Protein kinase C [theta] activation induces insulin-mediated constriction of muscle resistance arteries

Citation metadata

From: Diabetes(Vol. 57, Issue 3)
Publisher: American Diabetes Association
Document Type: Article
Length: 5,454 words
Lexile Measure: 1460L

Document controls

Main content

Article Preview :

OBJECTIVE--Protein kinase C (PKC) [theta] activation is associated with insulin resistance and obesity, but the underlying mechanisms have not been fully elucidated. Impairment of insulin-mediated vasoreactivity in muscle contributes to insulin resistance, but it is unknown whether PKC[theta] is involved. In this study, we investigated whether PKC[theta] activation impairs insulin-mediated vasoreactivity and insulin signaling in muscle resistance arteries.

RESEARCH DESIGN AND METHODS--Vasoreactivity of isolated resistance arteries of mouse gracilis muscles to insulin (0.02-20 nmol/l) was studied in a pressure myograph with or without PKC[theta] activation by palmitic acid (PA) (100 [micro]mol/l).

RESULTS--In the absence of PKC[theta] activation, insulin did not alter arterial diameter, which was caused by a balance of nitric oxide-dependent vasodilator and endothelin-dependent vasoconstrictor effects. Using three-dimensional microscopy and Western blotting of muscle resistance arteries, we found that PKC[theta] is abundantly expressed in endothelium of muscle resistance arteries of both mice and humans and is activated by pathophysiological levels of PA, as indicated by phosphorylation at [Thr.sup.538] in mouse resistance arteries. In the presence of PA, insulin induced vasoconstriction (21 [+ or -] 6% at 2 nmol/l insulin), which was abolished by pharmacological or genetic inactivation of PKC[theta]. Analysis of intracellular signaling in muscle resistance arteries showed that PKC[theta] activation reduced insulin-mediated Akt phosphorylation ([Ser.sup.473]) and increased extracellular signal-related kinase (ERK) 1/2 phosphorylation. Inhibition of PKC[theta] restored insulin-mediated vasoreactivity and insulin-mediated activation of Akt and ERK1/2 in the presence of PA.

CONCLUSIONS--PKC[theta] activation induces insulin-mediated vasoconstriction by inhibition of Akt and stimulation of ERK1/2 in muscle resistance arteries. This provides a new mechanism linking PKC[theta] activation to insulin resistance. Diabetes 57: 706-713, 2008

Obesity is associated with disturbed insulin signaling (1), leading to muscle insulin resistance (i.e., impaired insulin-mediated glucose uptake in muscle) (2). Insulin resistance increases the risk for development of type 2 diabetes and hypertension (3). The impairment of vasoactive responses to insulin in microcirculation (4) has been described to contribute to insulin resistance by reducing appropriate delivery of insulin and glucose to skeletal muscle myocytes. However, the exact mechanism behind impaired vascular insulin responses leading to insulin resistance remains to be elucidated.

Impairment of insulin-mediated vasoreactivity in the muscle microcirculation is characterized by an imbalance between insulin-mediated nitric oxide (NO) and endothelin-1 (ET-1) production. In microcirculation, insulin regulates vasoactive responses by stimulating both vasodilator and vasoconstrictor effects. Insulin has been shown to induce vasodilatation by activation of Akt, which enhances [Ser.sup.1177] phosphorylation and activity of endothelial NO synthase (5). This vasodilator effect regulates nutritive muscle blood flow and, consequently, contributes to insulin-mediated glucose uptake in muscle (6). Vasoconstrictor effects of insulin are critically dependent on the activation of extracellular signal-related kinase (ERK) 1/2, which controls ET-1 release by the endothelium (7-9). Increased ET-1 activity, as observed in insulin-resistant states, has been shown to impair blood flow and glucose uptake (10). In microvessels of insulin-resistant animals, it has been observed that insulin-mediated Akt activation is selectively impaired, whereas ERK1/2 activation is not altered (11).

Protein kinase C (PKC) [theta] activation impairs insulin signaling and may be...

Source Citation

Source Citation   

Gale Document Number: GALE|A176652706