The Experts below are selected from a list of 90 Experts worldwide ranked by ideXlab platform
Ad R M M Hermus - One of the best experts on this subject based on the ideXlab platform.
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role of Hexosamines in insulin resistance and nutrient sensing in human adipose and muscle tissue
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, C G J Sweep, Frank C Huvers, J A Lutterman, Ad R M M HermusAbstract:It has been proposed that the hexosamine pathway acts as a nutrient-sensing pathway, protecting the cell against abundant fuel supply, and that accumulation of Hexosamines represents a biochemical mechanism by which hyperglycemia and hyperlipidemia induce insulin resistance. We hypothesized that if an increased flux through the hexosamine pathway caused insulin resistance in humans, the hexosamine levels should be increased in adipose and/or muscle tissue in insulin-resistant subjects, such as patients with type 2 diabetes and obese individuals. In addition, we reasoned that if the hexosamine pathway were a nutrient-sensing pathway, hexosamine levels in adipose and skeletal muscle tissue should be correlated with levels of circulating nutrients, such as glucose and free fatty acids (FFAs) and leptin concentrations. In a human cross-sectional study of 55 patients [20 with type 2 diabetes mellitus (DM) and 21 normal-lean (NL) and 14 normal-obese (NO) subjects] who underwent hip replacement surgery, adipose ...
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Hexosamines are unlikely to function as a nutrient sensor in 3t3 l1 adipocytes a comparison of udp hexosamine levels after increased glucose flux and glucosamine treatment
Endocrine, 2004Co-Authors: Remko R Bosch, Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, Ad R M M Hermus, C G J SweepAbstract:Whether the hexosamine biosynthesis pathway acts as a nutrient-sensing pathway is still unclear. Glucose is directed into this pathway by GFAT. Because the activity of GFAT is tightly regulated, we examined whether UDP-hexosamine levels can increase significantly and dose-dependently in response to elevated glucose concentrations. In glucosamine-treated 3T3-L1 adipocytes, inhibition of insulin-stimulated glucose uptake was highly correlated with UDP-hexosamine levels (r=−0.992; p<0.0001 for UDP-GlcNAc and r=−0.996; p<0.0001 for UDP-GalNAc). Incubation of 3T3-L1 adipocytes with 0.1 µM insulin for 24 h in medium containing 1 and 5 mM glucose increased the rate of glucose uptake by 365% and 175% compared to untreated cells, respectively. This increase was not observed when the cells were incubated for 24 h with insulin in medium containing 10 or 25 mM glucose. However, treatment of cells with insulin and 1, 5, 10, or 25 mM glucose resulted in similar increases in levels of UDP-GlcNAc and UDP-GalNAc that always amounted to approx 30–40% above baseline values. This led us to conclude that despite exposure of adipocytes to conditions of extreme and prolonged glucose disposal, the increases in cellular UDP-Hexosamines were minimal and not dependent on the extracellular glucose concentration. Taken together, our results are in line with the hypothesis that in glucosamine-treated adipocytes UDP-Hexosamines influence insulin-stimulated glucose uptake. However, our observations in glucose-treated adipocytes argue against the possibility that UDP-Hexosamines function as a nutrient-sensor, and question the role of the hexosamine biosynthesis pathway in the pathogenesis of insulin resistance.
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Hexosamines are unlikely to function as a nutrient-sensor in 3T3-L1 adipocytes: a comparison of UDP-hexosamine levels after increased glucose flux and glucosamine treatment.
Endocrine, 2004Co-Authors: Remko R Bosch, Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, Ad R M M Hermus, C G J SweepAbstract:Whether the hexosamine biosynthesis pathway acts as a nutrient-sensing pathway is still unclear. Glucose is directed into this pathway by GFAT. Because the activity of GFAT is tightly regulated, we examined whether UDP-hexosamine levels can increase significantly and dose-dependently in response to elevated glucose concentrations. In glucosamine-treated 3T3-L1 adipocytes, inhibition of insulin-stimulated glucose uptake was highly correlated with UDP-hexosamine levels (r=−0.992; p
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muscle uridine diphosphate Hexosamines do not decrease despite correction of hyperglycemia induced insulin resistance in type 2 diabetes
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, C G J Sweep, J A Lutterman, Baziel G M Van Engelen, Jan G De Jong, Ad R M M HermusAbstract:Animal studies suggest that overactivity of the hexosamine pathway, resulting in increased UDP-Hexosamines [UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine (UDP-GalNAc)] is an important mechanism by which hyperglycemia causes insulin resistance. This study was performed to test this hypothesis in patients with type 2 diabetes mellitus (DM). Eight obese patients with uncontrolled DM type 2 and severe insulin resistance were treated with iv insulin for 28 ± 6 d aimed at euglycemia. Before and after iv insulin treatment, insulin sensitivity was measured using a hyperinsulinemic euglycemic clamp, and a muscle biopsy was taken for measurement of UDP-GlcNAc, UDP-GalNAc, UDP-glucose, and UDP-galactose levels. Also, isoelectric focusing patterns of serum transferrin and the urinary excretion of glycosaminoglycans as measures of final products of the hexosamine pathway were examined. After euglycemia, insulin resistance improved, as demonstrated by an increase in the glucose infusion rate during...
C G J Sweep - One of the best experts on this subject based on the ideXlab platform.
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role of Hexosamines in insulin resistance and nutrient sensing in human adipose and muscle tissue
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, C G J Sweep, Frank C Huvers, J A Lutterman, Ad R M M HermusAbstract:It has been proposed that the hexosamine pathway acts as a nutrient-sensing pathway, protecting the cell against abundant fuel supply, and that accumulation of Hexosamines represents a biochemical mechanism by which hyperglycemia and hyperlipidemia induce insulin resistance. We hypothesized that if an increased flux through the hexosamine pathway caused insulin resistance in humans, the hexosamine levels should be increased in adipose and/or muscle tissue in insulin-resistant subjects, such as patients with type 2 diabetes and obese individuals. In addition, we reasoned that if the hexosamine pathway were a nutrient-sensing pathway, hexosamine levels in adipose and skeletal muscle tissue should be correlated with levels of circulating nutrients, such as glucose and free fatty acids (FFAs) and leptin concentrations. In a human cross-sectional study of 55 patients [20 with type 2 diabetes mellitus (DM) and 21 normal-lean (NL) and 14 normal-obese (NO) subjects] who underwent hip replacement surgery, adipose ...
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Hexosamines are unlikely to function as a nutrient sensor in 3t3 l1 adipocytes a comparison of udp hexosamine levels after increased glucose flux and glucosamine treatment
Endocrine, 2004Co-Authors: Remko R Bosch, Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, Ad R M M Hermus, C G J SweepAbstract:Whether the hexosamine biosynthesis pathway acts as a nutrient-sensing pathway is still unclear. Glucose is directed into this pathway by GFAT. Because the activity of GFAT is tightly regulated, we examined whether UDP-hexosamine levels can increase significantly and dose-dependently in response to elevated glucose concentrations. In glucosamine-treated 3T3-L1 adipocytes, inhibition of insulin-stimulated glucose uptake was highly correlated with UDP-hexosamine levels (r=−0.992; p<0.0001 for UDP-GlcNAc and r=−0.996; p<0.0001 for UDP-GalNAc). Incubation of 3T3-L1 adipocytes with 0.1 µM insulin for 24 h in medium containing 1 and 5 mM glucose increased the rate of glucose uptake by 365% and 175% compared to untreated cells, respectively. This increase was not observed when the cells were incubated for 24 h with insulin in medium containing 10 or 25 mM glucose. However, treatment of cells with insulin and 1, 5, 10, or 25 mM glucose resulted in similar increases in levels of UDP-GlcNAc and UDP-GalNAc that always amounted to approx 30–40% above baseline values. This led us to conclude that despite exposure of adipocytes to conditions of extreme and prolonged glucose disposal, the increases in cellular UDP-Hexosamines were minimal and not dependent on the extracellular glucose concentration. Taken together, our results are in line with the hypothesis that in glucosamine-treated adipocytes UDP-Hexosamines influence insulin-stimulated glucose uptake. However, our observations in glucose-treated adipocytes argue against the possibility that UDP-Hexosamines function as a nutrient-sensor, and question the role of the hexosamine biosynthesis pathway in the pathogenesis of insulin resistance.
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Hexosamines are unlikely to function as a nutrient-sensor in 3T3-L1 adipocytes: a comparison of UDP-hexosamine levels after increased glucose flux and glucosamine treatment.
Endocrine, 2004Co-Authors: Remko R Bosch, Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, Ad R M M Hermus, C G J SweepAbstract:Whether the hexosamine biosynthesis pathway acts as a nutrient-sensing pathway is still unclear. Glucose is directed into this pathway by GFAT. Because the activity of GFAT is tightly regulated, we examined whether UDP-hexosamine levels can increase significantly and dose-dependently in response to elevated glucose concentrations. In glucosamine-treated 3T3-L1 adipocytes, inhibition of insulin-stimulated glucose uptake was highly correlated with UDP-hexosamine levels (r=−0.992; p
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muscle uridine diphosphate Hexosamines do not decrease despite correction of hyperglycemia induced insulin resistance in type 2 diabetes
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, C G J Sweep, J A Lutterman, Baziel G M Van Engelen, Jan G De Jong, Ad R M M HermusAbstract:Animal studies suggest that overactivity of the hexosamine pathway, resulting in increased UDP-Hexosamines [UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine (UDP-GalNAc)] is an important mechanism by which hyperglycemia causes insulin resistance. This study was performed to test this hypothesis in patients with type 2 diabetes mellitus (DM). Eight obese patients with uncontrolled DM type 2 and severe insulin resistance were treated with iv insulin for 28 ± 6 d aimed at euglycemia. Before and after iv insulin treatment, insulin sensitivity was measured using a hyperinsulinemic euglycemic clamp, and a muscle biopsy was taken for measurement of UDP-GlcNAc, UDP-GalNAc, UDP-glucose, and UDP-galactose levels. Also, isoelectric focusing patterns of serum transferrin and the urinary excretion of glycosaminoglycans as measures of final products of the hexosamine pathway were examined. After euglycemia, insulin resistance improved, as demonstrated by an increase in the glucose infusion rate during...
Mariejose J Pouwels - One of the best experts on this subject based on the ideXlab platform.
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role of Hexosamines in insulin resistance and nutrient sensing in human adipose and muscle tissue
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, C G J Sweep, Frank C Huvers, J A Lutterman, Ad R M M HermusAbstract:It has been proposed that the hexosamine pathway acts as a nutrient-sensing pathway, protecting the cell against abundant fuel supply, and that accumulation of Hexosamines represents a biochemical mechanism by which hyperglycemia and hyperlipidemia induce insulin resistance. We hypothesized that if an increased flux through the hexosamine pathway caused insulin resistance in humans, the hexosamine levels should be increased in adipose and/or muscle tissue in insulin-resistant subjects, such as patients with type 2 diabetes and obese individuals. In addition, we reasoned that if the hexosamine pathway were a nutrient-sensing pathway, hexosamine levels in adipose and skeletal muscle tissue should be correlated with levels of circulating nutrients, such as glucose and free fatty acids (FFAs) and leptin concentrations. In a human cross-sectional study of 55 patients [20 with type 2 diabetes mellitus (DM) and 21 normal-lean (NL) and 14 normal-obese (NO) subjects] who underwent hip replacement surgery, adipose ...
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Hexosamines are unlikely to function as a nutrient sensor in 3t3 l1 adipocytes a comparison of udp hexosamine levels after increased glucose flux and glucosamine treatment
Endocrine, 2004Co-Authors: Remko R Bosch, Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, Ad R M M Hermus, C G J SweepAbstract:Whether the hexosamine biosynthesis pathway acts as a nutrient-sensing pathway is still unclear. Glucose is directed into this pathway by GFAT. Because the activity of GFAT is tightly regulated, we examined whether UDP-hexosamine levels can increase significantly and dose-dependently in response to elevated glucose concentrations. In glucosamine-treated 3T3-L1 adipocytes, inhibition of insulin-stimulated glucose uptake was highly correlated with UDP-hexosamine levels (r=−0.992; p<0.0001 for UDP-GlcNAc and r=−0.996; p<0.0001 for UDP-GalNAc). Incubation of 3T3-L1 adipocytes with 0.1 µM insulin for 24 h in medium containing 1 and 5 mM glucose increased the rate of glucose uptake by 365% and 175% compared to untreated cells, respectively. This increase was not observed when the cells were incubated for 24 h with insulin in medium containing 10 or 25 mM glucose. However, treatment of cells with insulin and 1, 5, 10, or 25 mM glucose resulted in similar increases in levels of UDP-GlcNAc and UDP-GalNAc that always amounted to approx 30–40% above baseline values. This led us to conclude that despite exposure of adipocytes to conditions of extreme and prolonged glucose disposal, the increases in cellular UDP-Hexosamines were minimal and not dependent on the extracellular glucose concentration. Taken together, our results are in line with the hypothesis that in glucosamine-treated adipocytes UDP-Hexosamines influence insulin-stimulated glucose uptake. However, our observations in glucose-treated adipocytes argue against the possibility that UDP-Hexosamines function as a nutrient-sensor, and question the role of the hexosamine biosynthesis pathway in the pathogenesis of insulin resistance.
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Hexosamines are unlikely to function as a nutrient-sensor in 3T3-L1 adipocytes: a comparison of UDP-hexosamine levels after increased glucose flux and glucosamine treatment.
Endocrine, 2004Co-Authors: Remko R Bosch, Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, Ad R M M Hermus, C G J SweepAbstract:Whether the hexosamine biosynthesis pathway acts as a nutrient-sensing pathway is still unclear. Glucose is directed into this pathway by GFAT. Because the activity of GFAT is tightly regulated, we examined whether UDP-hexosamine levels can increase significantly and dose-dependently in response to elevated glucose concentrations. In glucosamine-treated 3T3-L1 adipocytes, inhibition of insulin-stimulated glucose uptake was highly correlated with UDP-hexosamine levels (r=−0.992; p
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muscle uridine diphosphate Hexosamines do not decrease despite correction of hyperglycemia induced insulin resistance in type 2 diabetes
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, C G J Sweep, J A Lutterman, Baziel G M Van Engelen, Jan G De Jong, Ad R M M HermusAbstract:Animal studies suggest that overactivity of the hexosamine pathway, resulting in increased UDP-Hexosamines [UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine (UDP-GalNAc)] is an important mechanism by which hyperglycemia causes insulin resistance. This study was performed to test this hypothesis in patients with type 2 diabetes mellitus (DM). Eight obese patients with uncontrolled DM type 2 and severe insulin resistance were treated with iv insulin for 28 ± 6 d aimed at euglycemia. Before and after iv insulin treatment, insulin sensitivity was measured using a hyperinsulinemic euglycemic clamp, and a muscle biopsy was taken for measurement of UDP-GlcNAc, UDP-GalNAc, UDP-glucose, and UDP-galactose levels. Also, isoelectric focusing patterns of serum transferrin and the urinary excretion of glycosaminoglycans as measures of final products of the hexosamine pathway were examined. After euglycemia, insulin resistance improved, as demonstrated by an increase in the glucose infusion rate during...
Donald A Mcclain - One of the best experts on this subject based on the ideXlab platform.
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Hexosamines regulate sensitivity of glucose stimulated insulin secretion in β cells
American Journal of Physiology-endocrinology and Metabolism, 2006Co-Authors: Robert C Cooksey, Sumitha Pusuluri, Mark Hazel, Donald A McclainAbstract:Hexosamines serve a nutrient-sensing function through enzymatic O-glycosylation of proteins. We previously characterized transgenic (Tg) mice with overexpression of the rate-limiting enzyme in hexosamine production, glutamine:fructose-6-phosphate amidotransferase, in β-cells. Animals were hyperinsulinemic, resulting in peripheral insulin resistance. Glucose tolerance deteriorated with age, and males developed diabetes. We therefore examined islet function in these mice by perifusion in vitro. Young (2-mo-old) Tg animals had enhanced sensitivity to glucose of insulin secretion. Insulin secretion was maximal at 20 mM and half maximal at 9.9 ± 0.5 mM glucose in Tg islets compared with maximal at 30 mM and half maximal at 13.5 ± 0.7 mM glucose in wild type (WT; P < 0.005). Young Tg animals secreted more insulin in response to 20 mM glucose (Tg, 1,254 ± 311; WT, 425 ± 231 pg·islet−1·35 min−1; P < 0.01). Islets from older (8-mo-old) Tg mice became desensitized to glucose, with half-maximal secretion at 16.1 ± 0...
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Hexosamines as mediators of nutrient sensing and regulation in diabetes
Journal of Diabetes and Its Complications, 2002Co-Authors: Donald A McclainAbstract:Abstract High concentrations of glucose induce insulin resistance, impair insulin secretion, and affect hepatic glucose production in a manner that mirrors Type 2 diabetes, and Hexosamines mimic many of these effects. This has led to the hypothesis that cells use hexosamine flux as a glucose- and satiety-sensing pathway. The hexosamine hypothesis for glucose sensing has been validated by overexpressing the rate-limiting enzyme for hexosamine synthesis, glutamine: fructose-6-phosphate amidotransferase (GFA) in several tissues including muscle, liver, fat, and beta cells. With overexpression of GFA in transgenic animals, skeletal muscle becomes insulin resistant, the liver synthesizes excess fatty acid, and the beta cell secretes excess insulin leading to hyperinsulinemia. Thus, excess hexosamine flux leads to a coordinated response whereby fuel is shunted toward long-term storage, mirroring the “thrifty phenotype.” Chronically, however, these same adaptive changes result ultimately in obesity, hyperlipidemia, beta cell failure, and Type 2 diabetes. These results suggest a mechanism by which chronic overnutrition leads to the phenotype of Type 2 diabetes.
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Hexosamines as mediators of nutrient sensing relevance to obesity insulin resistance and diabetes
Current Opinion in Endocrinology & Diabetes, 2001Co-Authors: Donald A McclainAbstract:High concentrations of glucose induce insulin resistance, impair insulin secretion, and affect hepatic glucose production in a manner that mirrors type 2 diabetes. High concentrations of Hexosamines mimic many of these effects. This has led to the hypothesis that cells use hexosamine flux as a glucose-and satiety-sensing pathway. The hexosamine hypothesis for glucose sensing has been validated in several model systems. For example, with overexpression of the rate-limiting enzyme for hexosamine synthesis in transgenic mice, skeletal muscle becomes insulin resistant, the liver synthesizes excess fatty acid, and the β cells increase insulin secretion. Thus, excess hexosamine flux leads to a coordinated response whereby fuel is shunted toward long-term storage, mirroring the thrifty phenotype. However when these same adaptive changes occur chronically, they ultimately result in obesity, hyperlipidemia, β-cell failure, and type 2 diabetes. Recent work indicates that these effects may be the result of enzymatic O-linked glycosylation of proteins and that this glycosylation is regulated by the levels of the end-product of the hexosamine pathway, UDP-N-acetyl glucosamine. The results suggest a mechanism by which chronic overnutrition leads to the phenotype of type 2 diabetes.
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Hexosamines stimulate leptin production in transgenic mice
Endocrinology, 2000Co-Authors: Donald A Mcclain, Thomas Alexander, Robert C Cooksey, Robert V ConsidineAbstract:ABSTRACT Hexosamine flux has been shown to mediate aspects of nutrient sensing in insulin sensitive tissues and has been hypothesized to represent a satiety signal that results in shunting of fuel toward storage as fat. It has been recently reported that in vitro treatment of fat and muscle cells with Hexosamines and acute glucosamine infusion in intact rats stimulate leptin secretin. In order to investigate the effects of chronic, physiologic increases in hexosamine flux on leptin we have examined leptin mRNA and serum leptin in mice overexpressing the rate-limiting enzyme for hexosamine synthesis, GFA, in muscle and fat. Increased levels of UDP-N-acetylglucosamine, the principal end-product of the hexosamine pathway were seen in transgenic fat, consistent with the overexpression of GFA. After overnight fasting, the transgenic mice were hyperleptinemic compared to littermate controls (4.5 ± 0.5 ng/ml in transgenic, 2.8 ± 0.2 in control, p = 0.005) despite equal body weights. In the random-fed state, the ...
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Hexosamines and insulin resistance
Diabetes, 1996Co-Authors: Donald A Mcclain, Errol D CrookAbstract:Glucose is an important regulator of cell growth and metabolism. Thus, it is likely that some of the adverse effects of hyperglycemia are reflections of normal regulation by abnormal concentrations of glucose. How the cell senses glucose, however, is still incompletely understood. Evidence has been presented that the hexosamine biosynthesis pathway serves this function for regulation of aspects of glucose uptake, glycogen synthesis, glycolysis, and synthesis of growth factors. Excess hexosamine flux causes insulin resistance in cultured cells, tissues, and intact animals. Further evidence for the possible role of this pathway in normal glucose homeostasis and disease is that the level of activity of the rate-limiting enzyme in hexosamine synthesis, glutamine:fructose-6-phosphate amidotransferase, is correlated with glucose disposal rates (GDRs) in normal humans and transgenic mice.
Paul N Span - One of the best experts on this subject based on the ideXlab platform.
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role of Hexosamines in insulin resistance and nutrient sensing in human adipose and muscle tissue
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, C G J Sweep, Frank C Huvers, J A Lutterman, Ad R M M HermusAbstract:It has been proposed that the hexosamine pathway acts as a nutrient-sensing pathway, protecting the cell against abundant fuel supply, and that accumulation of Hexosamines represents a biochemical mechanism by which hyperglycemia and hyperlipidemia induce insulin resistance. We hypothesized that if an increased flux through the hexosamine pathway caused insulin resistance in humans, the hexosamine levels should be increased in adipose and/or muscle tissue in insulin-resistant subjects, such as patients with type 2 diabetes and obese individuals. In addition, we reasoned that if the hexosamine pathway were a nutrient-sensing pathway, hexosamine levels in adipose and skeletal muscle tissue should be correlated with levels of circulating nutrients, such as glucose and free fatty acids (FFAs) and leptin concentrations. In a human cross-sectional study of 55 patients [20 with type 2 diabetes mellitus (DM) and 21 normal-lean (NL) and 14 normal-obese (NO) subjects] who underwent hip replacement surgery, adipose ...
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Hexosamines are unlikely to function as a nutrient sensor in 3t3 l1 adipocytes a comparison of udp hexosamine levels after increased glucose flux and glucosamine treatment
Endocrine, 2004Co-Authors: Remko R Bosch, Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, Ad R M M Hermus, C G J SweepAbstract:Whether the hexosamine biosynthesis pathway acts as a nutrient-sensing pathway is still unclear. Glucose is directed into this pathway by GFAT. Because the activity of GFAT is tightly regulated, we examined whether UDP-hexosamine levels can increase significantly and dose-dependently in response to elevated glucose concentrations. In glucosamine-treated 3T3-L1 adipocytes, inhibition of insulin-stimulated glucose uptake was highly correlated with UDP-hexosamine levels (r=−0.992; p<0.0001 for UDP-GlcNAc and r=−0.996; p<0.0001 for UDP-GalNAc). Incubation of 3T3-L1 adipocytes with 0.1 µM insulin for 24 h in medium containing 1 and 5 mM glucose increased the rate of glucose uptake by 365% and 175% compared to untreated cells, respectively. This increase was not observed when the cells were incubated for 24 h with insulin in medium containing 10 or 25 mM glucose. However, treatment of cells with insulin and 1, 5, 10, or 25 mM glucose resulted in similar increases in levels of UDP-GlcNAc and UDP-GalNAc that always amounted to approx 30–40% above baseline values. This led us to conclude that despite exposure of adipocytes to conditions of extreme and prolonged glucose disposal, the increases in cellular UDP-Hexosamines were minimal and not dependent on the extracellular glucose concentration. Taken together, our results are in line with the hypothesis that in glucosamine-treated adipocytes UDP-Hexosamines influence insulin-stimulated glucose uptake. However, our observations in glucose-treated adipocytes argue against the possibility that UDP-Hexosamines function as a nutrient-sensor, and question the role of the hexosamine biosynthesis pathway in the pathogenesis of insulin resistance.
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Hexosamines are unlikely to function as a nutrient-sensor in 3T3-L1 adipocytes: a comparison of UDP-hexosamine levels after increased glucose flux and glucosamine treatment.
Endocrine, 2004Co-Authors: Remko R Bosch, Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, Ad R M M Hermus, C G J SweepAbstract:Whether the hexosamine biosynthesis pathway acts as a nutrient-sensing pathway is still unclear. Glucose is directed into this pathway by GFAT. Because the activity of GFAT is tightly regulated, we examined whether UDP-hexosamine levels can increase significantly and dose-dependently in response to elevated glucose concentrations. In glucosamine-treated 3T3-L1 adipocytes, inhibition of insulin-stimulated glucose uptake was highly correlated with UDP-hexosamine levels (r=−0.992; p
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muscle uridine diphosphate Hexosamines do not decrease despite correction of hyperglycemia induced insulin resistance in type 2 diabetes
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Mariejose J Pouwels, Paul N Span, Andre J Olthaar, Cees J Tack, C G J Sweep, J A Lutterman, Baziel G M Van Engelen, Jan G De Jong, Ad R M M HermusAbstract:Animal studies suggest that overactivity of the hexosamine pathway, resulting in increased UDP-Hexosamines [UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine (UDP-GalNAc)] is an important mechanism by which hyperglycemia causes insulin resistance. This study was performed to test this hypothesis in patients with type 2 diabetes mellitus (DM). Eight obese patients with uncontrolled DM type 2 and severe insulin resistance were treated with iv insulin for 28 ± 6 d aimed at euglycemia. Before and after iv insulin treatment, insulin sensitivity was measured using a hyperinsulinemic euglycemic clamp, and a muscle biopsy was taken for measurement of UDP-GlcNAc, UDP-GalNAc, UDP-glucose, and UDP-galactose levels. Also, isoelectric focusing patterns of serum transferrin and the urinary excretion of glycosaminoglycans as measures of final products of the hexosamine pathway were examined. After euglycemia, insulin resistance improved, as demonstrated by an increase in the glucose infusion rate during...