transfected PAI-1 promoter-luciferase reporter gene (P < 0.01). Cotransfection of an expression vector for a dominant-negative type II TGF-␤ receptor with the PAI-1 promoter-reporter gene did not interfere with this effect of glucosamine. However, mutation of 2 putative Sp1 sites in the PAI-1 promoter, at -76 to -71 and -44 to -39, markedly reduced induction of PAI-1 luciferase activity by glucosamine, from 8.9 ± 1.9-fold to 1.7 ± 0.5-fold (P < 0.01). An electrophoretic mobility shift assay demonstrated that glucosamine increased Sp1 DNA binding by 31 ± 11% (P < 0.05), implying that the effects of glucosamine were explained, in part, by changes in Sp1 DNA binding. High glucose (20 mmol/l) also activated the transiently transfected PAI-1 promoter (2.5 ± 0.4-fold). This effect was diminished by mutation of both the PAI-1 promoter Sp1 sites (1.2 ± 0.3-fold, P < 0.05). In addition, 6-diazo-5-oxo-L-norleucine, a glutamine:fructose-6-phosphateamidotransferase inhibitor, blocked the induction by high glucose (4.7 ± 0.8-to 0.9 ± 0.1-fold, P < 0.01). These results indicate that stimulation of the PAI-1 promoter by both high glucose and glucosamine involves Sp1 and that the hexosamine pathway may be involved in the regulation of gene expression by high glucose in glomerular mesangial cells. Diabetes 49:863-871, 2000

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“…Others have also shown that incubation of multiple insulin-sensitive rat and human tissues with glucosamine to generate increased concentrations of UDP-Gl c NA c induces insulin resistance [16,17,18,19,20]. Streptozotocin-induced diabetes and sustained hyperglycaemia in normal rats also increase total UDP-hexosamine content in muscle tissue [21].…”

mentioning

confidence: 99%

Dietary fatty acid composition during pregnancy and lactation in the rat programs growth and glucose metabolism in the offspring

et al. 2002

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Aims/hypothesis. We investigated of the effects of fatty acid composition of the maternal diet on fetal and postnatal growth, morphology of the pancreas and glucose metabolism and muscle hexosamine concentrations in the adult offspring of rats. Methods. High-fat diets enriched with either saturated or unsaturated fatty acids were fed to female adult rats 2 weeks before mating until the end of the weaning period. After weaning, the offspring was maintained on a diet with a balanced fatty acid content. At 3 months of age, pancreatic Langerhans islet size and number were assessed by morphometric analysis and oral glucose tolerance tests (OGTT) were carried out. Results. The unsaturated fatty acid diet showed lower birth weight and reduced postnatal weight gain. Furthermore, this group showed increased pancreatic islet numbers without affected glucose tolerance at the age of 12 weeks. The offspring of the saturated fatty acid diet group showed a reduced number of large pancreatic islets. Moreover, a faster and higher insulin response was observed after an oral glucose load in these animals. Muscle hexosamine concentrations were not different between groups. Conclusion/interpretation. Maternal diets enriched with either saturated fatty acids or unsaturated fatty acids had opposite effects on pancreatic islet development in rat offspring, with consequences for the insulin response at 12 weeks of age. Therefore, maternal dietary fatty acid composition plays a role in programming growth, pancreatic development and glucose metabolism in the offspring. [Diabetologia (2002[Diabetologia ( ) 45:1397[Diabetologia ( -1403

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Effects of diabetes and hyperglycemia on the hexosamine synthesis pathway in rat muscle and liver

Cited by 82 publications

References 0 publications

High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats

High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats

Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells.

Dietary fatty acid composition during pregnancy and lactation in the rat programs growth and glucose metabolism in the offspring

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