No abstract

Systemic inhibition of nitric oxide synthase (NOS) with N Gmonomethyl-L -arginine ( L -NMMA) causes acute insulin resistance (IR), but the mechanism is unknown. We tested whether L -NMMA-induced IR occurs via NOS blockade in the central nervous system (CNS). Six groups of SpragueDawley rats were studied after chronic implantation of an intracerebroventricular (ICV) catheter into the lateral ventricle and catheters into the carotid artery and jugular vein. Animals were studied after overnight food deprivation, awake, unrestrained, and unstressed; all ICV infusion of L -NMMA or D -NMMA (control) were performed with artificial cerebrospinal fluid. ICV administration of L -NMMA resulted in a 30% rise in the basal glucose level after 2 h, while ICV D -NMMA had no effect on glucose levels. Insulin, epinephrine, and norepinephrine levels were unchanged from baseline in both groups. Tracer ( 3 H-3-glucose)-determined glucose disposal rates during 2 h euglycemic hyperinsulinemic (300 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 defects in insulin secretion and insulin action, thus recapitulating abnormalities observed in type 2 diabetes. The data suggest the novel concept that central NOS-dependent pathways may control peripheral insulin action and secretion. This control is not likely to be mediated via adrenergic mechanisms and could occur via nonadrenergic, noncholinergic nitrergic neural and/or endocrine pathways. These data support previously published data suggesting that CNS mechanisms may be involved in the pathogenesis of some forms of insulin resistance and type 2 diabetes independent of adiposity. ( J. Clin. Invest.

No abstract

We previously reported that perinatal exposure to hypergravity affects cerebellar structure and motor coordination in rat neonates. In the present study, we explored the hypothesis that neonatal cerebellar structure and motor coordination may be particularly vulnerable to the effects of hypergravity during specific developmental stages. To test this hypothesis, we compared neurodevelopment, motor behavior and cerebellar structure in rat neonates exposed to 1.65 G on a 24-ft centrifuge during discrete periods of time: the 2 nd week of pregnancy [gestational day (G) 8 through G15; group A], the 3 rd week of pregnancy (G15 through birth on G22/G23; group B), the 1 st week of nursing [birth through postnatal day (P) 6; group C], the 2 nd and 3 rd weeks of nursing (P6 through P21; group D), the combined 2 nd and 3 rd weeks of pregnancy and nursing (G8 through P21; group E) and stationary control (SC) neonates (group F). Prenatal exposure to hypergravity resulted in intrauterine growth retardation as reflected by a decrease in the number of pups in a litter and lower average mass at birth. Exposure to hypergravity immediately after birth impaired the righting response on P3, while the startle response in both males and females was most affected by exposure during the 2 nd and 3 rd weeks after birth. Hypergravity exposure also impaired motor functions, as evidenced by poorer performance on a rotarod; while both males and females exposed to hypergravity during the 2 nd and 3 rd weeks after birth performed poorly on P21, male neonates were most dramatically affected by exposure to hypergravity during the second week of gestation, when the duration of their recorded stay on the rotarod was one half that of SC males. Cerebellar mass was most reduced by later postnatal exposure. Thus, for the developing rat cerebellum, the postnatal period that overlaps the brain growth spurt is the most vulnerable to hypergravity. However, male motor behavior is also affected by midpregnancy exposure to hypergravity, suggesting discrete and sexually dimorphic windows of vulnerability of the developing central nervous system to environmental perturbations.

No abstract