We evaluated whether early-life protein restriction alters structural parameters that affect β-cell mass on the 15th day and 20th day of gestation in control pregnant (CP), control non-pregnant (CNP), low-protein pregnant (LPP) and low-protein non-pregnant (LPNP) rats from the fetal to the adult life stage as well as in protein-restricted rats that recovered after weaning (recovered pregnant (RP) and recovered non-pregnant). On the 15th day of gestation, the CNP group had a higher proportion of smaller islets, whereas the CP group exhibited a higher proportion of islets larger than the median. The β-cell mass was lower in the low-protein group than that in the recovered and control groups. Gestation increased the β-cell mass, β-cell proliferation frequency and neogenesis frequency independently of the nutritional status. The apoptosis frequency was increased in the recovered groups compared with that in the other groups. On the 20th day of gestation, a higher proportion of islets smaller than the median was observed in the non-pregnant groups, whereas a higher proportion of islets larger than the median was observed in the RP, LPP and CP groups. β-Cell mass was lower in the low-protein group than that in the recovered and control groups, regardless of the physiological status. The β-cell proliferation frequency was lower, whereas the apoptosis rate was higher in recovered rats compared with those in the low-protein and control rats. Thus, protein malnutrition early in life did not alter the mass of β-cells, especially in the first two-thirds of gestation, despite the increase in apoptosis.

Undernutrition is a stressor with long-term consequences, and the effect of nutritional recovery on cortisol and thyroid hormone status is unknown. To investigate basal thyroid hormones and the cortisol response to a cold pressor test in children recovered from undernutrition, a cross-sectional study was undertaken on children (6–16 years) separated into four groups: control (n 41), stunted (n 31), underweight (n 27) and recovered (n 31). Salivary cortisol was collected over the course of 10 h: upon awakening, before and after an unpleasant and a pleasant stimulus. Cortisol upon awakening was highest in the stunted and lowest in the underweight groups: control=5·05 (95 % CI 3·71, 6·89) nmol/l, stunted=6·62 (95 % CI 3·97, 11·02) nmol/l, underweight=2·51 (95 % CI 1·75, 3·63) nmol/l and recovered=3·46 (95 % CI 2·46, 4·90) nmol/l (P=0·005). Girls had higher cortisol concentrations upon awakening compared with boys (P=0·021). The undernourished groups showed an elevated cortisol response both to the unpleasant stimulus and at the last measurement (16.00 hours) compared with that of the recovered group: AUC, control=2·07 (95 % CI 1·69, 2·45) nmol/l×30 min, stunted=2·48 (95 % CI 1·91, 3·06) nmol/l×30 min, underweight=2·52 (95 % CI 2·07, 2·97) nmol/l×30 min, recovered=1·68 (95 % CI 1·26, 2·11) nmol/l×30 min (P=0·042); and control=2·03 (95 % CI 1·75, 2·39) nmol/l×30 min, stunted=2·51 (95 % CI 1·97, 3·19) nmol/l×30 min, underweight=2·61 (95 % CI 2·16, 3·16) nmol/l×30 min, recovered=1·70 (95 % CI 1·42, 2·03) nmol/l×30 min (P=0·009). Lower free thyroxine (T4) was found in the recovered and stunted groups: control=1·28 (95 % CI 1·18, 1·39) pmol/l, stunted=0·98 (95 % CI 0·87, 1·10) pmol/l, underweight=1·10 (95 % CI 1·01, 1·21) pmol/l and recovered=0·90 (95 % CI 0·83, 0·99) pmol/l (P<0·001). Multivariate analysis showed a lower cortisol concentration along 10 h (06.00–16.00 hours) in the recovered compared with the other groups (P=0·017), and similar concentrations between the recovered and control group. In conclusion, the children with recovery in weight and height had a cortisol stress response similar to control but a lower basal free T4. Longitudinal studies are warranted to determine the extent of these endocrine changes after recovery of undernutrition and in adulthood.

Undernutrition in early life has been reported to be closely associated with the development of non-communicable diseases in adulthood. Adequate treatment is important for reversing these effects. In the present study, we investigated the effects of undernutrition and anthropometric recovery on the weights and heights of children in relation to the concentrations of leptin, adiponectin and plasminogen activator inhibitor-1 (PAI-1). A total of 119 children (aged 6–16 years) from the slums of São Paulo were selected according to their nutritional status and divided into three groups as follows: control (healthy without intervention, n 38) with a height-for-age Z score (HAZ) and a BMI-for-age Z score (BAZ) > − 1·6; undernourished (HAZ and/or BAZ < − 1·6, n 54); recovered from undernutrition (after treatment in a rehabilitation centre; HAZ and BAZ > − 1·6, n 27). Blood samples were collected to determine insulin, glucose, leptin, adiponectin and PAI-1 concentrations. Leptin concentrations in the undernourished group were lower than those in the control and recovered groups (mean 0·92 (95 % CI 0·67, 1·25), 2·03 (95 % CI 1·46, 2·82) and 1·66 (95 % CI 1·15, 2·44) ng/ml, P= 0·003), which had similar leptin concentrations. There were no differences in adiponectin and PAI-1 concentrations among the groups. A positive correlation between waist circumference and leptin concentrations was observed in all the girls and boys of the control group (control: r 0·729, P< 0·01; undernourished: r 0·490, P< 0·05; and recovered: r 0·829, P< 0·01; r 0·673, P< 0·05). Stronger correlations between leptin and insulin concentrations were observed in the recovered group. The results of the present study indicate that normal leptin concentrations are found when normal height and weight are achieved.

Malnutrition in early life impairs glucose-stimulated insulin secretion in adulthood. Conversely, pregnancy is associated with a significant increase in glucose-stimulated insulin secretion under conditions of normoglycaemia. A failure in β-cell adaptive changes may contribute to the onset of diabetes. Thus, glucose homeostasis and β-cell function were evaluated in control-fed pregnant (CP) and non-pregnant (CNP) or protein-restricted pregnant (LPP) and non-pregnant (LPNP) rats, from fetal to adult life, and in protein-restricted rats that were recovered after weaning (RP and RNP). The typical insulin resistance of pregnancy was not observed in the RP rats, nor did pregnancy increase the insulin content/islet in the LPP group. The glucose dose–response curves from pregnant rats were shifted to the left in relation to the non-pregnant rats, except in the recovered group. Glucose utilisation but not oxidation in islets from the RP and LPP groups was reduced at a concentration of 8·3 mm-glucose compared with islets from the CP group. Cyclic AMP content and the potentiation of glucose-stimulated insulin secretion by isobutylmethylxanthine at a concentration of 2·8 mm-glucose indicated increased adenylyl cyclase 3 activity but reduced protein kinase A-α activity in islets from the RP and LPP rats. Protein kinase C (PKC)-α but not phospholipase C (PLC)-β1 expression was reduced in islets from the RP group. Phorbol-12-myristate 13-acetate produced a less potent stimulation of glucose-stimulated insulin secretion in the RP group. Thus, the alterations exhibited by islets from the LPP group appeared to be due to reduced islet mass and/or insulin biosynthesis. In the RP group the loss of the adaptive capacity apparently resulted from uncoupling between glucose metabolism and the amplifying signals of the secretory process, as well as a severe attenuation of the PLC/PKC pathway.

Nutritional recovery with a soyabean diet decreases body and fat weights when compared with a casein diet. We investigated whether the reduced adiposity observed in rats recovering from early-life malnutrition with a soyabean diet results from alterations in lipid metabolism in white adipose tissue (WAT) and/or brown adipose tissue (BAT). Male rats from mothers fed either 17 or 6 % protein during pregnancy and lactation were maintained on 17 % casein (CC and LC groups), 17 % soyabean (CS and LS groups) or 6 % casein (LL group) diets over 60 d. The rats maintained on a soyabean diet had similar relative food intakes, but lower body and retroperitoneal WAT weights and a reduced lipid content in the retroperitoneal WAT. The insulin levels were lower in the recovered rats and were elevated in those fed a soyabean diet. Serum T3 concentration and uncoupling protein 1 content in the BAT were decreased in the recovered rats. The thermogenic capacity of the BAT was not affected by the soyabean diet. The lipogenesis rate in the retroperitoneal WAT was similar in all of the groups except for the LL group, which had exacerbated lipogenesis. The enhancement of the lipolysis rate by isoproterenol was decreased in white adipocytes from the soyabean-recovered rats and was elevated in adipocytes from the soyabean-control rats. Thus, in animals maintained on a soyabean diet, the proportions of fat deposits are determined by the lipolysis rate, which differs depending on the previous nutritional status.

Protein–energy malnutrition promotes adaptive hormonal changes that result in stunting. A previous study showed that stunted children had increased insulin sensitivity and diminished pancreatic β-cell function. The objectives of the present study were to analyse the glucose, insulin, homeostasis model assessment of insulin sensitivity (HOMA-S) and homeostasis model assessment of pancreatic β-cell function (HOMA-B) levels after nutritional recovery. The recovered group (n 62) consisted of malnourished children after treatment at a nutrition rehabilitation centre. At the beginning of treatment their age was 2·41 (sd 1·28) and 2·31 (sd 1·08) years, weight-for-age Z score − 2·09 (sd 0·94) and − 2·05 (sd 0·55) and height-for-age Z score − 1·85 (sd 1·11) and − 1·56 (sd 0·90), for boys and girls respectively. The control group consisted of well-nourished children without treatment (n 26). After treatment, boys of the recovered group gained 1·29 (sd 1·06) Z scores of height-for-age and 1·14 (sd 0·99) Z scores of weight-for-age, and girls, 1·12 (sd 0·91) and 1·21 (sd 0·74) Z scores respectively. No differences were found between control and recovered groups in insulin levels for boys (P = 0·704) and girls (P = 0·408), HOMA-B for boys (P = 0·451) and girls (P = 0·330), and HOMA-S (P = 0·765) for boys and girls (P = 0·456) respectively. The present study shows that the changes observed previously in glucose metabolism and insulin were reverted in children who received adequate treatment at nutritional rehabilitation centres and showed linear catch-up.

The objective of the present study is to demonstrate the effect of nucleotide intake and intensive nutritional support on the concentration of insulin-like growth factor I (IGF-I) and other hormonal biomarkers in severely malnourished children. Twenty-six severely malnourished children <48 months of age received formula without lactose via enteral feeding for 2 weeks and ad libitum for an additional 2 weeks. Anthropometrical measurements were performed and serum concentrations of IGF-I, insulin-like growth factor binding protein-3 (IGFBP-3), leptin, soluble leptin receptor (sOB-R), as well as the estimated molar excess of sOB-R over leptin were obtained. Two groups were formed. One group received formula with nucleotides (NT+; n 13) and the other without nucleotides (NT−; n 13). A control group was included (n 13). Parametric and non-parametric tests as well as ANOVA models were used. Nutritional recovery, nucleotides intake, type of malnutrition, age and the interaction between gender and malnutrition influenced the concentration of IGF-I (P<0·001). Nutritional recovery, nucleotides intake, gender and type of malnutrition had an effect on IGFBP-3 (P<0·001). Nutritional recovery had a significant effect on serum leptin (P=0·001). Age and nutritional recovery had an effect on sOB-R (P<0·001); all variables included affected the molar excess of sOB-R over leptin (P<0·001). In conclusion, nucleotide intake and nutritional recovery had a notable effect on IGF-I, IGFBP-3 and other hormonal biomarkers. This outcome could stimulate the catch-up growth of severely malnourished infants and toddlers during the nutritional recovery period.