Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperglycemia can lead directly to a secondary state of insulin resistance or can worsen a preexisting insulin-resistant state. Troglitazone is an orally active hypoglycemic agent that has been shown to ameliorate insulin resistance and hyperinsulinemia in both diabetic animal models and NIDDM subjects. To determine whether this drug could prevent the development of hyperglycemia-induced insulin resistance and to investigate the mechanism by which this might occur, we studied troglitazone's effect on insulin action in rats made hyperglycemic or infused with glucosamine. Normal male SD rats were fed regular powdered diet with or without troglitazone as a food admixture (0.2%). After 2 weeks, rats were made hyperglycemic with glucose (52 mg x kg(-1) x min[-1]) and somatostatin (0.8 microg x kg(-1) x min[-1]) infusion or were infused with glucosamine (6.5 mg x kg(-1) x min[-1]) for 6.5 h. In vivo insulin action was measured by the hyperinsulinemic-euglycemic clamp technique at a submaximal (24 pmol x kg(-1) x min[-1]) or maximal (240 pmol x kg(-1) x min[-1]) insulin infusion rate. The infusion of glucose and somatostatin caused a pronounced rise in the plasma glucose concentration (19.8 +/- 0.6 mmol/l) compared with saline-infused animals (8.0 +/- 0.2 mmol/l; P < 0.001). Hyperglycemia resulted in insulin resistance, as evidenced by a marked reduction in the submaximal glucose disposal rate (GDR) (78 +/- 7 vs. 135 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) and maximal GDR (141 +/- 9 vs. 237 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) compared with the control group. Troglitazone treatment largely prevented the hyperglycemia-induced decline in submaximal (116 +/- 7 micromol x kg(-1) x min[-1]) and maximal GDR (209 +/- 9 micromol x kg(-1) x min(-1); P < 0.05). Glucosamine infusion also resulted in a marked reduction in the submaximal GDR (85 +/- 3 vs. 135 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) and maximal GDR (137 +/- 14 vs. 237 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) compared with the control group. In contrast to the results in the hyperglycemic animals, troglitazone treatment had no effect on glucosamine-induced insulin resistance. In summary, 1) in normal rats, experimental hyperglycemia, as well as glucosamine infusion, led to a marked state of peripheral and hepatic insulin resistance; 2) troglitazone treatment prevented the hyperglycemia-induced, but not the glucosamine-induced, insulin resistance; and 3) either troglitazone acts at one or more sites proximal to the entry of glucosamine into the hexosamine pathway, or the increased flux of glucose-derived products through the hexosamine pathway is not a major mechanism for the hyperglycemia-induced defect in insulin action in these animals.
Diabetes 1998 Mar
PMID:Troglitazone prevents hyperglycemia-induced but not glucosamine-induced insulin resistance. 951 45

We have recently cloned the murine glucagon receptor (GR) gene and shown that it is expressed mainly in liver. In this organ, the glucagon-GR system is involved in the control of glucose metabolism as it initiates a cascade of events leading to release of glucose into the blood stream, which is a main feature in several physiological and pathological conditions. To better define the metabolic regulators of GR expression in liver we analyzed GR mRNA concentration in physiological conditions associating various glucose metabolic pathways in vivo and in vitro in the rat and in the mouse. First, we report that the concentration of the GR mRNA progressively increased from the first day of life to the adult stage. This effect was abolished when newborn rodents were fasted. Second, under conditions where intrahepatic glucose metabolism was active such as during fasting, diabetes, and hyperglycemic clamp, the concentration of GR mRNA increased independent of the origin of the pathway that generated the glucose flux. These effects were blunted when hyperglycemia was corrected by phlorizin treatment of diabetic rats or not sustained during euglycemic clamp. In accordance with these observations, we demonstrated that the glycolytic substrates glucose, mannose, and fructose, as well as the gluconeognic substrates glycerol and dihydroxyacetone, increased the concentration of GR mRNA in primary cultures of hepatocytes from fed rats. Glucagon blunted the effect of glucose without being dominant. The stimulatory effect of those substrates was not mimicked by the nonmetabolizable carbohydrate L-glucose or the glucokinase inhibitor glucosamine or when hepatocytes were isolated from starved rats. In addition, inhibitors of gluconeogenesis and lipolysis could decrease the concentration of GR mRNA from hepatocytes of starved rats. Combined, these data strongly suggest that glucose flux in the glycolytic and gluconeogenic pathways at the level of triose intermediates could control expression of GR mRNA and participate in controlling its own metabolism.
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PMID:In vivo and in vitro regulation of hepatic glucagon receptor mRNA concentration by glucose metabolism. 952 10

Sustained hyperglycemia can cause peripheral insulin resistance and pancreatic beta-cell dysfunction and has been termed glucose toxicity or glucose-induced desensitization. Glucosamine, a product of glucose flux through the hexosamine biosynthetic pathway (HBP), causes insulin resistance in peripheral tissues and has been shown to cause abnormal glucose-insulin secretion coupling, and thus has been implicated in the pathogenesis of glucose toxicity. Here, we investigate whether glucosamine-induced insulin secretory dysfunction is specific to glucose or also extends to nonglucose secretagogues such as arginine. Two groups of 12 weight-matched Sprague-Dawley rats underwent hyperglycemic clamp studies (steady-state blood glucose, approximately 220 mg x dL(-1)) during infusion of normal saline or glucosamine 3.5 mg x kg(-1) x min(-1) over a 100-minute period. Insulin levels were measured at baseline and between 90 and 100 minutes. One hundred minutes into the hyperglycemic clamp, subgroups of seven rats each (saline- and glucosamine-infused rats) received a bolus of arginine (100 mg x kg(-1)) while the glucose infusion rate was unaltered. Glucose and insulin levels were measured at 1, 3, 5, 10, 15, and 30 minutes after the arginine bolus. Both groups had similar fasting glucose and insulin levels. At steady state (60 to 100 minutes), glucose levels were almost identical in both groups (223.58+/-3.94 v 224.58+/-4.34 mg x dL(-1)), but the glucose infusion rate (26.55+/-1.60 v 8.83+/-1.35 mg x kg(-1) x min(-1), P < .0001) and insulin level (41.36+/-6.47 v 18.04+/-2.95 mU x mL(-1), P < .0001) were markedly reduced in animals receiving glucosamine. Peak insulin levels 1 minute after the arginine bolus were lower in rats infused with glucosamine versus saline (274.00+/-30.38 v 176.25+/-20.12 microU x ml(-1), P=.0319). Total insulin secretion in response to arginine was significantly lower in the glucosamine group as determined by the area under the curve (1,268.09+/-142.27 v 706.77+/-84.79 microU x mL(-1) x min, P=.0054). In conclusion, glucosamine causes severe impairment in glucose-induced insulin secretion. Further, glucosamine-induced beta-cell secretory dysfunction extends to nonglycemic stimuli like arginine. This pattern of insulin secretory dysfunction is similar to that observed in patients with non-insulin-dependent diabetes mellitus (NIDDM). These data suggest that glucosamine may participate in the pathogenesis of glucose toxicity at the level of the beta cell in NIDDM patients.
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PMID:Glucosamine infusion in rats mimics the beta-cell dysfunction of non-insulin-dependent diabetes mellitus. 959 49

Activation of protein kinase C (PKC) has been implicated in the high glucose-induced stimulation of matrix protein production in mesangial cells. Since we have found (Kolm-Litty et al., 1998) that glucosamine, similar to the PKC activator phorbol myristate acetate (PMA), mimicks high glucose-induced TGF-beta1 overexpression and subsequent matrix overproduction, the action of these agents on the translocation of PKC isoenzymes was studied in cultured mesangial cells. Exposure to 12 mM glucosamine resulted in rapid and specific translocation of PKC-isoenzymes in mesangial cells i.e. glucosamine caused an increased and sustained translocation of PKC-alpha, -beta and -epsilon while PKC-zeta was essentially unaffected. Comparison with PMA-induced translocation exhibited distinct differences. Exposure to high glucose concentrations of mesangial cells induced translocation of PKC-beta and down-regulation of PKC-epsilon while PKC-alpha and -zeta were essentially unaltered. Presence of azaserine an inhibitor of glutamine: fructose-6-phosphate amidotransferase, the key enzyme of the hexosamine pathway, attenuated the high glucose-induced effects on the membrane fraction of PKC-beta. Our results indicate that i) glucosamine is a potent stimulator of PKC-translocation exhibiting an isoenzyme specific translocation kinetic which is different from PMA-induced PKC-isoenzyme translocation ii) the hexosamine pathway may be possibly involved in the high glucose-induced activation of PKC.
Exp Clin Endocrinol Diabetes 1998
PMID:Glucosamine induces translocation of protein kinase C isoenzymes in mesangial cells. 983 2

To study the effects of a glucosamine infusion on skeletal muscle metabolism, microdialysis was performed in the medial femoral muscle in Sprague-Dawley rats during a euglycemic-hyperinsulinemic clamp (insulin infusion 18 mU x kg(-1) x min(-1)). During steady-state clamping conditions (70 min), an infusion of glucosamine (30 micromol x kg(-1) x min(-1)) or saline was given for 240 min. Blood flow was measured by the microsphere technique at the end of the clamp. An approximately 36% (P < 0.001) reduction in the glucose infusion rate was seen after 170 min in the glucosamine-treated rats compared with control rats. There were no significant differences in interstitial or plasma levels of either insulin or glucose between the two groups. Both interstitial (2.31 +/- 0.18 vs. 1.71 +/- 0.24 mmol/l, P < 0.05) and arterial plasma lactate concentrations (1.29 +/- 0.09 vs. 0.79 +/- 0.09 mmol/l, P < 0.01) were significantly higher in control rats compared with glucosamine-treated rats. Blood flow was significantly reduced in hind limb femoral muscles in the glucosamine-treated rats compared with control rats. The most pronounced reduction in blood flow was seen in the Soleus muscle (27.6 +/- 3.4 vs. 14.7 +/- 2.0 ml x 100 g(-1) x min(-1), P < 0.01). These results demonstrate that induction of insulin resistance by glucosamine results in a reduction of the blood flow rate as well as the uptake of glucose and the production of lactate in skeletal muscle. As a result of the inhibited glucose metabolism, the interstitial glucose concentration was unchanged despite the reduced blood flow after glucosamine administration. The data suggest the importance of regulation of blood flow by nonoxidative metabolism of glucose in resting muscle.
Diabetes 1999 Jan
PMID:Induction of insulin resistance by glucosamine reduces blood flow but not interstitial levels of either glucose or insulin. 989 29

Estrogen deficiency, hyperinsulinemia, type II diabetes, atherosclerosis, and a past history of elevated blood pressure may be associated with increased risk of Alzheimer's disease (AD). Common to all of these risk factors is a diminished capacity of vascular endothelium to generate nitric oxide (NO). Vascular NO has the potential to enhance the membrane polarization of cerebral neurons by increasing the open probability of calcium-activated potassium channels; this may protect neurons from the excessive calcium influx, potentiated by beta-amyloid peptides that is thought to mediate neuronal damage in AD. The possibility that NO/cyclic guanosine 3', 5'-phosphate (cGMP) may modulate the synthesis or processing of the amyloid precursor protein, also merits evaluation. Practical measures for promoting vascular NO production may include increased intakes of arginine, potassium, antioxidants, and fish-oil, as well as lifestyle measures that typically lower elevated blood pressure; potential benefits of chromium, glucosamine, and silicon should also be explored. In hypertensives, angiotensin-converting enzyme (ACE) inhibitors and sodium restriction may favorably influence endothelial function. Fish-oil should have the additional benefit of antagonizing the contribution of interleukin-1 to AD pathogenesis. Ancillary anti-excitotoxic measures such as magnesium, taurine, phenytoin, and vasodilators targeting ATP-dependent potassium (KATP) channels, may likewise reduce AD risk. Most of the nutritional measures suggested here would in any case be recommendable for preservation of vascular health.
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PMID:Vascular nitric oxide may lessen Alzheimer's risk. 1005 65

Type 2 diabetes is characterized by insulin resistance as well as impaired insulin secretion. Thus, the enhancement of insulin sensitivity is a possible treatment modality. The mechanism of insulin resistance is still unknown. However, some genetic backgrounds may be involved and modulated by environmental factors. Obesity is considered to be one of major factors to induce insulin resistance. Regarding mechanism of obesity-induced insulin resistance, the increased expression of Tumor necrosis factor alpha and abnormality in PTPase are postulated. Prolonged hyperglycemia also induces the impairment of insulin action, resulting in worsening glycemic control. Abnormal glucosamine biosynthesis and impaired receptor kinase are considered to be involved in the hyperglycemia-induced insulin resistance.
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PMID:[Molecular mechanism and clinical impact of insulin resistance in type 2 diabetes mellitus]. 1019 30

Glucosamine infusion induces insulin resistance in vivo, but the effect of glucosamine on intracellular metabolites of the hexosamine pathway, especially glucosamine-6-phosphate (GlcN6P) is unknown. Because of the structural similarity of glucose-6-phosphate (G-6-P) and GlcN6P, we hypothesized that accumulation of this metabolite might alter the activities of enzymes such as glycogen synthase and hexokinase. We infused glucosamine (30 micromol x kg(-1) x min(-1)) to induce insulin resistance in rats during a euglycemic-hyperinsulinemic clamp. Glucosamine induced whole-body insulin resistance, which was apparent after 90 min and continued progressively for 360 min. Despite inducing severe whole-body insulin resistance and decrease in glycogen synthase fractional activity in rectus abdominis muscle (69+/-3 vs. 83+/-1%, P<0.01) and heart (7+/-1 vs. 32+/-4%, P<0.001), glucosamine did not change the glycogen content in rectus and even increased it in the heart (209+/-13 vs. 117+/-9 mmol/kg dry wt, P<0.001). Glucosamine increased tissue concentrations of UDP-GlcNAc 4.4- and 4.6-fold in rectus abdominis and heart, respectively. However, GlcN6P concentrations increased 500- and 700-fold in glucosamine-infused animals in rectus abdominis (590+/-80 vs. 1.2+/-0.1 micromol/kg wet wt, P<0.001) and heart (7,703+/-993 vs. 11.2+/-2.3 micromol/kg wet wt, P<0.001). To assess the possible significance of GlcN6P accumulation, we measured the effect of GlcN6P on glycogen synthase and hexokinase activity in vitro. At the GlcN6P concentrations measured in rectus abdominis and heart in vivo, glycogen synthase was activated by 21 and 542%, while similar concentrations inhibited hexokinase activity by 5 and 46%, respectively. This study demonstrates that infusion of glucosamine during a euglycemic-hyperinsulinemic clamp results in marked accumulation of intracellular GlcN6P. The GlcN6P concentrations in the heart and rectus abdominis muscle reach levels sufficient to cause allosteric activation of glycogen synthase and inhibition of hexokinase.
Diabetes 1999 May
PMID:Allosteric regulation of glycogen synthase and hexokinase by glucosamine-6-phosphate during glucosamine-induced insulin resistance in skeletal muscle and heart. 1033 16

Glucosamine, a metabolite of glucose via the hexosamine biosynthetic pathway, potently induces insulin resistance in skeletal muscle by impairing insulin-induced GLUT4 translocation to the plasma membrane. Activation of phosphoinositide (PI) 3-kinase is necessary for insulin-stimulated GLUT4 translocation, and the serine/threonine kinase Akt/protein kinase B (PKB) is a downstream mediator of some actions of PI 3-kinase. To determine whether glucosamine-induced insulin resistance could be due to impaired signaling, we measured insulin receptor substrate (IRS)-1 and insulin receptor tyrosine phosphorylation; PI 3-kinase activity associated with IRS-1, IRS-2, and phosphotyrosine; and Akt activity and phosphorylation in skeletal muscle of rats infused for 2 h with glucosamine (6.0 mg x kg(-1) x min(-1)) or saline. Euglycemic-hyperinsulinemic clamp studies (12 mU x kg(-1) x min(-1) insulin) in awake rats showed that glucosamine infusion resulted in rapid induction of insulin resistance, with a 33% decrease in glucose infusion rate (P < 0.01). Tissues were harvested after saline alone (basal), 1 min after an insulin bolus (10 U/kg), or after 2 h of insulin clamp in saline- and glucosamine-infused rats. After 1 min of insulin stimulation, phosphorylation of IRS-1 and insulin receptor increased 6- to 8-fold in saline-infused rats and 7- to 10-fold in glucosamine-infused rats. In saline-infused rats, 1 min of insulin stimulation increased PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine 7.6-, 6.4-, and 10-fold, respectively. In glucosamine-infused rats treated for 1 min with insulin, PI 3-kinase activity associated with IRS-1 was reduced 28% (P < 0.01) and that associated with phosphotyrosine was reduced 43% (P < 0.01). Insulin for 1 min stimulated Akt/PKB activity approximately 5-fold in both saline- and glucosamine-infused rats; insulin-induced hyperphosphorylation of Akt/PKB was not different between groups. Glucosamine infusion alone had no effect on tyrosine phosphorylation of the insulin receptor or IRS-1 or on stimulation of PI 3-kinase or Akt/PKB activity. However, 2 h of insulin clamp reduced PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine to <30% of that seen with 1 min of insulin. No effect of glucosamine was seen on these signaling events when compared with 2 h of insulin clamp without glucosamine. Our data show that 1) glucosamine infusion in rats is associated with an impairment in the early activation of PI 3-kinase by insulin in skeletal muscle, 2) this insulin-resistant state does not involve alterations in the activation of Akt/PKB, and 3) prolonged insulin infusion under clamp conditions results in a blunting of the PI 3-kinase response to insulin.
Diabetes 1999 Feb
PMID:Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle. 1033 7

The skin of rats with experimental (streptozotocin-induced) chronic diabetes mellitus exhibits significant decrease in glycosaminoglycans (GAGs) content. In the present study we asked the question whether the decrease in GAGs content is a result of decline in GAG biosynthesis or an increase in their degradation. We demonstrated by a pulse-labeling experiments that diabetes results in a decrease of [14C]-glucosamine incorporation into both hyaluronic acid and sulphated GAGs. During the chase period, there was no significant degradation of the pulse-labeled GAGs, suggesting that the reduction of GAGs content in the skin of diabetic rats is a result of decrease in GAG biosynthesis. Especially the biosynthesis of sulphated GAGs is deeply reduced. This phenomenon may be one of the factors which impairs the wound healing in diabetic subjects.
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PMID:Decreased biosynthesis of glycosaminoglycans in the skin of rats with chronic diabetes mellitus. 1033 65


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