Lipid Infusion Impairs Physiologic Insulin-Mediated Capillary Recruitment and Muscle Glucose Uptake In Vivo

Clerk, Lucy H.; Rattigan, Stephen; Clark, Michael G.

doi:10.2337/diabetes.51.4.1138

Cited by 146 publications

(136 citation statements)

References 64 publications

Supporting

Mentioning

129

Contrasting

Order By: Relevance

“…We propose that glucosamine inhibits insulin signalling in as yet unidentified site(s), thereby blocking the increases in total flow and capillary recruitment. In so doing, impaired access for insulin and glucose may ensue, contributing to insulin resistance in a similar way to previous experimental situations, where capillary recruitment by insulin was blocked [12][13][14].…”

Section: Discussionsupporting

confidence: 54%

“…In Table 1 Arterial and venous plasma 1-MX concentrations, femoral arterial flow rate and calculated hind limb 1-MX metabolism for anaesthetised rats infused with saline, N-glucosamine, insulin or both N-glucosamine and insulin Data were collected 180 min after the commencement of the infusions as shown in Fig. 1 Values are means±SE for n=8 in each group *p<0.05 difference from saline; # p<0.05 difference from insulin contrast, there is growing evidence that insulin-mediated capillary recruitment may play a key role in muscle glucose uptake, particularly in animal models [18] and is impaired in animal models of muscle insulin resistance [12][13][14]41] and in obese humans [42,43]. Capillary recruitment is controlled independently of limb blood flow [17,18,21] and occurs in response to locally administered physiological insulin in human forearm in association with glucose uptake [44].…”

Section: Discussionmentioning

confidence: 99%

“…However, it is also possible that there is a haemodynamic element with resultant impairment of both insulin-mediated limb blood flow and capillary recruitment. Inhibition of insulin's haemodynamic action has been shown to be associated with decreased insulin-mediated glucose uptake [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2005

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2005

View full text Add to dashboard Cite

show abstract

“…26 Interestingly, infusing intra-lipid into rats to raise circulating FFA levels causes a significant 65% impairment in insulin-mediated skeletal muscle capillary recruitment with a concomitant 40% decrease in glucose disposal during a glucose clamp. 27 The finding by Kim et al that FFA-mediated activation of IKK␤ in vascular endothelium leads to impaired insulin signaling and decreased insulin-stimulated production of NO provides further support for the idea that parallel signaling mechanisms in skeletal muscle and vascular endothelium serve to couple metabolic and vascular pathophysiology.…”

Section: Coupling Of Vascular and Metabolic Pathophysiology Through Imentioning

confidence: 87%

The Union of Vascular and Metabolic Actions of Insulin in Sickness and in Health

Kim

Koh

Quon

2005

ATVB

View full text Add to dashboard Cite

Disorders of metabolic homeostasis including type 2 diabetes, obesity, and dyslipidemias are characterized by both insulin resistance and endothelial dysfunction. 1 Insulin resistance and endothelial dysfunction are also prominent features of important cardiovascular disorders including hypertension, coronary artery disease, and atherosclerosis. 2 Indeed, insulin resistance is thought to be the tie that binds metabolic and cardiovascular disorders together in an unhappy union called the metabolic syndrome (aka the insulin resistance syndrome). 3,4 Although these associations are well established, molecular mechanisms explaining the underlying pathophysiology are not completely understood. Interestingly, inflammation mediated by innate immune signaling pathways has been implicated in both metabolic insulin resistance and vascular endothelial dysfunction. 1,5,6 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Kim et al demonstrate that treatment of vascular endothelial cells with the free fatty acid (FFA) palmitate activates IKK␤ (a proinflammatory signaling molecule), impairs insulin signaling, and decreases insulin-stimulated production of nitric oxide (NO). 7 Importantly, inhibitory effects of FFA treatment on insulin signaling and NO production are blocked by overexpression of a dominant inhibitory mutant of IKK␤. Moreover, deleterious effects of FFA treatment are recapitulated by overexpression of wildtype IKK␤. Thus, Kim et al have uncovered an additional link between metabolic and vascular pathophysiology that helps to explain mechanisms underlying the metabolic syndrome and related cardiovascular diseases. To understand the importance of these findings it is useful to review the mechanisms coupling vascular and metabolic physiology, the role of inflammation in insulin resistance, and the role of insulin resistance to couple vascular and metabolic pathophysiology (Figure). See page 989 Coupling of Hemodynamic and Metabolic Physiology Through Insulin ActionRegulation of hemodynamic and metabolic homeostasis may be coupled by physiological actions of insulin in the vascular endothelium to stimulate production of NO. 4 The metabolic action of insulin to promote glucose uptake in skeletal muscle and adipose tissue is initiated by activation of the insulin receptor tyrosine kinase, subsequent phosphorylation of IRS-1, binding and activation of PI 3-kinase, activation of the serine kinase PDK-1, that in turn phosphorylates and activates Akt and PKC-, leading to recruitment of GLUT4 glucose transporters to the cell surface. 8 A similar pathway exists in vascular endothelium involving the insulin receptor, IRS-1, PI 3-kinase, PDK-1, and Akt that leads to phosphorylation and activation of eNOS by Akt with a resultant increase in production of NO. 9 -12 Insulin-stimulated production of NO leads to capillary recruitment, vasodilation, and increased blood flow to skeletal muscle that improves delivery of glucose and insulin to skeletal muscle. 4 Indeed, insulin-stimulated increases in capillary recr...

show abstract

“…Infusion of triglycerides in rats raises circulating FFA levels, causing significant impairment in skeletal muscle capillary recruitment. During a glucose clamp procedure, a 40% decrease in glucose disposal was observed in the rats, with steady state plasma insulin levels of approximately 600 pm [78] . In lean women, acute elevation of FFA levels impairs capillary recruitment and acetylcholine-mediated vasodilation before and during hyperinsulinemia [79] .…”

Section: Pathogenic Role Of Insulin Resistance In Hyperlipidemia Indumentioning

confidence: 98%

Adiponectin resistance and vascular dysfunction in the hyperlipidemic state

Liang

2010

Acta Pharmacol Sin

View full text Add to dashboard Cite

Insulin plays an important role in the stimulation of vascular nitric oxide production, with both short term (vasomotility and antithrombotic effects) and long term (smooth muscle cell growth and migration inhibition) benefits. Impaired vasodilatory response to insulin, the hallmark of vascular insulin resistance (IR), has important implications for circulatory pathophysiology. An association between adipokines and IR has been observed in both diabetic and nondiabetic states. Adiponectin (APN) is an insulin-sensitizing adipokine known to stimulate skeletal muscle fatty acid (FA) oxidation and reduce lipid accumulation. Recent demonstrations of potential cross-talk between APN and insulin in vascular function regulation are particularly interesting. The lipid accumulation observed after chronic high-fat (HF) diets and in the obese state may reduce vascular response to APN, a pathologic state termed as APN resistance. This review highlights the importance of insulin sensitivity and APN activity in the maintenance of endothelial function. It explores the relationships between vascular IR and APN resistance in the hyperlipidemic pathological condition, representative of the metabolic syndrome. The investigation of vascular insulin and APN resistance provides not only better understanding of vascular pathophysiology, but also an opportunity for therapeutic targeting in individuals affected by the metabolic syndrome.

show abstract

Lipid Infusion Impairs Physiologic Insulin-Mediated Capillary Recruitment and Muscle Glucose Uptake In Vivo

Cited by 146 publications

References 64 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

The Union of Vascular and Metabolic Actions of Insulin in Sickness and in Health

Adiponectin resistance and vascular dysfunction in the hyperlipidemic state

Contact Info

Product

Resources

About