Early weaning induces short- and long-term effects on pancreatic islets in Wistar rats of both sexes.

KEY POINTS: The World Health Organization recommends exclusive breastfeeding until 6 months of age as an important strategy to reduce child morbidity and mortality. Studies have associated early weaning with the development of obesity and type 2 diabetes in adulthood. In our model, we demonstrated that early weaning leads to increased insulin secretion in adolescent males and reduced insulin secretion in adult offspring. Early weaned males exhibit insulin resistance in skeletal muscle. Early weaning did not change insulin signalling in the muscle of female offspring. Taking into account that insulin resistance is one of the primary factors for the development of type 2 diabetes mellitus, this work demonstrates the importance of breastfeeding in the fight against this disease. ABSTRACT: Early weaning (EW) leads to short- and long-term obesity and diabetes. This phenotype is also observed in experimental models, in which early-weaned males exhibit abnormal insulinaemia in adulthood. However, studies regarding the effect of EW on pancreatic islets are rare. We investigated the mechanisms by which glycaemic homeostasis is altered in EW models through evaluations of insulin secretion and its signalling pathway in offspring. Lactating Wistar rats and their pups were divided into the following groups: non-pharmacological EW (NPEW): mothers were wrapped with an adhesive bandage on the last 3 days of lactation; pharmacological EW (PEW): mothers received bromocriptine to inhibit prolactin (1 mg/kg body mass/day) on the last 3 days of lactation; and control (C): pups underwent standard weaning at PN21. Offspring of both sexes were euthanized at PN45 and PN180. At PN45, EW males showed higher insulin secretion (vs. C). At PN170, PEW males exhibited hyperglycaemia in an oral glucose tolerance test (vs. C and NPEW). At PN180, EW male offspring were heavier; however, both sexes showed higher visceral fat. Insulin secretion was lower in EW offspring of both sexes. Males from both EW groups had lower glucokinase in islets, but unexpectedly, PEW males showed higher GLUT2, than did C. EW males exhibited lower insulin signalling in muscle. EW females exhibited no changes in these parameters compared with C. We demonstrated distinct alterations in the insulin secretion of EW rats at different ages. Despite the sex dimorphism in insulin secretion in adolescence, both sexes showed impaired insulin secretion in adulthood due to EW.

Nutritional recovery from a low-protein diet during pregnancy does not restore the kinetics of insulin secretion and Ca2+ or alterations in the cAMP/PKA and PLC/PKC pathways in islets from adult rats.

We investigated the insulin release induced by glucose, the Ca2+ oscillatory pattern, and the cyclic AMP (cAMP)/protein kinase A (PKA) and phospholipase C (PLC)/protein kinase C (PKC) pathways in islets from adult rats that were reared under diets with 17% protein (C) or 6% protein (LP) during gestation, suckling, and after weaning and in rats receiving diets with 6% protein during gestation and 17% protein after birth (R). First-phase glucose-induced insulin secretion was reduced in LP and R islets, and the second phase was partially restored in the R group. Glucose stimulation did not modify intracellular Ca2+ concentration, but it reduced the Ca2+ oscillatory frequency in the R group compared with the C group. Intracellular cAMP concentration was higher and PKA-Cα expression was lower in the R and LP groups compared with the C group. The PKCα content in islets from R rats was lower than that in C and LP rats. Thus, nutritional recovery from a low-protein diet during fetal life did not repair the kinetics of insulin release, impaired Ca2+ handling, and altered the cAMP/PKA and PLC/PKC pathways.

Nutritional recovery with a soybean diet after weaning reduces lipogenesis but induces inflammation in the liver in adult rats exposed to protein restriction during intrauterine life and lactation.

We evaluated the effects of postweaning nutritional recovery with a soybean flour diet on de novo hepatic lipogenesis and inflammation in adult rats exposed to protein restriction during intrauterine life and lactation. Rats from mothers fed with protein (casein) in a percentage of 17% (control, C) or 6% (low, L) during pregnancy and lactation were fed with diet that contained 17% casein (CC and LC groups, resp.) or soybean (CS and LS groups, resp.) after weaning until 90 days of age. LS and CS rats had low body weight, normal basal serum triglyceride levels, increased ALT concentrations, and high HOMA-IR indices compared with LC and CC rats. The soybean diet reduced PPARγ as well as malic enzyme and citrate lyase contents and activities. The lipogenesis rate and liver fat content were lower in LS and CS rats relative to LC and CC rats. TNFα mRNA and protein levels were higher in LS and CS rats than in LC and CC rats. NF-κB mRNA levels were lower in the LC and LS groups compared with the CC and LC groups. Thus, the soybean diet prevented hepatic steatosis at least in part through reduced lipogenesis but resulted in TNFα-mediated inflammation.

A low-protein diet during pregnancy prevents modifications in intercellular communication proteins in rat islets

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Nutritional recovery promotes hypothalamic inflammation in rats during adulthood.

We evaluated whether protein restriction in fetal life alters food intake and glucose homeostasis in adulthood by interfering with insulin signal transduction through proinflammatory mechanisms in the hypothalamus and peripheral tissues. Rats were divided into the following: a control group (C); a recovered group (R); and a low protein (LP) group. Relative food intake was greater and serum leptin was diminished in LP and R compared to C rats. Proinflammatory genes and POMC mRNA were upregulated in the hypothalamus of R group. Hypothalamic NPY mRNA expression was greater but AKT phosphorylation was diminished in the LP than in the C rats. In muscle, AKT phosphorylation was higher in restricted than in control animals. The HOMA-IR was decreased in R and C compared to the LP group. In contrast, the K(itt) in R was similar to that in C and both were lower than LP rats. Thus, nutritional recovery did not alter glucose homeostasis but produced middle hyperphagia, possibly due to increased anorexigenic neuropeptide expression that counteracted the hypothalamic inflammatory process. In long term protein deprived rats, hyperphagia most likely resulted from increased orexigenic neuropeptide expression, and glucose homeostasis was maintained, at least in part, at the expense of increased muscle insulin sensitivity.

Protein restriction in early life is associated with changes in insulin sensitivity and pancreatic ß-cell function during pregnancy.

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 ß-cell adaptive changes may contribute to the onset of diabetes. Thus, glucose homeostasis and ß-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)-ß1 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 soybean flour diet improves the insulin response to a glucose load without modifying glucose homeostasis.

OBJECTIVE: We investigated the effect of nutritional recovery with a soybean flour diet on glucose tolerance, insulin response to a glucose load, and the action of insulin in adult rats exposed to a protein deficiency during intrauterine life and lactation. METHODS: Male Wistar rats from dams fed a normal- or low-protein diet during pregnancy and lactation were maintained after weaning by feeding them normal-protein isoenergetic diets containing soybean flour or casein and low-protein casein diet. RESULTS: Rats fed a soybean flour diet had a lower final body weight, epididymal fat pad, carcass fat content, and liver glycogen level. The serum glucose concentrations in the basal and fed states and the area under the glucose curves during the glucose tolerance test were not significantly different among the four groups. Their serum insulin levels during fasting were observed to be similar to those fed a casein diet. These rats also had a higher serum insulin levels in a fed state and total area under the insulin curves in response to a glucose load, but a lower ratio of area under the glucose/insulin curves during the glucose tolerance test than those fed a casein diet. CONCLUSION: These results indicate that nutritional recovery with a soybean flour diet improved the insulin response to a glucose load and decreased the sensitivity to insulin, at least in hepatic tissue.

Alterações do metabolismo da glicose na deficiência de magnésio / Metabolic changes of glucose in the magnesium deficiency

O magnésio é um cátion essencial o qual age co-fator para adenosina trifosfatases em inúmeras reações enzimáticas. Vários estudos mostram seu envolvimento na ação e secreção de insulina e os efeitos deste hormônio sobre o metabolismo e transporte do magnésio. Entretanto, os resultados são conflitantes. Sugerem que a deficiência de magnésio está implicada direta ou indiretamente com a resistência à insulina no diabetes mellitus, enquanto outros descrevem uma relação inversa ou, um aumento da captação de glicose decorrente da falta de magnésio. A interação deste cátion com outros íons, os mecanismos hormonais e neuro-hormonais compensadores e possivelmente a duração da deficiência são alguns dos fatores descritos como responsáveis pelas variações na regulação glicêmica observadas durante a deficiência de magnésio