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.

Kim, Y B; Zhu, Jin-Su; Zierath, Juleen R.; Shen, Hua; Baron, Alain; Kahn, Barbara B.

doi:10.2337/diabetes.48.2.310

Cited by 89 publications

(81 citation statements)

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“…Despite this, there was no significant reduction in glucose uptake until 110 min of glucosamine infusion. Insulinstimulated Akt/PKB activity was unaltered by glucosamine [32]. Although those studies were performed on skeletal muscle, similar alterations in insulin signalling may also be effected in vascular tissue, leading to the impaired total flow and capillary recruitment seen here.…”

Section: Discussionmentioning

confidence: 64%

“…While there is some evidence for the former, there are some discrepancies in the findings. One research group [31] reported that insulinstimulated IRS-1 tyrosine phosphorylation was reduced by glucosamine, whereas another [32] found this was preserved in glucosamine-treated rats. When measured 1 min after a bolus injection of insulin, PI3 kinase (PI3K) activity associated with IRS-1 was decreased by glucosamine infusion, on the other hand, when the activity was measured following 2 h of insulin infusion, no effect of glucosamine was observed [32].…”

Section: Discussionmentioning

confidence: 99%

“…One research group [31] reported that insulinstimulated IRS-1 tyrosine phosphorylation was reduced by glucosamine, whereas another [32] found this was preserved in glucosamine-treated rats. When measured 1 min after a bolus injection of insulin, PI3 kinase (PI3K) activity associated with IRS-1 was decreased by glucosamine infusion, on the other hand, when the activity was measured following 2 h of insulin infusion, no effect of glucosamine was observed [32]. Also, it was found that glucosamine reduced insulinstimulated IRS-1-associated PI3K activity [31]; however, these measurements were taken at the end of a 6 h infusion of insulin and glucosamine.…”

Section: Discussionmentioning

confidence: 99%

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Acute glucosamine-induced insulin resistance in muscle in vivo is associated with impaired capillary recruitment

et al. 2005

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Aims/hypothesis: Glucose toxicity and glucosamine-induced insulin resistance have been attributed to products of glucosamine metabolism. In addition, endothelial cell nitric oxide synthase is inhibited by glucosamine. Since insulin has endothelial nitric-oxide-dependent vasodilatory effects in muscle, we hypothesise that glucosamine-induced insulin resistance in muscle in vivo is associated with impaired vascular responses including capillary recruitment. Materials and methods: Glucosamine (6.48 mg kg −1 min −1 for 3 h) was infused with or without insulin (10 mU kg −1 min −1 ) into anaesthetised rats under euglycaemic conditions. Results: Glucosamine infusion alone increased blood glucosamine (1.9±0.1 mmol/l) and glucose (5.4±0.2 to 7.7± 0.3 mmol/l) (p<0.05) but not insulin. Glucosamine induced both hepatic and muscle insulin resistance as evident from measures of glucose appearance and disposal as well as hindleg glucose uptake, which was inhibited by approx. 50% (p<0.05). Insulin-mediated increases in femoral arterial blood flow and capillary recruitment were completely blocked by glucosamine. Conclusion/interpretation: Glucosamine mediates a major impairment of insulin action in muscle vasculature associated with the insulin resistance of muscle. Further studies will be required to assess whether the impaired capillary recruitment contributes to insulin resistance.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Acute glucosamine-induced insulin resistance in muscle in vivo is associated with impaired capillary recruitment

et al. 2005

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“…It is known that hyperglycaemia or an increased flux through the hexosamine pathway reduces insulin signalling at the level of PI3′-kinase or Akt in rat skeletal muscle [25,26]. In addition, NEFA concentrations are usually increased in the diabetic state, and increased NEFA concentrations have been shown to substantially reduce PI3′-kinase activity in human skeletal muscle [27].…”

Section: Discussionmentioning

confidence: 99%

“…Thus it has been demonstrated in rat skeletal muscle that hyperglycaemia or an increased flux through the hexosamine pathway can influence insulin signalling on the level of PI3′-kinase or Akt [25,26]. It has also been shown that increased NEFA concentrations decrease PI3′-kinase activity in human skeletal muscle [27].…”

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confidence: 99%

Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease

et al. 2002

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Aims/hypothesis. Alterations in insulin signalling could contribute to insulin resistance in Type II (non-insulindependent) diabetes mellitus. Some of these alterations could be secondary to the diabetic state, ie. the hyperglycaemia or increased NEFA concentrations. We sought to exclude such secondary factors and to investigate whether Type II diabetes in itself is associated with altered insulin signalling in skeletal muscle. Methods. Hyperinsulinaemic-euglycaemic clamps were performed in 10 obese Type II diabetic patients whose glucose concentrations had been normalised for 8 h by plasma glucose-adapted insulin infusion, 10 BMImatched first-degree relatives of Type II diabetic patients, and 10 BMI-matched non-diabetic subjects. Muscle biopsies were obtained before and at the end of the clamps, and insulin receptor kinase activity, phosphatidylinositol-3′-kinase activity, Akt-Thr 308 -phosphorylation, and glycogen synthase activity determined. Results. At similar steady-state clamp insulin concentrations (~400 pmol/l) similar receptor kinase activities, phosphatidylinositol-3′-kinase activities, AktThr 308 -phosphorylation, and glycogen synthase activities were found in all subject groups although glucose disposal was reduced in the diabetic subjects and relatives. Pre-clamp signalling levels were different between subject groups, most likely due to different preclamp insulin concentrations. Conclusion/interpretation. Our results in subjects at risk for the development of diabetes and Type II diabetic patients with normalized glucose concentrations suggest that Type II diabetes in itself is not associated with reduced signalling intensity at the studied signalling molecules, at least not at the chosen clamp insulin concentration and under the chosen conditions. Alterations responsible for the reduced glucose disposal could be located downstream of the investigated steps or in alternative insulin signalling pathways. A different spatial organisation of the investigated signalling molecules can also not be excluded. [Diabetologia (2002) Type II (non-insulin-dependent) diabetes mellitus is associated with a reduced insulin-stimulated glucose disposal in skeletal muscle and other tissues [1]. Because insulin resistance is also observed in non-diabetic first-degree relatives of diabetic subjects [2,3,4,5], and because it seems to precede the development of frank diabetes [6], an inherited basis of at least a part of the diabetes-associated insulin resistance has been proposed [7]. On the other hand metabolic abnormalities in the diabetic state itself such as hyper-

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Antiobesity pharmacotherapy in the management of Type 2 diabetes

Scheen¹,

Lefèbvre²

2000

Diabetes Metab. Res. Rev.

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Obesity is a well‐known risk factor for the development of Type 2 diabetes mellitus. The management of the obese diabetic patient remains a challenge for the clinician but, in any case, weight reduction should be considered as a key objective. In this respect, several antiobesity drugs have demonstrated potential. However, while fenfluramine and dexfenfluramine have been shown to promote weight loss and to directly improve insulin sensitivity, being two mechanisms contributing to better blood glucose control in obese Type 2 diabetic patients, they were recently withdrawn due to safety problems. Sibutramine, a new selective norepinephrine and serotonin reuptake inhibitor, promotes weight loss by decreasing food intake, an effect which leads to a mild improvement (significant in patients losing ≥5% of initial body weight) of blood glucose control in obese diabetic patients. Similarly, orlistat, a selective gastrointestinal lipase inhibitor which increases faecal fat losses, enhances diet‐induced weight reduction and improves both blood glucose control and vascular risk profile, especially dyslipidaemia, in obese Type 2 diabetic patients. Further studies are required to better identify good responders to pharmacotherapy and specify the role of antiobesity agents in the overall long‐term management of obese subjects with Type 2 diabetes. Other novel pharmacological approaches deserve further consideration, for instance beta‐3 agonists aiming to increase energy expenditure, drugs interfering with tumor necrosis factor‐alpha (TNF‐α) or free fatty acid release by the adipose tissue or agents that slow gastric emptying. However, until now, results regarding efficacy and/or safety have been disappointing or preliminary in humans. Copyright © 2000 John Wiley & Sons, Ltd.

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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.

Cited by 89 publications

References 0 publications

Acute glucosamine-induced insulin resistance in muscle in vivo is associated with impaired capillary recruitment

Acute glucosamine-induced insulin resistance in muscle in vivo is associated with impaired capillary recruitment

Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease

Antiobesity pharmacotherapy in the management of Type 2 diabetes

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