Glucosamine

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Glucosamine- Know the Risks so, as with the other recent threads... here's the list



1.Role of the glucosamine pathway in fat-induced insulin resistance.
J Clin Invest 1997 May 1;99(9):2173-82

2.Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance in multiple insulin sensitive tissues.
Endocrinology 1997 Jun;138(6):2501-7

3.Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle.
Diabetes 1999 Aug;48(8):1562-71

4.Excessive hexosamines block the neuroprotective effect of insulin and induce apoptosis in retinal neurons.
J Biol Chem 2001 Nov 23;276(47):43748-55

5.Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance.
J Biol Chem 1991 Mar 15;266(8):4706-12

6.Pre-exposure to glucosamine induces insulin resistance of glucose transport and glycogen synthesis in isolated rat skeletal muscles. Study of mechanisms in muscle and in rat-1 fibroblasts overexpressing the human insulin receptor.
Diabetes 1993 Sep;42(9):1333-46

7.Glucosamine levels in people with ischaemic heart disease with and without type II diabetes.
Pol Arch Med Wewn 1998 Nov;100(5):419-25

8.Exercise-stimulated glucose turnover in the rat is impaired by glucosamine infusion.
Diabetes 2001 Jan;50(1):139-42

9.Glucose transport by osmotic shock and vanadate is impaired by glucosamine.
Biochem Biophys Res Commun 2002 Mar 29;292(2):308-11

10.Glucosamine regulation of glucose metabolism in cultured human skeletal muscle cells: divergent effects on glucose transport/phosphorylation and glycogen synthase in non-diabetic and type 2 diabetic subjects.
Endocrinology 1999 Sep;140(9):3971-80

11.Effects of glucosamine infusion on insulin secretion and insulin action in humans.
Diabetes 2000 Jun;49(6):926-35

12.Immunosuppressive effects of glucosamine.
J Biol Chem 2002 Oct 18;277(42):39343-9

13.High glucose and glucosamine induce insulin resistance via different mechanisms in 3T3-L1 adipocytes.
Diabetes 2000 Jun;49(6):981-91

14.Glucosamine-induced insulin resistance in 3T3-L1 adipocytes.
Am J Physiol Endocrinol Metab 2000 Jan;278(1):E103-12

15.The role of glucose metabolites in the activation and translocation of glycogen synthase by insulin in 3T3-L1 adipocytes.
J Biol Chem 1999 Sep 24;274(39):27497-504

16.Hexosamines and nutrient excess induce leptin production and leptin receptor activation in pancreatic islets and clonal beta-cells.
Endocrinology 2001 Oct;142(10):4414-9

17.Endothelin-stimulated glucose uptake: effects of intracellular Ca(2+), cAMP and glucosamine.
Clin Sci (Lond) 2002 Aug;103 Suppl 48:418S-423S

18.Glucosamine-induced insulin resistance in 3T3-L1 adipocytes is caused by depletion of intracellular ATP.
J Biol Chem 1998 Aug 7;273(32):20658-68

19.Mechanisms of insulin resistance in non-oxidative glucose metabolism: the role of glycogen synthase.
J Basic Clin Physiol Pharmacol 1998;9(2-4):255-79

20.Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress.
J Biol Chem 2001 Aug 17;276(33):31099-104

 

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1.Role of the glucosamine pathway in fat-induced insulin resistance.

J Clin Invest 1997 May 1;99(9):2173-82

Hawkins M, Barzilai N, Liu R, Hu M, Chen W, Rossetti L.

Division of Endocrinology and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

To examine whether the hexosamine biosynthetic pathway might play a role in fat-induced insulin resistance, we monitored the effects of prolonged elevations in FFA availability both on skeletal muscle levels of UDP-N-acetyl-hexosamines and on peripheral glucose disposal during 7-h euglycemic-hyperinsulinemic (approximately 500 microU/ml) clamp studies. When the insulin-induced decrease in the plasma FFA levels (to approximately 0.3 mM) was prevented by infusion of a lipid emulsion in 15 conscious rats (plasma FFA approximately 1.4 mM), glucose uptake (5-7 h = 32.5+/-1.7 vs 0-2 h = 45.2+/-2.8 mg/kg per min; P < 0.01) and glycogen synthesis (P < 0.01) were markedly decreased. During lipid infusion, muscle UDP-N-acetyl-glucosamine (UDP-GlcNAc) increased by twofold (to 53.4+/-1.1 at 3 h and to 55.5+/-1.1 nmol/gram at 7 h vs 20.4+/-1.7 at 0 h, P < 0.01) while glucose-6-phosphate (Glc-6-P) levels were increased at 3 h (475+/-49 nmol/gram) and decreased at 7 h (133+/-7 vs 337+/-28 nmol/gram at 0 h, P < 0.01). To discern whether such an increase in the skeletal muscle UDP-GlcNAc concentration could account for the development of insulin resistance, we generated similar increases in muscle UDP-GlcNAc using three alternate experimental approaches. Euglycemic clamps were performed after prolonged hyperglycemia (18 mM, n = 10), or increased availability of either glucosamine (3 micromol/kg per min; n = 10) or uridine (30 micromol/kg per min; n = 4). These conditions all resulted in very similar increases in the skeletal muscle UDP-GlcNAc (to approximately 55 nmol/gram) and markedly impaired glucose uptake and glycogen synthesis. Thus, fat-induced insulin resistance is associated with: (a) decreased skeletal muscle Glc-6-P levels indicating defective transport/phosphorylation of glucose; (b) marked accumulation of the endproducts of the hexosamine biosynthetic pathway preceding the onset of insulin resistance. 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 UDP-N-acetyl-hexosamines. In conclusion, our results support the hypothesis that increased FFA availability induces skeletal muscle insulin resistance by increasing the flux of fructose-6-phosphate into the hexosamine pathway.

 

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2.Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance in multiple insulin sensitive tissues.

Endocrinology 1997 Jun;138(6):2501-7

Virkamaki A, Daniels MC, Hamalainen S, Utriainen T, McClain D, Yki-Jarvinen H.

Minerva Foundation Institute for Medical Research, University of Helsinki, Finland. [email protected]

We determined the effect of infusion of glucosamine (GlcN), which bypasses the rate limiting reaction in the hexosamine pathway, on insulin-stimulated rates of glucose uptake and glycogen synthesis in vivo in rat tissues varying with respect to their glutamine:fructose-6-phosphate amidotransferase (GFA) activity. Three groups of conscious fasted rats received 6-h infusions of either saline (BAS), insulin (18 mU/kg x min) and saline (INS), or insulin and GlcN (30 micromol/ kg x min, GLCN). [3-(3)H]glucose was infused to trace whole body glucose kinetics and glycogen synthesis, and rates of tissue glucose uptake were determined using a bolus injection of [1-(14)C]2-deoxyglucose at 315 min. GlcN decreased insulin-stimulated glucose uptake (315-360 min) by 49% (P < 0.001) at the level of the whole body, and by 31-53% (P < 0.05 or less) in the heart, epididymal fat, submandibular gland and in soleus, abdominis and gastrocnemius muscles. GlcN completely abolished glycogen synthesis in the liver. GlcN decreased insulin-stimulated glucose uptake similarly in the submandibular gland (1.3 +/- 0.2 vs. 2.0 +/- 0.3 nmol/mg protein x min, GLCN vs. INS, P < 0.05) and gastrocnemius muscle (1.4 +/- 0.3 vs. 3.1 +/- 0.5 nmol/mg protein x min), although the activity of the hexosamine pathway, as judged from basal GFA activity, was 10-fold higher in the submandibular gland (286 +/- 35 pmol/mg protein x min) than in gastrocnemius muscle (27 +/- 3 pmol/mg protein x min, P < 0.001). These data raise the possibility that overactivity of the hexosamine pathway may contribute to glucose toxicity not only in skeletal muscle but also in other insulin sensitive tissues. They also imply that the magnitude of insulin resistance induced between tissues is determined by factors other than GFA.

 

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3.Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle.

Diabetes 1999 Aug;48(8):1562-71

Patti ME, Virkamaki A, Landaker EJ, Kahn CR, Yki-Jarvinen H.

Research Division, Joslin Diabetes Center, Boston, Massachusetts 02215, USA. [email protected]

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 2-6 h with saline, insulin (18 mU x kg(-1) x min(-1)), or insulin and glucosamine (30 micromol x kg(-1) x min(-1)) under euglycemic conditions. Glucosamine infusion increased muscle UDP-N-acetylglucosamine concentrations 3.9- and 4.3-fold over saline- or insulin-infused animals, respectively (P < 0.001). Glucosamine induced significant insulin resistance to glucose uptake both at the level of the whole body and in rectus abdominis muscle, and it blunted the insulin-induced increase in muscle glycogen content. At a cellular level, these metabolic effects were paralleled by inhibition of postreceptor insulin signaling critical for glucose transport and glycogen storage, including a 45% reduction in insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation (P = 0.02), a 44% decrease in IRS-1 association with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase (P = 0.03), a 34% reduction in IRS-1-associated PI 3-kinase activity (P = 0.03), and a 51% reduction in insulin-stimulated glycogen synthase activity (P = 0.03). These alterations in postreceptor insulin signaling were time-dependent and paralleled closely the progressive inhibition of systemic glucose disposal from 2 to 6 h of glucosamine infusion. We also demonstrated that glucosamine infusion results in O-linked N-acetylglucosamine modification of IRS-1 and IRS-2. These data indicate that activation of the hexosamine pathway may directly modulate early postreceptor insulin signal transduction, perhaps via posttranslation modification of IRS proteins, and thus contribute to the insulin resistance induced by chronic hyperglycemia.

 

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4.Excessive hexosamines block the neuroprotective effect of insulin and induce apoptosis in retinal neurons.

J Biol Chem 2001 Nov 23;276(47):43748-55

Nakamura M, Barber AJ, Antonetti DA, LaNoue KF, Robinson KA, Buse MG, Gardner TW.

Pennsylvania State Retina Research Group, The Ulerich Ophthalmology Research Center, the Department of Ophthalmology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.

In addition to microvascular abnormalities, neuronal apoptosis occurs early in diabetic retinopathy, but the mechanism is unknown. Insulin may act as a neurotrophic factor in the retina via the phosphoinositide 3-kinase/Akt pathway. Excessive glucose flux through the hexosamine biosynthetic pathway (HBP) is implicated in the development of insulin resistance in peripheral tissues and diabetic complications such as nephropathy. We tested whether increased glucose flux through the HBP perturbs insulin action and induces apoptosis in retinal neuronal cells. Exposure of R28 cells, a model of retinal neurons, to 20 mm glucose for 24 h attenuated the ability of 10 nm insulin to rescue them from serum deprivation-induced apoptosis and to phosphorylate Akt compared with 5 mm glucose. Glucosamine not only impaired the neuroprotective effect of insulin but also induced apoptosis in R28 cells in a dose-dependent fashion. UDP-N-acetylhexosamines (UDP-HexNAc), end products of the HBP, were increased approximately 2- and 15-fold after a 24-h incubation in 20 mm glucose and 1.5 mm glucosamine, respectively. Azaserine, a glutamine:fructose-6-phosphate amidotransferase inhibitor, reversed the effect of 20 mm glucose, but not that of 1.5 mm glucosamine, on attenuation of the ability of insulin to promote cell survival and phosphorylate Akt as well as accumulation of UDP-HexNAc. Glucosamine also impaired insulin receptor processing in a dose-dependent manner but did not decrease ATP content. By contrast, in L6 muscle cells, glucosamine impaired insulin receptor processing but did not induce apoptosis. These results suggest that the excessive glucose flux through the HBP may direct retinal neurons to undergo apoptosis in a bimodal fashion; i.e. via perturbation of the neuroprotective effect of insulin mediated by Akt and via induction of apoptosis possibly by altered glycosylation of proteins. The HBP may be involved in retinal neurodegeneration in diabetes.

 

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5.Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance.

J Biol Chem 1991 Mar 15;266(8):4706-12

Marshall S, Bacote V, Traxinger RR.

Department of Biochemistry, University of Tennessee, Memphis 38163.

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. Two approaches were used to test this hypothesis. First, we assessed whether glucose-induced desensitization of the GTS could be prevented by glutamine analogs that irreversibly inactivate glutamine-requiring enzymes, such as glutamine:fructose-6-phosphate amidotransferase (GFAT) the first and the rate-limiting enzyme in hexosamine biosynthesis. Both O-diazoacetyl-L-serine (azaserine) and 6-diazo-5-oxonorleucine inhibited desensitization in 18-h treated cells without affecting maximal insulin responsiveness in control cells. Moreover, close agreement was seen between the ability of azaserine to prevent desensitization of the GTS in intact adipocytes (70% inhibition, ED50 = 1.1 microM), its ability to inactivate GFAT in intact adipocytes (64% inhibition, ED50 = 1.0 microM) and its ability to inactivate GFAT activity in a cytosolic adipocyte preparation (ED50 = 1.3 microM). From these results we concluded that a glutamine amidotransferase is involved in the induction of insulin resistance. As a second approach, we determined whether glucosamine, an agent known to preferentially enter the hexosamine pathway at a point distal to enzymatic amidation by GFAT, could induce cellular insulin resistance. When adipocytes were exposed to various concentrations of glucosamine for 5 h, progressive desensitization of the GTS was observed (ED50 = 0.36 mM) that culminated in a 40-50% loss of insulin responsiveness. Moreover, we estimated that glucosamine is at least 40 times more potent than glucose in mediating desensitization, since glucosamine entered adipocytes at only one-quarter of the glucose uptake rate, yet induced desensitization at an extra-cellular dose 10 times lower than glucose. In addition, we found that glucosamine-induced desensitization did not require glutamine and was unaffected by azaserine treatment. Thus, we conclude that glucosamine enters the hexosamine-desensitization pathway at a point distal to GFAT amidation. Overall, these studies indicate that a unique metabolic pathway exists in adipocytes that mediates desensitization of the insulin-responsive GTS, and reveal that an early step in this pathway involves the conversion of fructose 6-phosphate to glucosamine 6-phosphate by the first and rate-limiting enzyme of the hexosamine pathway, glutamine:fructose-6-phosphate amidotransferase.

 

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6.Pre-exposure to glucosamine induces insulin resistance of glucose transport and glycogen synthesis in isolated rat skeletal muscles. Study of mechanisms in muscle and in rat-1 fibroblasts overexpressing the human insulin receptor.

Diabetes 1993 Sep;42(9):1333-46

Robinson KA, Sens DA, Buse MG.

Department of Medicine, Medical University of South Carolina, Charleston.

Increased routing of glucose through the hexosamine-biosynthetic pathway has been implicated in the development of glucose-induced insulin resistance of glucose transport in cultured adipocytes. Because both glucosamine and glucose enter this pathway as glucosamine-6-phosphate, we examined the effects of preincubation with glucosamine in isolated rat diaphragms and in fibroblasts overexpressing the human insulin receptor (HIR-cells). In muscles, pre-exposure to glucosamine inhibited subsequent basal and, to a greater extent, insulin-stimulated glucose transport in a time- and dose-dependent manner and abolished the stimulation by insulin of glycogen synthesis. Insulin receptor number, activation of the insulin receptor tyrosine kinase in situ and after solubilization, and the total pool of glucose transporters (GLUT4) were unaffected, and glycogen synthase was activated by glucosamine pretreatment. In HIR-cells, which express GLUT1 and not GLUT4, basal and insulin-stimulated glucose transport were unaffected by glucosamine, but glycogen synthesis was markedly inhibited. Insulin-stimulated activation of protein kinases (MAP and S6) was unaffected, and the fractional velocity and apparent total activity of glycogen synthase was increased in glucosamine-treated HIR-cells. In pulse-labeling studies, addition of glucosamine during the chase prolonged processing of insulin proreceptors to receptors and altered the electrophoretic mobility of proreceptors and processed alpha-subunits, consistent with altered glycosylation. Glucosamine-induced insulin resistance of glucose transport appears to be restricted to GLUT4-expressing cells, i.e., skeletal muscle and adipocytes; it may reflect impaired translocation of GLUT4 to the plasmalemma. The glucosamine-induced imbalance in UDP sugars, i.e., increased UDP-N-acetylhexosamines and decreased UDP-glucose, may alter glycosylation of critical proteins and limit the flux of glucose into glycogen.

 

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7.Glucosamine levels in people with ischaemic heart disease with and without type II diabetes.

Pol Arch Med Wewn 1998 Nov;100(5):419-25

Nowak A, Szczesniak L, Rychlewski T, Dylewicz P, Przywarska I.

Chair of Physiology, Biochemistry and Hygiene, University School of Physical Education, Poznan, Poland.

Glucosamine has a major influence on the impairment of some metabolic mechanisms in the human body. As shown in vitro experiments, it takes part in inducing mechanisms of insulin resistance. Therefore, the purpose of our study was to evaluate glucosamine levels in the serum of patients who suffered myocardial infarction (MI) and who either had or didn't have diagnosed type II diabetes in relation to healthy people. The levels of glucosamine, immunoreactive insulin, C-peptide, glucose and lipid indexes were measured in venous blood in investigated patients. In patients with MI without diabetes the highest concentrations of glucosamine, insulin and C-peptide were noted as compared to the results obtained from other groups of patients. In patients with diabetes, on the other hand, the highest glucose levels were noted as compared to the results of other patients. There were no statistically differences of lipid indexes between two groups of patients following MI. A negative correlation between glucosamine levels and glucose concentrations in patients without diabetes may suggest that glucose does not directly determine glucosamine levels. The returning of insulin levels to normal in patients with hyperinsulinemia (antidiabetic drugs) may play a role in the lowering of glucosamine induced peripheral insulin resistance.

 

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8.Exercise-stimulated glucose turnover in the rat is impaired by glucosamine infusion.

Diabetes 2001 Jan;50(1):139-42

Miles PD, Higo K, Olefsky JM.

Department of Surgery, University of California-San Diego, USA. [email protected]

The infusion of glucosamine causes insulin resistance, presumably by entering the hexosamine biosynthetic pathway; it has been proposed that this pathway plays a role in hyperglycemia-induced insulin resistance. This study was undertaken to determine if glucosamine infusion could influence exercise-stimulated glucose uptake. Male SD rats were infused with glucosamine at 0.1 mg x kg(-1) x min(-1) (low-GlcN group), 6.5 mg x kg(-1) x min(-1) (high-GlcN group), or saline (control group) for 6.5 h and exercised on a treadmill for 30 min (17 m/min) at the end of the infusion period. Glucosamine infusion caused a modest increase in basal glycemia in both experimental groups, with no change in tracer-determined basal glucose turnover. During exercise, glucose turnover increased approximately 2.2-fold from 46 +/- 2 to 101 +/- 5 pmol x kg(-1) x min(-1) in the control group. Glucose turnover increased to a lesser extent in the glucosamine groups and was limited to 88% of control in the low-GlcN group (47 +/- 2 to 90 +/- 3 pmol x kg(-1) x min(-1); P < 0.01) and 72% of control in the high-GlcN group (43 +/- 1 to 73 +/- 3 pmol kg(-1) 1 min(-1); P < 0.01). Similarly, the metabolic clearance rate (MCR) in the control group increased 72% from 6.1 +/- 0.2 to 10.5 +/- 0.7 ml kg(-1) x min(-1) in response to exercise. However, the increase in MCR was only 83% of control in the low-GlcN group (5.2 +/- 0.5 to 8.7 +/- 0.5 ml x kg(-1) x min(-1); P < 0.01) and 59% of control in the high-GlcN group (4.5 +/- 0.2 to 6.2 +/- 0.3 ml x kg(-1) x min(-1); P < 0.01). Neither glucosamine infusion nor exercise significantly affected plasma insulin or free fatty acid (FFA) concentrations. In conclusion, the infusion of glucosamine, which is known to cause insulin resistance, also impaired exercise-induced glucose uptake. This inhibition was independent of hyperglycemia and FFA levels.

 

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9.Glucose transport by osmotic shock and vanadate is impaired by glucosamine.

Biochem Biophys Res Commun 2002 Mar 29;292(2):308-11

Heart E, Sung CK.

Department of Physiology and Biophysics, University of Southern California, Los Angeles, California 90089-9142, USA.

In 3T3-L1 adipocytes, we previously reported that glucosamine impairs insulin stimulation of glucose transport, which is accompanied by impaired insulin stimulation of serine/threonine kinase Akt. To examine the role of Akt in glucosamine-induced insulin resistance, we investigated time course for insulin stimulation of Akt activity and glucose transport during recovery from glucosamine-induced insulin resistance. After induction of insulin resistance by glucosamine, we washed cells to remove glucosamine and incubated them for various times. After one hour, insulin stimulated-glucose transport was significantly increased and continued to increase up to 6-24 h. Insulin stimulation of Akt, however, did not increase after 1-3 h and began to slightly increase after 6 h. Next, we investigated effects of osmotic shock and vanadate on glucose transport in glucosamine-treated cells and found that glucosamine completely inhibited their actions in these cells. These data suggest that an Akt-independent mechanism is operative in glucosamine-induced insulin resistance and glucosamine impairs glucose transport stimulated by various stimuli involving and not involving Akt activation. (c)2002 Elsevier Science (USA).

 

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10.Glucosamine regulation of glucose metabolism in cultured human skeletal muscle cells: divergent effects on glucose transport/phosphorylation and glycogen synthase in non-diabetic and type 2 diabetic subjects.

Endocrinology 1999 Sep;140(9):3971-80

Ciaraldi TP, Carter L, Nikoulina S, Mudaliar S, McClain DA, Henry RR.

Department of Medicine, University of California, San Diego, La Jolla 92093, USA.

Chronic exposure (48 h) to glucosamine resulted in a dose-dependent reduction of basal and insulin-stimulated glucose uptake activities in human skeletal muscle cell cultures from nondiabetic and type 2 diabetic subjects. Insulin responsiveness of uptake was also reduced. There was no change in total membrane expression of either GLUT1, GLUT3, or GLUT4 proteins. While glucosamine treatment had no significant effects on hexokinase activity measured in cell extracts, glucose phosphorylation in intact cells was impaired after treatment. Under conditions where glucose transport and phosphorylation were down regulated, the fractional velocity (FV) of glycogen synthase was increased by glucosamine treatment. Neither the total activity nor protein expression of glycogen synthase were influenced by glucosamine treatment. The stimulation of glycogen synthase by glucosamine was not due totally to soluble mediators. Reflective of the effects on transport/phosphorylation, total glycogen content and net glycogen synthesis were reduced after glucosamine treatment. These effects were similar in nondiabetic and type 2 cells. In summary: 1) Chronic treatment with glucosamine reduces glucose transport/phosphorylation and storage into glycogen in skeletal muscle cells in culture and impairs insulin responsiveness as well. 2) Down-regulation of glucose transport/phosphorylation occurs at a posttranslational level of GLUTs. 3) Glycogen synthase activity increases with glucosamine treatment. 4) Nondiabetic and type 2 muscle cells display equal sensitivity and responsiveness to glucosamine. Increased exposure of skeletal muscle to glucosamine, a substrate/precursor of the hexosamine pathway, alters intracellular glucose metabolism at multiple sites and can contribute to insulin resistance in this tissue.

 

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11.Effects of glucosamine infusion on insulin secretion and insulin action in humans.

Diabetes 2000 Jun;49(6):926-35

Monauni T, Zenti MG, Cretti A, Daniels MC, Targher G, Caruso B, Caputo M, McClain D, Del Prato S, Giaccari A, Muggeo M, Bonora E, Bonadonna RC.

Division of Endocrinology and Metabolic Diseases, University of Verona School of Medicine, Italy.

Glucose toxicity (i.e., glucose-induced reduction in insulin secretion and action) may be mediated by an increased flux through the hexosamine-phosphate pathway. Glucosamine (GlcN) is widely used to accelerate the hexosamine pathway flux, independently of glucose. We tested the hypothesis that GlcN can affect insulin secretion and/or action in humans. In 10 healthy subjects, we sequentially performed an intravenous glucose (plus [2-3H]glucose) tolerance test (IVGTT) and a euglycemic insulin clamp during either a saline infusion or a low (1.6 micromol x min(-1) x kg(-1)) or high (5 micromol x min(-1) x kg(-1) [n = 5]) GlcN infusion. Beta-cell secretion, insulin (SI*-IVGTT), and glucose (SG*) action on glucose utilization during the IVGTT were measured according to minimal models of insulin secretion and action. Infusion of GlcN did not affect readily releasable insulin levels, glucose-stimulated insulin secretion (GSIS), or the time constant of secretion, but it increased both the glucose threshold of GSIS (delta approximately 0.5-0.8 mmol/l, P < 0.03-0.01) and plasma fasting glucose levels (delta approximately 0.3-0.5 mmol/l, P < 0.05-0.02). GlcN did not change glucose utilization or intracellular metabolism (glucose oxidation and glucose storage were measured by indirect calorimetry) during the clamp. However, high levels of GlcN caused a decrease in SI*-IVGTT (delta approximately 30%, P < 0.02) and in SG* (delta approximately 40%, P < 0.05). Thus, in humans, acute GlcN infusion recapitulates some metabolic features of human diabetes. It remains to be determined whether acceleration of the hexosamine pathway can cause insulin resistance at euglycemia in humans.

 

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12.Immunosuppressive effects of glucosamine.

J Biol Chem 2002 Oct 18;277(42):39343-9

Ma L, Rudert WA, Harnaha J, Wright M, Machen J, Lakomy R, Qian S, Lu L, Robbins PD, Trucco M, Giannoukakis N.

Department of Surgery, T. E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.

Glucosamine is a naturally occurring derivative of glucose and is an essential component of glycoproteins and proteoglycans, important constituents of many eukaryotic proteins. In cells, glucosamine is produced enzymatically by the amidation of glucose 6-phosphate and can then be further modified by acetylation to result in N-acetylglucosamine. Commercially, glucosamine is sold over-the-counter to relieve arthritis. Although there is evidence in favor of the beneficial effects of glucosamine, the mechanism is unknown. Our data demonstrate that glucosamine suppresses the activation of T-lymphoblasts and dendritic cells in vitro as well as allogeneic mixed leukocyte reactivity in a dose-dependent manner. There was no inherent cellular toxicity involved in the inhibition, and the activity was not reproducible with other amine sugars. More importantly, glucosamine administration prolonged allogeneic cardiac allograft survival in vivo. We conclude that, despite its documented effects on insulin sensitivity, glucosamine possesses immunosuppressive activity and could be beneficial as an immunosuppressive agent.

 

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13.High glucose and glucosamine induce insulin resistance via different mechanisms in 3T3-L1 adipocytes.

Diabetes 2000 Jun;49(6):981-91

Nelson BA, Robinson KA, Buse MG.

Department of Medicine, Medical University of South Carolina, Charleston 29425, USA.

Sustained hyperglycemia induces insulin resistance, but the mechanism is still incompletely understood. Glucosamine (GlcN) has been extensively used to model the role of the hexosamine synthesis pathway (HSP) in glucose-induced insulin resistance. 3T3-L1 adipocytes were preincubated for 18 h in media +/- 0.6 nmol/l insulin containing either low glucose (5 mmol/l), low glucose plus GlcN (0.1-2.5 mmol/l), or high glucose (25 mmol/l). Basal and acute insulin-stimulated (100 nmol/l) glucose transport was measured after re-equilibration in serum and insulin-free media. Preincubation with high glucose or GlcN (1-2.5 mmol/l) inhibited basal and acute insulin-stimulated glucose transport only if insulin was present during preincubation. However, only preincubation with GlcN plus insulin inhibited insulin-stimulated GLUT4 translocation. GLUT4 and GLUT1 protein expression were not affected. GlcN (2.5 mmol/l) increased cellular UDP-N-acetylhexosamines (UDP-HexNAc) by 400 and 900% without or with insulin, respectively. High glucose plus insulin increased UDP-HexNAc by 30%. GlcN depleted UDP-hexoses, whereas high glucose plus insulin increased them. Preincubation with 0.5 mmol/l GlcN plus insulin maximally increased UDP-HexNAc without affecting insulin-stimulated or basal glucose transport. GlcN plus insulin (but not high glucose plus insulin) caused marked GlcN dose-dependent accumulation of GlcN-6-phosphate, which correlated with insulin resistance of glucose transport (r = 0.935). GlcN plus insulin (but not high glucose plus insulin) decreased ATP (10-30%) and UTP (>50%). GTP was not measured, but GDP increased. Neither high glucose plus insulin nor GlcN plus insulin prevented acute insulin stimulation (approximately 20-fold) of insulin receptor substrate 1-associated phosphatidylinositol (PI)-3 kinase. We have come to the following conclusions. 1) Chronic exposure to high glucose or GlcN in the presence of low insulin caused insulin resistance of glucose transport by different mechanisms. 2) GlcN inhibited GLUT4 translocation, whereas high glucose impaired GLUT4 "intrinsic activity" or membrane intercalation. 3) Both agents may act distally to PI-3 kinase. 4) GlcN has metabolic effects not shared by high glucose. GlcN may not model HSP appropriately, at least in 3T3-L1 adipocytes.

 

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14.Glucosamine-induced insulin resistance in 3T3-L1 adipocytes.

Am J Physiol Endocrinol Metab 2000 Jan;278(1):E103-12

Heart E, Choi WS, Sung CK.

Department of Physiology and Biophysics, University of Southern California, School of Medicine, Los Angeles, California 90033, USA.

To study molecular mechanisms for glucosamine-induced insulin resistance, we induced complete and reversible insulin resistance in 3T3-L1 adipocytes with glucosamine in a dose- and time-dependent manner (maximal effects at 50 mM glucosamine after 6 h). In these cells, glucosamine impaired insulin-stimulated GLUT-4 translocation. Glucosamine (6 h) did not affect insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 and -2 and weakly, if at all, impaired insulin stimulation of phosphatidylinositol 3-kinase. Glucosamine, however, severely impaired insulin stimulation of Akt. Inhibition of insulin-stimulated glucose transport was correlated with that of Akt activity. In these cells, glucosamine also inhibited insulin stimulation of p70 S6 kinase. Glucosamine did not alter basal glucose transport and insulin stimulation of GLUT-1 translocation and mitogen-activated protein kinase. In summary, glucosamine induced complete and reversible insulin resistance in 3T3-L1 adipocytes. This insulin resistance was accompanied by impaired insulin stimulation of GLUT-4 translocation and Akt activity, without significant impairment of upstream molecules in insulin-signaling pathway.

 

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15.The role of glucose metabolites in the activation and translocation of glycogen synthase by insulin in 3T3-L1 adipocytes.

J Biol Chem 1999 Sep 24;274(39):27497-504

Brady MJ, Kartha PM, Aysola AA, Saltiel AR.

Department of Cell Biology, Parke-Davis Pharmaceutical Research Division, Ann Arbor, Michigan 48105, USA.

The role of increased glucose transport in the hormonal regulation of glycogen synthase by insulin was investigated in 3T3-L1 adipocytes. Insulin treatment stimulated glycogen synthase activity 4-5-fold in these cells. Cytosolic glycogen synthase levels decreased by 75% in response to insulin, whereas, conversely, the glycogenolytic agent isoproterenol increased cytosolic enzyme levels by 200%. Removal of extracellular glucose reduced glycogen synthase activation by 40% and completely blocked enzymatic translocation. Addition of 5 mM 2-deoxyglucose did not restore glycogen synthase translocation but did augment dephosphorylation of the protein by insulin. The translocation event could be reconstituted in vitro only by the addition of UDP-glucose to basal cell lysates. Amylase pretreatment of the extracts suppressed glycogen synthase translocation, indicating that the enzyme was binding to glycogen. Incubation of 3T3-L1 adipocytes with 10 mM glucosamine induced a state of insulin resistance, blocked the translocation of glycogen synthase, and inhibited insulin-stimulated glycogen synthesis by 50%. Surprisingly, glycogen synthase activation by insulin was enhanced 4-fold, in part due to allosteric activation by a glucosamine metabolite. In vitro, glucosamine 6-phosphate and glucose 6-phosphate stimulated glycogen synthase activity with similar concentration curves. These results indicate that glucose metabolites have an impact on the regulation of glycogen synthase activation and localization by insulin.

 

[Biggs]

16.Hexosamines and nutrient excess induce leptin production and leptin receptor activation in pancreatic islets and clonal beta-cells.

Endocrinology 2001 Oct;142(10):4414-9

Emilsson V, O'Dowd J, Nolan AL, Cawthorne MA.

Clore Laboratory, University of Buckingham, Buckingham, United Kingdom MK18 1EG.

Activation of the hexosamine biosynthesis pathway leads to insulin resistance in muscle and adipose tissue. In these tissues leptin gene expression is increased by glucosamine. In the present study we found that glucosamine rapidly activates the production of leptin and OB-Rb, which encodes the functional leptin receptor, in both primary pancreatic islets and clonal beta-cells. Secretion of leptin from clonal beta-cells into the medium was detected readily. In addition, the level of the transcripts encoding signal transducer and activator of transcription-3 and -5, both implicated in leptin signal transduction in islet beta-cells, was increased by glucosamine, although to a lesser degree than mRNA levels of leptin and OB-Rb. High glucose (16.7 mM) induced leptin biosynthesis in primary pancreatic islet cells, and the addition of 1 mM palmitate caused an additional incremental effect. The hexosamine-mediated induction of the leptin system in clonal beta-cells was associated with increased responsiveness to leptin, as demonstrated by a 2.6 +/- 0.3-fold (P < 0.01) increase in tyrosine phosphorylation of signal transducer and activator of transcription-3. These findings are the first evidence of inducible leptin production in pancreatic islets and suggest that islet cells, like skeletal muscle, demonstrate a linkage between increased nutrient availability and both leptin expression and leptin responsiveness.

 

[Biggs]

17.Endothelin-stimulated glucose uptake: effects of intracellular Ca(2+), cAMP and glucosamine.

Clin Sci (Lond) 2002 Aug;103 Suppl 48:418S-423S

Wu-Wong JR, Berg CE, Dayton BD.

Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL, U.S.A. [email protected]

Endothelin-1 (ET-1) is a 21-amino-acid peptide that binds to G-protein-coupled receptors to evoke biological responses. Previously we have shown that ET-1 stimulates glucose uptake in 3T3-L1 adipocytes and neonatal rat cardiomyocytes, but the mechanism is not completely understood. ET-1 is known to modulate intracellular Ca(2+) and cAMP levels. Depletion of intracellular Ca(2+) by treating 3T3-L1 adipocytes with EDTA and 1,2-bis(2-amino-5-methylphenoxy)ethane-N,N,N',N'-tetra-acetic acid tetra-acetoxymethyl ester (MAPTAM) did not have a significant effect on ET-1-induced glucose uptake. Forskolin, a potent stimulator which stimulates adenylate cyclase and increases the intracellular cAMP level, partially inhibited insulin-stimulated glucose uptake in 3T3-L1 cells, but had no significant impact on the effect of ET-1. Forskolin also did not show an effect on the tyrosine phosphorylation of a 75 kDa protein induced by ET-1. Glucosamine treatment causes insulin resistance in cells, possibly by entering the hexosamine biosynthetic pathway. In neonatal rat cardiomyocytes, glucosamine treatment blocked both insulin and ET-1-stimulated glucose uptake and also eliminated the translocation of IRAP, an aminopeptidase in GLUT4-containing vesicles, from the cytoplasm to the plasma membrane. These results suggest that ET-1-induced glucose uptake is independent of its effects on modulating intracellular Ca(2+) and cAMP levels, but is likely linked to the hexosamine biosynthetic pathway.

 

[Biggs]

18.Glucosamine-induced insulin resistance in 3T3-L1 adipocytes is caused by depletion of intracellular ATP.

J Biol Chem 1998 Aug 7;273(32):20658-68

Hresko RC, Heimberg H, Chi MM, Mueckler M.

Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Glucosamine, which enters the hexosamine pathway downstream of the rate-limiting step, has been routinely used to mimic the insulin resistance caused by high glucose and insulin. We investigated the effect of glucosamine on insulin-stimulated glucose transport in 3T3-L1 adipocytes. The Delta-insulin (insulin-stimulated minus basal) value for 2-deoxyglucose uptake was dramatically inhibited with increasing concentrations of glucosamine with an ED50 of 1.95 mM. Subcellular fractionation experiments demonstrated that reduction in insulin-stimulated 2-deoxyglucose uptake by glucosamine was due to an inhibition of translocation of both Glut 1 and Glut 4 from the low density microsomes (LDM) to the plasma membrane. Analysis of the insulin signaling cascade revealed that glucosamine impaired insulin receptor autophosphorylation, insulin receptor substrate (IRS-1) phosphorylation, IRS-1-associated PI 3-kinase activity in the LDM, and AKT-1 activation by insulin. Measurement of intracellular ATP demonstrated that the effects of glucosamine were highly correlated with its ability to reduce ATP levels. Reduction of intracellular ATP using azide inhibited Glut 1 and Glut 4 translocation from the LDM to the plasma membrane, insulin receptor autophosphorylation, and IRS-1 tyrosine phosphorylation. Additionally, both the reduction in intracellular ATP and the effects on insulin action caused by glucosamine could be prevented by the addition of inosine, which served as an alternative energy source in the medium. We conclude that direct administration of glucosamine can rapidly lower cellular ATP levels and affect insulin action in fat cells by mechanisms independent of increased intracellular UDP-N-acetylhexosamines and that increased metabolism of glucose via the hexosamine pathway may not represent the mechanism of glucose toxicity in fat cells.

 

[Biggs]

19.Mechanisms of insulin resistance in non-oxidative glucose metabolism: the role of glycogen synthase.

J Basic Clin Physiol Pharmacol 1998;9(2-4):255-79

Beck-Nielsen H.

Odense University Hospital, Department of Endocrinology and Internal Medicine M, Denmark.

Insulin-mediated non-oxidative glucose metabolism is more or less identical to glycogen synthesis in skeletal muscle and that is why this pathway is specifically discussed in this paper. All three major steps in non-oxidative glucose processing--glucose transport, phosphorylation and glycogen synthesis--are found to be reduced in response to insulin in insulin-resistant type 2 diabetic subjects compared with controls. The insulin-signalling cascade from the insulin receptor to PI-3-K was also found to be abnormal, resulting in a severely reduced phosphorylation degree of the IRS-1 (IRS-2?)-PI-3-K complex, which can explain both reduced glucose transport and glycogen synthesis. The most pronounced finding in our studies is reduced glycogen synthase activation by insulin which is found in prediabetic subjects with normal glucose tolerance as well as in type 2 diabetics, but more severely. This defect was not reversible after treatment (normalization of blood glucose) and is therefore a candidate for the primary defect which is likely to be of genetic origin, but also could be caused by genetic imprinting, intrauterine malnutrition and social inheritance (obesity). Most of the abnormalities in non-oxidative glucose metabolism may be of secondary origin due to hyperglycemia itself or obesity. Both events may stimulate production of glucosamine, malonyl CoA and intramuscular triglyceride accumulation. These metabolites can theoretically induce most of the defects in glucose processing and furthermore impair insulin signalling. Whether the primary defect in activation of glycogen synthase is due to an abnormality in the enzyme complex itself or in the insulin signalling cascade still has to be investigated.

 

[Biggs]

20.Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress.

J Biol Chem 2001 Aug 17;276(33):31099-104

Kaneto H, Xu G, Song KH, Suzuma K, Bonner-Weir S, Sharma A, Weir GC.

Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.

It is known well that activation of the hexosamine pathway causes insulin resistance, but how this activation influences pancreatic beta-cell function remains unclear. In this study, we found that in isolated rat islets adenovirus-mediated overexpression of glutamine:fructose-6-phosphate amidotransferase (GFAT), the first and rate-limiting enzyme of the hexosamine pathway, leads to deterioration of beta-cell function, which is similar to that found in diabetes. Overexpression of GFAT or treatment with glucosamine results in impaired glucose-stimulated insulin secretion and reduction in the expression levels of several beta-cell specific genes (insulin, GLUT2, and glucokinase). Additionally, the DNA binding activity of PDX-1, an important transcription factor for these three genes, was markedly reduced. These phenomena were not mimicked by the induction of O-linked glycosylation with an inhibitor of O-GlcNAcase, PUGNAc. It was also found that glucosamine increases hydrogen peroxide levels and that several hexosamine pathway-mediated changes were suppressed by treatment with the antioxidant N-acetyl-l-cysteine. In conclusion, activation of the hexosamine pathway leads to deterioration of beta-cell function through the induction of oxidative stress rather than O-linked glycosylation. Thus, the hexosamine pathway may contribute to the deterioration of beta-cell function found in diabetes.

 

[RaulJimenez]

Well i guess my insulin is fuxed then, I had to take glucosamine for 7 straight months due to a shoulder injury, nasty. thanks god im taking some chromium to try and fix that insulin sensivity problem haha. good work like always biggin!.

 

[Draven]

As always, nice job biggin. Looks like this could make an interesting topic for my next article, if I ever find the time to write another .

 

[jweave23]

Wow, I really had no idea!

Luckily my joints are fine, I roll them real tight you see.....nevermind

This could definitely be an issue for some though

 

[Alpha Dog]

Don't Sweat It

There a number of problems with these studies relating to human supplementation of glucosamine for joint ailments. First, the dosages administered in these studies are enormous compared to typical supplementation. For example, in study #8 above, the low dosage glucosamine group is defined as 0.1 mg x kg(-1) x min(-1). This equates to about 13 grams/day for a 200 lb person. I would also assume the method of administration was not oral (most likely intravenous). Yet, oral administration of glucosamine yields approx a 26% bioavailability. If the average 200 lb person consumes 2 grams a day, with a 26% bioavailability, this yields approx .5 grams/day of glucosamine blood plasma levels. So, as defined by the “low dosage” group, blood plasma levels are 26 times higher in the conservative studies as compared to typical human supplementation. Another point, with intravenous administration, they are maintaining a relatively constant blood plasma level. Yet, oral administration of glucosamine yields a short half life. Most studies indicate blood plasma levels after oral administration peak after about 1.1 hours. If a person is supplementing with glucosamine twice daily, they are far from maintaining a constant blood plasma level as demonstrated in the studies above. Finally, these studies are with rats. There are studies that contradict these results with healthy humans.

Bottom line, don’t worry about it

 

[Alpha Dog]

Short-Term Glucosamine Infusion Does Not Affect Insulin Sensitivity in Humans

Marie-Jose J. Pouwels, Judith R. Jacobs, Paul N. Span, Jos A. Lutterman, Paul Smits and Cees J. Tack

Abstract
Overactivity of the hexosamine biosynthetic pathway may underlie hyperglycemia-associated insulin resistance, but to date human studies are lacking. Hexosamine pathway activation can be mimicked by glucosamine (GlcN). In the present placebo-controlled study we determined whether GlcN infusion affects insulin resistance in vivo. In 18 healthy subjects, we applied the double forearm balance technique (infused arm vs. control arm) combined with the euglycemic hyperinsulinemic clamp (60 mU/m2·min insulin) for at least 300 min. During the clamp, subjects received infusions in the brachial artery of 4 µmol/dL·min GlcN from 90–240 min (n = 6) or from 0–300 min (n = 6) or saline (placebo; n = 6). We studied the effects of GlcN on forearm glucose uptake (FGU; infused arm vs. control arm, and vs. placebo experiments) and on whole body glucose uptake.
GlcN infusion raised the plasma GlcN concentration in the infusion arms to 0.42 ± 0.14 and 0.81 ± 0.46 mmol/L; plasma GlcN remained very low (<0.07 mmol/L) in the control arms and in the placebo group. GlcN infusion did not change forearm blood flow. During insulin, FGU increased more than 10-fold. At all time points, FGU was similar in the GlcN-infused arm compared with the control arm and was not different from FGU in the placebo experiments. Similar results were obtained for forearm arteriovenous glucose differences or extraction and for whole body glucose uptake. Thus, despite relevant GlcN concentrations for 5 h in the infused forearm, GlcN had no effect on insulin-induced glucose uptake. These results do not support involvement of the hexosamine pathway in the regulation of insulin sensitivity in humans, at least not in the short-term setting.

 

[CROWLER]

OK I do HIGH supplementation with glucosamine.

I also have done slin in the past and can go hypo on as little as 6 IUS.

I also feel the onset of hypo with just 500mg of ALA if my carbs are low.

 

[Jag]

i've got a kilo of glucosamine from "Kilosports" & according to the label one t-spoon is 7 grams.

if i put 1/3 of a t-spoon in my post w/o shake with whey & creatine how is this going to affect anything?

i was thinking it may be a benefit!! now i'm extremely confused. :frustrate

Jag

 

[Scottyo]

If you look on avant, they are pretty much saying the opposite things. In fact, Glucosamine HCL is one of the biggest ingredients in Leptigen. So take it for what its worth.

 

[wdecuir]

can anyone put this in plain english? i have a elbow injury and have just started taking this. What problems will I encounter?

 

[Jag]

If you look on avant, they are pretty much saying the opposite things. In fact, Glucosamine HCL is one of the biggest ingredients in Leptigen. So take it for what its worth.

i just had a bit of a browse through the thread i think you mean.

i think they were talking about best results occurring while in a calorie deficit. also Spook mentioned that it may not be a good idea for endomorphs.

for some reason i can't post the link!!!

Jag

 

[Dan]

Hmm, what about chronditin?

 

[Dan]

I know VPX likes to overhype their products, but I noticed this particular product that looked interesting for join repair, Glucosa Cream. http://www.1fast400.com/?products_id=1343

 

[Scottyo]

Seriously, don't worry about glucosamine and negative impacts. Almost all studies that had these used ridiculously high levels. Par, Spook, and Nandi have all commented on it, and thats enough for me.

 

[DevilSmack]

I can tell you from personal experience that glucosamine will make you fat in no time. It messes up glucose metabolism really fast. Even small doses. At least it does for me. I had to kiss my 5% bodyfat goodbye when I started taking it and I even improved my diet while taking Glucosamine because I have gotten an increace in BF from it before, but it's hopless. I will never use it again.