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

Abstract

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.

Oral Glucosamine for 6 Weeks at Standard Doses Does Not Cause or Worsen Insulin Resistance or Endothelial Dysfunction in Lean or Obese Subjects

“…potential mechanism for hyperglycemia to contribute to development of both insulin resistance and endothelial dysfunction (13,(15)(16)(17)(18)(19)(20)(21)23,24,(35)(36)(37)(38). Indeed, treatment of cells in vitro with glucosamine (1-10 mmol/l) causes both insulin resistance and endothelial cell dysfunction.…”

“…Indeed, treatment of cells in vitro with glucosamine (1-10 mmol/l) causes both insulin resistance and endothelial cell dysfunction. More importantly, intravenous infusions of glucosamine that achieve plasma concentrations of 0.5-1.8 mmol/l in both animals and humans causes insulin resistance and endothelial dysfunction (20,25). Thus, there are significant potential safety concerns associated with glucosamine therapy for osteoarthritis.…”

“…Incubation of muscle, adipose, or endothelial cells with high levels of glucosamine (1-10 mmol/l) causes impairment in metabolic actions of insulin as well as endothelial dysfunction (15)(16)(17)(18)(19). Indeed, glucosamine is often used in laboratory studies as a tool to investigate mechanisms of insulin resistance caused by increased flux through the HBP (11,15,20). Moreover, intravenous glucosamine administration causes metabolic insulin resistance and vascular endothelial dysfunction in both animals and humans (13,20 -25).…”

Blueberry Tea Enhances Insulin Sensitivity by Augmenting Insulin-Mediated Metabolic and Microvascular Responses in Skeletal Muscle of High Fat Fed Rats

“…We have shown that acute defects in insulin-mediated microvascular recruitment can contribute to the development of muscle insulin resistance in vivo. Infusion of α-methyl serotonin [26], endothelin-1 [27], L-N G -Nitroarginine methyl ester [7,29,37], TNFα [38], Intralipid® plus heparin [39] and glucosamine [40] in healthy animals attenuate insulin-mediated microvascular recruitment and insulin-mediated muscle glucose uptake. In addition, chronic models of insulin resistance including the high fat-fed rat (36% fat wt/ wt) [3], and obese Zucker rat [41] display marked attenuation in insulin-mediated microvascular recruitment and muscle glucose uptake.…”

Acute effects of wortmannin on insulin's hemodynamic and metabolic actions in vivo

“…Reduced delivery of insulin and glucose would give rise to a reduced R d and HLGU. Based on previous studies where insulin-mediated capillary recruitment has been blocked by a 5-hydroxytryptamine agonist (25), tumor necrosis factor-␣ (40), free fatty acids (7), or glucosamine (34), this could amount to ϳ50% inhibition of the insulin-mediated increase in muscle glucose uptake, with the expectation of a similar magnitude of inhibition of R d and muscle P-Akt/Akt. In addition to this, it appears likely that the relatively water-insoluble wortmannin is unable to fully diffuse to those myocytes that are unaffected by capillary recruitment (i.e., where insulin delivery is unrestricted).…”