Reduced liver insulin-like growth factor-I gene expression in young zinc-deprived rats is associated with a decrease in liver growth hormone (GH) receptors and serum GH-binding protein.

Zinc depletion attenuates growth and decreases circulating IGF-I. To investigate the mechanisms responsible for the IGF-I decline, we determined the effects of dietary zinc (Zn) deficiency on body and organ growth, serum IGF-I, serum GH-binding protein (GHBP), liver GH receptors and liver expression of their corresponding gene. After 1 week of adaptation to a normal zinc diet, a zinc-deficient diet (ZD; Zn, 0 p.p.m.) or a zinc-normal diet (CTR; Zn, 75 p.p.m.) was available ad libitum to 4-week-old Wistar rats for 4 weeks. Pair-fed animals (PF) received the zinc-normal diet in the same absolute amount as that consumed the day before by the ZD group. The food intake of ZD and PF rats was reduced by 32% (P < 0.001) compared with the CTR group. Zinc depletion specifically reduced body weight gain (-22%, P < 0.05), serum IGF-I concentrations (-52%, P < 0.001), hepatic GH receptors (-28%; P < 0.05) and serum GHBP levels (-51%; P < 0.05), compared with the PF group. GH concentrations were reduced in ZD animals compared with CTR rats (P < 0.01). The caloric restriction of PF animals also decreased body weight gain (-50%, P < 0.001), serum IGF-I concentrations (-21%, P < 0.05), liver GH receptors (-38%, P < 0.001) and serum GHBP levels (-38%, P < 0.01), when compared with the CTR group. Both ZD and PF groups had reduced liver IGF-I and GH receptor/GHBP mRNA levels in comparison with the CTR group (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS

Failure of exogenous IGF-I to restore normal growth in rats submitted to dietary zinc deprivation.

Dietary zinc deficiency in rats causes growth retardation associated with decreased circulating IGF-I concentrations. To investigate the potential role of low IGF-I in this condition, we attempted to reverse the growth failure by administration of exogenous IGF-I. Rats were fed for 4 weeks a zinc-deficient diet (ZD, Zn 0 ppm) or were pair-fed a zinc-normal diet (PF, Zn 75 ppm). We compared the anabolic action of recombinant human (rh) IGF-I infused at the dose of 120 microg/day for the last experimental week in ZD, PF and freely fed control (CTRL) rats. Zinc deficiency caused growth stunting (weight gain 47% of PF; P<0.001), decreased circulating IGF-I (52% of PF; P<0.01) and liver IGF-I mRNA (67% of PF; P<0.01). Serum insulin-like growth factor-binding protein-3 (IGFBP-3) assessed by ligand blot was also reduced in ZD rats (65% of PF; P<0. 01). While exogenous IGF-I increased body weight in CTRL (+12 g; P<0. 01) and PF (+7 g; not significant) animals, growth was not stimulated in ZD rats (-1.5 g) in comparison with the corresponding untreated groups. However, circulating IGF-I and IGFBP-3 levels were restored by IGF-I infusion to levels similar to those in untreated CTRL rats. In conclusion, restoration of normal circulating levels of IGF-I and IGFBP-3 by rhIGF-I infusion fails to reverse the growth retardation induced by zinc deficiency. These results suggest that growth retardation related to zinc deficiency is not only caused by low serum IGF-I concentrations, but also by inhibition of the anabolic actions of IGF-I

Zinc supplementation increases growth and circulating insulin-like growth factor I (IGF-I) in growth-retarded Vietnamese children.

To determine whether zinc deficiency might be involved in the failure to thrive observed in undernourished Vietnamese children, we assessed growth, incidence of infections, and circulating insulin-like growth factor I (IGF-I) concentrations in a double-blind study of zinc supplementation. Growth-retarded children (n=146) aged 4-36 mo were paired according to age, sex, commune, Z scores for weight (WAZ) and for height (HAZ), and number of siblings, and were randomly assigned to receive either 153 micromol (10 mg) Zn/d or a placebo for 5 mo. Weight, height, and episodes of infection were recorded each month and plasma IGF-I was measured 1 and 5 mo after the start of zinc supplementation. Multiple-linear-regression analysis for paired data showed that zinc supplementation increased weight (+0.5 +/- 0.1 kg; P<0.001) and height (+1.5+/-0.2 cm; P<0.001) after 5 mo compared with placebo treatment. The relative risk of infectious episodes in the zinc-treated subjects was reduced 3-fold for diarrhea (P=0.012) and 2.5-fold for respiratory infections (p=0.057). The probability of having at least two episodes of diarrhea or respiratory infection was 2.9- and 3.2-fold lower, respectively, in zinc-treated subjects between 1 and 5 mo (P=0.018), whereas they did not change in placebo-treated subjects (P-0.584). After 1 mo, IGF-I concentration (-x+/-SD) in zinc-treated subjects was 2.8+/-0.3 nmol/L compared with 1.9+/-0.2 nmol/L in placebo-treated subjects (P=0.021). After 5 mo, the values were 3.4+/-0.5 nmol/L (zinc-treated) and 2.0+/-0.3 nmol/L (placebo-treated; P=0.044). Our study suggests that zinc deficiency may limit growth in nutritionally deprived children. Because the increase in growth velocity resulting from zinc supplementation was associated with increased plasma IGF-I concentrations, we suggest that the growth-stimulating effect of zinc might be mediated through changes in circulating IGF-I

Continuous administration of growth hormone does not prevent the decrease of IGF-I gene expression in zinc-deprived rats despite normalization of liver GH binding.

To determine the role of reduced liver GH binding (GHR) in the decreased IGF-I observed in zinc-deficient (ZD) animals, we investigated the effects of GHR restoration on growth, insulin-like growth factor I (IGF-I) and its binding proteins (IGFBPs) in ZD rats. Rats were fed for 4 weeks a zinc-deficient diet (ZD Zn, 0 ppm) or a Zinc-normal diet (pair-fed or PF; Zn, 75 ppm). ZD rats received continuous s.c. infusion of bovine growth hormone (bGH) (100 microg/d) for the 4 weeks or for the last week of the study. Compared with pair-fed rats, zinc deficiency produced attenuated weight gain (-43%, P < 0.001), lower serum IGF-I and liver IGF-I mRNA (-52%, P < 0.001 and -44%, P < 0.05), lower serum IGFBPs (IGFBP-3 -66%, IGFBP-4 -48%, 34-29 kDa IGFBP cluster -53%, P < 0.05), lower liver GHR and its mRNA (-20 and -34%, P < 0.05) and lower serum growth hormone binding protein (GHBP) and its mRNA (-56 and -48%, P < 0.05; all comparisons vs PF rats). Exogenous bGH given continuously normalized the liver GHR, serum GHBP and their liver mRNAs, as well as circulating IGFBPs. Despite restoration of GHR and GHBP to normal, growth, serum IGF-I and its liver mRNA were not stimulated by GH infusion in ZD rats, indicating that IGF-I synthesis requires the presence of zinc in addition to GH, and that the lack of growth-promoting action of GH in zinc-deprived rats results from a defect beyond GH binding to its liver receptors

Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials

Background: Zinc deficiency is prevalent in children in developing countries. Supplemental zinc provides therapeutic benefits in diarrhea.Objective: We sought to measure the effect of supplemental zinc given with oral rehydration therapy during recovery from acute or persistent diarrhea.Design: We conducted pooled analyses including all available published and unpublished randomized controlled trials of the effects of supplementary oral zinc in children aged \u3c5 y with acute or persistent diarrhea. We used Cox survival regression analysis to evaluate the overall effect of zinc on continuation of diarrhea and possible differential effects in subgroups divided by sex, age, weight-for-height, and initial plasma zinc concentration. Dichotomous outcomes were analyzed by logistic regression. To assess the effects of excluding studies without original data from the pooled analyses, effect-size was estimated for all studies by using random-effects models.Results: Zinc-supplemented children had a 15% lower probability of continuing diarrhea on a given day (95% CI: 5%, 24%) in the acute-diarrhea trials and a 24% lower probability of continuing diarrhea (95% CI: 9%, 37%) and a 42% lower rate of treatment failure or death (95% CI: 10%, 63%) in the persistent-diarrhea trials. In none of the subgroup analyses were the 2 subgroups of each pair significantly different from each other; however, in persistent diarrhea there tended to be a greater effect in subjects aged \u3c12 mo, who were male, or who had wasting or lower baseline plasma zinc concentrations.CONCLUSION: Zinc supplementation reduces the duration and severity of acute and persistent diarrhea