Glucosamine glmn, a product of glucose metabolism via the hexosamine pathway, causes insulin resistance in. To examine whether the hexosamine biosynthetic pathway might play a role in fatinduced insulin resistance, we monitored the effects of prolonged elevations in ffa availability both on skeletal muscle levels of udpnacetyl hexosamines and on peripheral glucose disposal during 7h euglycemichyperinsulinemic approximately 500 microuml clamp studies. As a second approach, we determined whether glucosamine, an agent known to preferentially enter the hexosamine. Infusion of glucosamine, which increases intracellular hexosamine concentrations and thereby flux via the hexosamine pathway, by bypassing the reaction catalyzed by gfa, induces insulin resistance in skeletal muscle of normal rats 8, 9. Muniyappa r, karne rj, hall g, crandon sk, bronstein ja, ver mr, et al. Evidence that increased hexosamine biosynthesis pathway flux. Glucosamine c 6 h no 5 is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. However, glucosamine is a sugar that uses some glucose processing pathways. The role of the hexosamine biosynthetic pathway in diabetic nephropathy. Glucosamine sulphate and osteoarthritis the lancet. Based on our previous finding that desensitization of the insulin responsive glucose transport system gts requires three components, glucose, insulin, and glutamine, we postulated that the routing of incoming glucose through the hexosamine biosynthesis pathway plays a key role in the development of insulin resistance in primary cultured adipocytes. Investigation of the relationship between hexosamine pathway. Trib3 mediates glucoseinduced insulin resistance via a.
Investigation of the relationship between hexosamine pathway and development of type 2 diabetes chronic high concentrations of chronic high concentrations of glucose. Glucosamine6phospate is then metabolized to uridine diphosphatenacetylglucosamine udpglcnac. The hexosamine olinked nacetyl glucosamine pathway. Involvement of hexosamine pathway products in glucoseinduced insulin resistance is supported by three observations. Imhypothesized to be involved in the development of insulin munohistochemical and biochemical studies indicated an resistance and diabetic vascular complications. Hexosamines, insulin resistance and the complications of diabetes.
A role for excess glucose flux via hsp in insulin resistance was first proposed. Evidence coupling increased hexosamine biosynthesis pathway. Furthermore, glucosamine, glcn which enters the hsp bypassing gfat. These data raise the possibility that overactivity of the hexosamine pathway may contribute to glucose toxicity not only in skeletal. May 19, 2001 the underlying mechanism is thought to be related to increased insulin resistance by accelerated hexosamine metabolism through the desensitisation of the insulin responsive glucose transport.
Insulin resistance is a hallmark of type 2 diabetes, of uncontrolled type 1 diabetes, of obesity and the metabolic syndrome and is associated with numerous other conditions, such as cystic fibrosis, uremia, septicemia, glucocorticoid excess, polycystic ovary syndrome, etc. Hyperglycemiainduced downregulation of apolipoprotein m. Research paper hexosamine pathway but not interstitial. Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle. High glucose stimulates angiotensinogen gene expression and cell hypertrophy via activation of the hexosamine biosynthesis pathway in rat kidney proximal tubular cells.
The effect of glucosamine on glucose metabolism in humans. Glucosamine is part of the structure of the polysaccharides, chitosan, and chitin. The propensity to insulin resistance is likely genetically determined 79. Most important, the same degree of insulin resistance can be reproduced in the absence of increased ffa availability by a similar increase in skeletal muscle udpnacetylhexosamines. Clinically, insulin resistance is defined as the reduced ability of insulin to lower plasma glucose, which reflects in. Mar 14, 2016 metabolic reprogramming by hexosamine biosynthetic and golgi nglycan branching pathways. The hexosamine biosynthetic pathway has been derived from an increase in mesangial matrix 25. Glucosamine may be obtained from exogenous supplements, or it may be endogenously synthesized from glucose through the hexosamine pathway, an alternate pathway to glycolysis. Metabolic reprogramming by hexosamine biosynthetic and golgi nglycan branching pathways. The hexosamine biosynthesis pathway hbp is a relatively minor branch of glycolysis. The effect of oral glucosamine sulfate on insulin sensitivity. Identification of a biochemical link between energy intake and energy expenditure. Thus, the hexosamine pathway may contribute to the deterioration of.
Glucosamine induces insulin resistance in vivo byaffecting. It was hypothesized that glmn causes insulin resistance in vivo by a similar. Hypotheses suggest that glucosamine causes insulin resistance by directly entering the hexosamine biosynthetic pathway. Preexposure to glucosamine also induces insulin resistance in isolated rat diaphragms. Activation of the hexosamine pathway by glucosamine in. Its product is uridine 5diphosphatenacetyl glucosamine udpnacetylglun, which is a precursor for glycosaminoglycans, proteoglycans, and glycoproteins. However, there is concern that glucosamine adversely affects glucose metabolism and causes insulin resistance through activation of the hexosamine biosynthetic pathway. Metabolic reprogramming by hexosamine biosynthetic. In conclusion, activation of the hexosamine pathway leads to deterioration of.
Dynamic actions of glucose and glucosamine on hexosamine. May 19, 2016 here, the authors show, using a networkbased approach, that inhibition of the hexosamine biosynthetic pathway is necessary to develop resistance and that increasing the activity of the pathway. Pdf activation of the hexosamine pathway by glucosamine in. In similar experiments, involvement of the hexosamine pathway in. Invitro and animal mainly rat studies demonstrate that glucosamine induces insulin resistance in a variety of tissues including adipose, muscle and liver 5. Hexosamines, insulin resistance and the complications of. Role of the glucosamine pathway in fatinduced insulin. Hexosamines, insulin resistance, and the complications of. Oral glucosamine effect on blood glucose and insulin levels. Hexosamines and insulin resistance request pdf researchgate. Metabolic reprogramming by hexosamine biosynthetic and golgi. Hexosamine pathway contribution to insulin resistance new insights from muscle specific gfat transgenic. It is processed mainly through the hexosamine biosynthetic pathway, which is involved in both glucose transport and the development of insulin resistancethe main cause of type 2 diabetes.
Glucosamineinduced insulin resistance in 3t3l1 adipocytes. Thus, use of glucosamine represents a method to mimic the high glucose effects that are mediated by the hexosamine pathway23. These data suggest that glucose and glucosamine share a common pathway to induce insulin resistance and that increased glucosamine. We hypothesized that there might be a molecular convergence of activated hbp and er stress pathways leading to insulin resistance. Ultimately, this hexosamine pathway in the pancreatic. Hexosamine biosynthetic pathway hbp intl textbook of. Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects. For example, it has been reported that glucosamine can induce insulin resistance by affecting glucose receptor glut4 translocation in skeletal muscle, an effect that may be due to impaired glut4. Pdf activation of the hexosamine pathway by glucosamine in vivo. May 01, 1997 to examine whether the hexosamine biosynthetic pathway might play a role in fatinduced insulin resistance, we monitored the effects of prolonged elevations in ffa availability both on skeletal muscle levels of udpnacetylhexosamines and on peripheral. Many subjects who take glucosamine for osteoarthritis are obese, insulin resistant, diabetic, or at risk for the development of diabetes, and it is established that glucosamine induces insulin resistance in rats and mice.
Role of the glucosamine pathway in fatinduced insulin resistance. One metabolic fate of glucose is the hexosamine biosynthetic pathway hbp, and high flux through this pathway, such as occurs in diabetes or overnutrition, has been convincingly linked to insulin resistance and. To explore potential cellular mechanisms by which activation of the hexosamine pathway induces insulin resistance, we have evaluated insulin signaling in conscious fasted rats infused for 26 h with saline, insulin 18 mu x kg1 x min1, or insulin and glucosamine 30 micromol x kg1 x min1 under euglycemic conditions. Glucoseinduced insulin resistance is a possible consequence of this shift to the hexosamine pathway and the resultant glucose toxicity 129 1. Most important, the same degree of insulin resistance can be reproduced in the absence of increased ffa availability by a similar increase in skeletal muscle udpnacetyl hexosamines. The hexosamine biosynthetic pathway has been hypothesized to be involved in the development of insulin resistance and diabetic vascular complications. Glucosamine may be obtained from exog enous supplements, or it may be endogenously synthesized from glucose through the hexosamine pathway, an alternate pathway to glycolysis. Acute exposure glucosamine glmn, a product of glucose metabolism via the hexosamine pathway, causes insulin resistance in isolated adipocytes by impairing insulin induced glut 4 glucose transporter translocation to the plasma membrane. Role of the hexosamine biosynthetic pathway in diabetic.
Role of the hexosamine biosynthetic pathway in diabetic nephropathy. Inhibition of the hexosamine biosynthetic pathway promotes. Activation of the hexosamine pathway leads to deterioration. Metabolic reprogramming by hexosamine biosynthetic and. Glucosamine induces insulin resistance in vivo by affecting glut 4. In the current study, we investigated the role of tribbles homolog 3 trib3 in glucoseinduced insulin resistance and whether the induction of trib3 by glucose is dependent on the nutrientsensing hexosamine biosynthetic pathway hbp known to mediate glucose toxicity in diabetes. In the present study we also determined apolipoprotein a1 apoa1 as a control gene.
Overexpression of enzymes involved in this pathway have led to high levels of glucose and insulin resistance in animals given huge doses of intravenous glucosamine 100200 times higher than oral therapeutic doses in humans. Pdf activation of the hexosamine pathway by glucosamine. Pdf to explore potential cellular mechanisms by which activation of the hexosamine pathway induces insulin resistance, we have evaluated insulin. Molecular convergence of hexosamine biosynthetic pathway and. Apr 16, 2009 augmentation of hexosamine biosynthetic pathway hbp and endoplasmic reticulum er stress were independently related to be the underlying causes of insulin resistance. Glucosamine is one of the most abundant monosaccharides.
Although high glucose, free fatty acids, and glucosamine glc can all induce insulin resistance, several studies have suggested that the hbp contributes in each. Preexposure to glucosamine also induces insulin resistance in isolated rat diaphragms 10. Augmentation of hbp in l6 skeletal muscle cells either by pharmacological glucosamine or. Activation of the hexosamine pathway by glucosamine in vivo. Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. As a result, the supplements are recommended by many physicians. The outcome of the hexosamine pathway is udpnacetyl glucosamine that. Do glucosamine and chondroitin worsen blood sugar control in. Evidence that increased hexosamine biosynthesis pathway flux generates insulin resistant, cholesterolladen plasma membrane via increasing the activity of key cholesterol transcription factors we have recently found that pe we have recently found that perturbations in plasma membrane pm structure and cytoskeletal defects in insulin sensitive tissues adipose and skeletal muscle have. Sustained hyperglycemia causes insulin resistance in humans 89 and in animal models 67, which leads to the. In particular, it was demonstrated that hyperglycemiainduced production of transforming growth factor. To examine whether the hexosamine biosynthetic pathway might play a role in fatinduced insulin resistance, we monitored the effects of prolonged elevations in ffa availability both on skeletal muscle levels of udpnacetylhexosamines and on peripheral glucose disposal during 7h euglycemichyperinsulinemic approximately 500 microuml clamp studies.
Glucose entry into the hbp is catalyzed by the first and ratelimiting enzyme glutaminefructose6phosphate amidotransferase gfat. To explore potential cellular mechanisms by which activation of the hexosamine pathway induces insulin resistance, we have evaluated insulin signaling in conscious fasted rats infused for 26 h. The hexosamine biosynthetic pathway and insulin resistance. Discovery of a metabolic pathway mediating glucoseinduced. Thus, the incoming glucose is routed through the hexosamine pathway with subsequent phosphorylation of fructose6phosphate to glucosamine 6phosphate by. Request pdf on researchgate hexosamines and insulin resistance glucose.
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