Insulin resistance in mice lacking neuronal nitric oxide synthase is related to an alpha-adrenergic mechanism.
BACKGROUND
nitric oxide (NO) plays an important role in the regulation of cardiovascular and glucose homeostasis. Mice lacking the gene encoding the neuronal isoform of nitric oxide synthase (nNOS) are insulin-resistant, but the underlying mechanism is unknown. nNOS is expressed in skeletal muscle tissue where it may regulate glucose uptake. Alternatively, nNOS driven NO synthesis may facilitate skeletal muscle perfusion and substrate delivery. Finally, nNOS dependent NO in the central nervous system may facilitate glucose disposal by decreasing sympathetic nerve activity.


METHODS
in nNOS null and control mice, we studied whole body glucose uptake and skeletal muscle blood flow during hyperinsulinaemic clamp studies in vivo and glucose uptake in skeletal muscle preparations in vitro. We also examined the effects of alpha-adrenergic blockade (phentolamine) on glucose uptake during the clamp studies.


RESULTS
as expected, the glucose infusion rate during clamping was roughly 15 percent lower in nNOS null than in control mice (89 (17) vs 101 (12) [-22 to -2]). Insulin stimulation of muscle blood flow in vivo, and intrinsic muscle glucose uptake in vitro, were comparable in the two groups. Phentolamine, which had no effect in the wild-type mice, normalised the insulin sensitivity in the mice lacking the nNOS gene.


CONCLUSIONS
insulin resistance in nNOS null mice was not related to defective insulin stimulation of skeletal muscle perfusion and substrate delivery or insulin signaling in the skeletal muscle cell, but to a sympathetic alpha-adrenergic mechanism.
Turini
P
P
Department of Internal Medicine and Botnar Center for Clinical Research, CHUV, Lausanne, Switzerland.
Thalmann
S
S
Jayet
P-Y
PY
Cook
S
S
Mathieu
C
C
Burcelin
R
R
Nicod
P
P
Vollenweider
P
P
Sartori
C
C
Scherrer
U
U
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D005260:Female; D015309:Glucose Clamp Technique; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics* / Q000378:metabolism*; D010646:Phentolamine / Q000378:metabolism / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D001786:Blood Glucose; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D010646:Phentolamine