Rates of fructose uptake by the small intestine of neonatal rats are typically very low from parturition through weaning but undergo a dramatic increase immediately after weaning is completed. In this study, we used intestinal fructose transport as a model to determine whether nutrient transport, normally enhanced only after completion of weaning, can be enhanced earlier during development. We found that ontogenetic changes in levels of GLUT5 mRNA correlate well with already known ontogenetic changes in rates of intestinal fructose transport: low levels and rates during suckling and weaning, and high levels and rates after weaning. In contrast, levels of GLUT2 and SGLT1 mRNA were relatively more elevated throughout the suckling and weaning periods. We then found that increased expression of GLUT5 mRNA caused by dietary fructose or sucrose paralleled diet-dependent increases in brush-border fructose uptake. Rates of brush-border glucose uptake and levels of SGLT1 and GLUT2 mRNA were not enhanced by dietary fructose, glucose, or sucrose. Finally, we found that rates of fructose uptake, levels of GLUT5 mRNA, and specific sucrase activity each increased with increasing concentrations of dietary fructose given precociously to midweaning rats. In contrast, brush-border glucose uptake was independent of dietary fructose concentration. Thus precocious introduction of dietary fructose causes enhanced expression of fructose transporters earlier during development. This effect is specific: only luminal fructose is effective, and only brush-border fructose transport can be modulated. These results unveil the potential for regulating nutrient transport early in development.
Otocephaly, characterized by mandibular hypoplasia or agnathia, ventromedial auricular malposition (melotia) and/or auricular fusion (synotia), and microstomia with oroglossal hypoplasia or aglossia, is an extremely rare anomalad, identified in less than 1 in 70,000 births. The malformation spectrum is essentially lethal, because of ventilatory problems, and represents a developmental field defect of blastogenesis primarily affecting thefirst branchial arch derivatives. Holoprosencephaly is the most commonly identified association, but skeletal, genitourinary, and cardiovascular anomalies, and situs inversus have been reported. Polyhydramnios may be the presenting feature, but prenatal diagnosis has been uncommon. We present five new cases of otocephaly, the largest published series to date, with comprehensive review of the literature and an update of research in the etiopathogenesis of this malformation complex. One of our cases had situs inversus, and two presented with unexplained polyhydramnios. Otocephaly, while quite rare, should be considered in the differential diagnosis of this gestational complication.
In neonatal rats, precocious introduction of dietary fructose significantly enhances brush-border fructose transport rates and GLUT-5 mRNA levels during early weaning. In this study, these rates and levels were more than two times higher in the anastomosed intestine compared with those in the bypassed loop of weaning pups that underwent Thiry-Vella surgery and consumed high-fructose (HF) diets. In Thiry-Vella pups fed fructose-free (NF) diets, uptake rates and mRNA levels in the anastomosed intestine were very low and similar to those in the bypassed loop. In sham-operated littermates, transport rates and mRNA levels were similar between intestinal regions that corresponded to anastomosed and bypassed loops in Thiry-Vella pups and were two to three times greater in pups fed HF than in those fed NF diet. In contrast, rates of brush-border glucose transport and levels of SGLT-1 and of GLUT-2 mRNA were independent of diet and were similar between bypassed and anastomosed regions. Changes in GLUT-5 expression did not follow a distinct diurnal rhythm. When pups were fed HF diet after 12 h of starvation to empty the intestinal lumen, fructose transport rates increased with feeding duration and reached a plateau 12–24 h after feeding; in contrast, GLUT-5 mRNA levels were highest within 4 h after arrival of chyme in the jejunum and then decreased gradually and returned to baseline levels 24 h later. In littermates fed NF diet, mRNA levels and uptake rates were each independent of feeding duration. Luminal, and not endocrine, signals regulate GLUT-5 expression in weaning pups.
The rat fructose transporter normally appears after completion of weaning but can be precociously induced by early feeding of a high-fructose diet. In this study, the crypt-villus site, the metabolic nature of the signal, and the age dependence of induction were determined. In weaning rats fed high-glucose pellets, GLUT-5 mRNA expression was modest, localized mainly in the upper three-fourths of the villus, and there was little expression in the villus base. When fed high-fructose pellets, GLUT-5 mRNA expression was two to three times greater in all regions except the villus base. Intestinal perfusion in vivo of a nonmetabolizable fructose analog, 3-O-methylfructose, tended to increase fructose uptake rate and moderately increased GLUT-5 mRNA abundance but had no effect on glucose uptake rates and SGLT1 mRNA abundance. Gavage feeding of high-fructose, but not high-glucose, solutions enhanced fructose uptake only in pups > or =14 days, suggesting that GLUT-5 regulation is markedly age dependent. Fructose or its metabolites upregulate GLUT-5 expression in all enterocytes, except those in the crypt and villus base and in pups <14 days old.
The onset of developmentally induced changes in rat intestinal nutrient absorption is well known: brushborder glucose and fructose transporters appear during prenatal and postweaning periods, respectively. The onset of diet-induced regulation, however, is unknown. To test the hypothesis that intestinal glucose and fructose transport is regulated by diet during weaning and postweaning, we fed rats experimental diets containing high (65%) glucose, high fructose, high sucrose, or no carbohydrate. In 16-d-old rats, 6 d of dietary fructose but not glucose modestly increased fructose absorption in everted sleeves of small intestine (SI) over control (mother-fed with access to chow) rats (p = 0.02). In 21-d-old (age when sucrase is present) rats, dietary fructose and sucrose each dramatically enhanced (p = 0.004) fructose absorption over control rats and rats fed high glucose or carbohydrate-free diets. In 35-(postweaning) and 60-d-old rats, dietary fructose and sucrose, but not glucose, stimulated fructose absorption (p < 0.005) over rats fed a carbohydrate-free diet. In all age groups, intestinal glucose absorption was independent of diet (p 2 0.12), and experimental rats grew at the same rate as control rats. Absorption of fructose or glucose was 2-3 times greater in the proximal and middle than in the distal SI. Intestinal fructose, but not glucose, absorption can be induced by diet even during early weaning, and dietary fructose followed by sucrose is the most potent inducer. Thus, mechanisms of diet regulation can change ontogenetically, and early introduction of certain diets can induce appearance of certain nutrient transporters. (Pediatr Res 37: 777-782, 1995) Abbreviations ANOVA, analysis of variance HF, high fructose HG, high glucose HS, high sucrose MMC, mother-fedlchow NC, no carbohydrate SI, small intestine Advances in infant nutritional support have increased premature infant survival, especially in the low birth weight neonates (1). Premature neonates are typically fed simple sugars and even infant formula not only to prime their gut but also to provide an enteral source of nutrition. Approximately 40% of the energy intake of all infants is provided by carbohydrates (2), mainly glucose, galactose, and even fructose, and the neonatal small intestine encounters them mainly as breakdown products of carbohydrate digestion. Intestinal glucose transport appears prenatally, at around the 24th wk of gestation in humans (3) and just before birth in rats (4, 5). The onset of intestinal fructose transport in rats, on the other hand, is postnatal (5). There is an enhancement of fructose transport at the end of weaning in rats, and this happens despite the absence
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