The insulin-like growth factors (IGFs) are small peptides that are present in serum and extracellular fluids and stimulate the growth of many cell types. In extracellular fluids the IGFs are bound to carrier proteins that are believed to modify the biological actions of the IGFs. At least three structurally distinct IGF-binding proteins (IGF-BPs) have been identified, and the serum concentrations of one of these has been shown to be regulated by pituitary GH. We report here that this GH responsive protein [39,000–45,000 mol wt (Mr)] can be induced (7-fold) by infusion of IGF-I in hypophysectomized rats or (3.5-fold) in protein-deprived rats, whereas two other forms of IGF-BP e.g. 31,000–34,000 and 24,000 Mr) showed no change in the hypophysectomized animals and minimal increases in the protein-deprived animals. Likewise, GH injections in hypophysectomized animals resulted in a 7-fold increase in the 39,000–45,000 Mr form and no change in the 31,000–34,000 and 24,000 Mr forms. The protein-deprived animals showed a 3.2-fold increase in the 39,000–45,000 Mr and 2.4- to 1.8-fold increases in the 31,000–34,000 and 24,000 Mr forms, respectively. Changes in the larger Mr IGF-BP in these experimental models are paralleled by changes in serum IGF-I, suggesting that the GH dependence of the former protein is mediated at least partially via IGF-I. Our findings also suggest that the secretion of IGF-I and at least one IGF-BP may be linked, providing a mechanism by which their extracellular fluid concentrations are coordinated. Because IGF-BPs are present in extracellular fluids and can modulate IGF-I-receptor interaction, induction of this protein may be an important mediator of IGF action.
Protein deprivation in young rats retards growth and decreases serum insulin-like growth factor-I (IGF-I) concentrations, neither of which is prevented by injections of GH once daily. Since four time daily injections of GH in hypophysectomized rats increase serum IGF-I concentrations more efficiently than single daily injections, we assessed whether this mode of GH delivery could overcome the GH resistance of protein malnutrition. Also, we evaluated whether continuous GH infusion could override this GH resistance. We fed 4-week-old female Wistar rats a low (5%) protein diet (P5) or a normal (15%) protein diet (P15) for 7 days. In a first experiment, rats fed a P5 diet received 40 or 400 μg/100 g BWday rat GH (rGH) in four daily sc injections, while control P5 rats were injected at the same frequency with vehicle. In a second experiment, rats fed a P5 diet received 200 μg rGH/100 g BW-day by continuous infusion, while P5 sham-operated rats served as controls. IGF-I was measured by RIA on extracted serum, and free and total liver GH binding were determined by incubation of [125I] bovine GH with water- or MgCl2-treated homogenates, respectively. Neither continuous infusion nor repeated injections of rGH normalized the indices of growth or restored the serum IGF-I level to P15 control values. Injections of 400 ng rGH increased serum IGF-I 2-fold (P < 0.01), but did not promote growth. Continuous GH infusion increased total and free liver GH binding to P15 control values, but had no effect on serum IGFI. The discordance between liver GH binding and IGF-I confirms that a postreceptor defect is responsible for the GH resistance in protein restriction. These observations demonstrate that the consequences of protein restriction on growth are not overridden by intermittent or continuous administration of GH. The increase in IGF-I in response to 400 μg GH given intermittently in the absence of growth-promoting effects suggests that nutritional sufficiency is essential for IGF-I to promote growth. (Endocrinology126: 908–913,1990)
Several catabolic states (sepsis, cancer, etc.) associated with acute inflammation are characterized by a loss of skeletal muscle due to accelerated proteolysis. The main proteolytic systems involved are the autophagy and the ubiquitin-proteasome (UPS) pathways. Among the signaling pathways that could mediate proteolysis induced by acute inflammation, the transcription factor NF-κB, induced by TNFα, and the transcription factor forkhead box O (FOXO), induced by glucocorticoids (GC) and inhibited by IGF-I, are likely to play a key role. The aim of this study was to identify the nature of the molecular mediators responsible for the induction of these muscle proteolytic systems in response to acute inflammation caused by LPS injection. LPS injection robustly stimulated the expression of several components of the autophagy and the UPS pathways in the skeletal muscle. This induction was associated with a rapid increase of circulating levels of TNFα together with a muscular activation of NF-κB followed by a decrease in circulating and muscle levels of IGF-I. Neither restoration of circulating IGF-I nor restoration of muscle IGF-I levels prevented the activation of autophagy and UPS genes by LPS. The inhibition of TNFα production and muscle NF-κB activation, respectively by using pentoxifilline and a repressor of NF-κB, did not prevent the activation of autophagy and UPS genes by LPS. Finally, inhibition of GC action with RU-486 blunted completely the activation of these atrogenes by LPS. In conclusion, we show that increased GC production plays a more crucial role than decreased IGF-I and increased TNFα/NF-κB pathway for the induction of the proteolytic systems caused by acute inflammation.
Nous rapportons le cas d'une patiente presentant un diabete insipide nephrogenique ainsi qu'une alteration de la filtration glomerulaire probablement secondaires a la prise de lithium pour le traitement d'une psychose maniaco-depressive. Nous passons en revue la pharmacocinetique du lithium, ses effets secondaires sur la fonction renale, a savoir l'alteration du pouvoir de concentration du rein allant jusqu'au diabete insipide nephrogenique ainsi que l'alteration de filtration glomerulaire et leur eventuelle reversibilite. Sur le plan physiopathologique, cet effet du lithium semble secondaire a une insensibilite des tubes collecteurs a la vasopressine qui amene une diminution de l'expression d'un canal responsable du transport de l'eau au niveau tubulaire (aquaporine-2).
