R. Shankar et al., CENTRAL-NERVOUS-SYSTEM NITRIC-OXIDE SYNTHASE ACTIVITY REGULATES INSULIN-SECRETION AND INSULIN ACTION, The Journal of clinical investigation, 102(7), 1998, pp. 1403-1412
Systemic inhibition of nitric oxide synthase (NOS) with N(G-)monomethy
l-L-arginine (L-NMMA) causes acute insulin resistance (IR), but the me
chanism is unknown, We tested whether L-NMMA-induced IR occurs via NOS
blockade in the central nervous system (CNS), Six groups of Sprague-D
awley rats were studied after chronic implantation of an intracerebrov
entricular (ICV) catheter into the lateral ventricle and catheters int
o the carotid artery and jugular vein, Animals were studied after over
night food deprivation, awake, unrestrained, and unstressed; all ICV i
nfusion of L-NMMA or D-NMMA (control) were performed with artificial c
erebrospinal fluid. ICV administration of L-NMMA resulted in a 30% ris
e in the basal glucose level after 2 h, while ICV D-NMMA had no effect
on glucose levels. Insulin, epinephrine, and norepinephrine levels we
re unchanged from baseline in both groups. Tracer (H-3-3-glucose)-dete
rmined glucose disposal rates during 2 h euglycemic hyperinsulinemic (
300 mu U/ml) clamps performed after ICV administration of L-NMMA were
reduced by 22% compared with D-NMMA, Insulin secretory responses to a
hyperglycemic clamp and to a superimposed arginine bolus were reduced
by 28% in L-NMMA-infused rats compared with D-NMMA. In conclusion, ICV
administration of L-NMMA causes hyperglycemia via the induction of de
fects in insulin secretion and insulin action, thus recapitulating abn
ormalities observed in type 2 diabetes. The data suggest the novel con
cept that central NOS-dependent pathways may control peripheral insuli
n action and secretion. This control is not likely to be mediated via
adrenergic mechanisms and could occur via nonadrenergic, noncholinergi
c nitrergic neural and/or endocrine pathways. These data support previ
ously published data suggesting that CNS mechanisms may be involved in
the pathogenesis of some forms of insulin resistance and type 2 diabe
tes independent of adiposity.