Dietary fructose inhibits intestinal calcium absorption and induces vitamin D insufficiency in CKD.

Renal disease leads to perturbations in calcium and phosphate homeostasis and vitamin D metabolism. Dietary fructose aggravates chronic kidney disease (CKD), but whether it also worsens CKD-induced derangements in calcium and phosphate homeostasis is unknown. Here, we fed rats diets containing 60% glucose or fructose for 1 mo beginning 6 wk after 5/6 nephrectomy or sham operation. Nephrectomized rats had markedly greater kidney weight, blood urea nitrogen, and serum levels of creatinine, phosphate, and calcium-phosphate product; dietary fructose significantly exacerbated all of these outcomes. Expression and activity of intestinal phosphate transporter, which did not change after nephrectomy or dietary fructose, did not correlate with hyperphosphatemia in 5/6-nephrectomized rats. Intestinal transport of calcium, however, decreased with dietary fructose, probably because of fructose-mediated downregulation of calbindin 9k. Serum calcium levels, however, were unaffected by nephrectomy and diet. Finally, only 5/6-nephrectomized rats that received dietary fructose demonstrated marked reductions in 25-hydroxyvitamin D(3) and 1,25-dihydroxyvitamin D(3) levels, despite upregulation of 1alpha-hydroxylase. In summary, excess dietary fructose inhibits intestinal calcium absorption, induces marked vitamin D insufficiency in CKD, and exacerbates other classical symptoms of the disease. Future studies should evaluate the relevance of monitoring fructose consumption in patients with CKD.

alpha-Glucosidase inhibitors prevent diet-induced increases in intestinal sugar transport in diabetic mice.

The recommended diet for diabetes mellitus is rich in complex carbohydrates. We have previously shown that high carbohydrate levels in the intestinal lumen induce adaptive increases in sugar absorption which in turn exacerbate postprandial hyperglycemia in diabetic mice. alpha-Glucosidase inhibitors (AGIs) hinder digestion of complex carbohydrates and therefore alleviate postprandial glycemic excursions. In this study, we tested the hypothesis that AGIs prevent the carbohydrate-induced upregulation of intestinal glucose and fructose transport in diabetes. Streptozotocin-diabetic mice were fed the following isocaloric diets: high carbohydrate (H), H plus acarbose (HA), H plus deoxy-nojirimycin (HD), and low carbohydrate (L), then nutrient uptakes were determined after 2 and 4 weeks. Body weight, intestinal weight, and length were independent of diet. Fasting and postprandial blood glucose levels were lower in HA and HD than in H mice. Uptakes of D-glucose and D-fructose were 2 to 3 times greater in H than in L mice, but HA and HM diets gradually reduced D-glucose uptakes to rates similar to L mice. Only HA diets reduced D-fructose uptake. Intestinal proline, aspartate, and glutamine uptakes were each greater in L than in H, HA, and HD mice. alpha-Glucosidase inhibitors did not alter intestinal permeability and amino acid transport rates. alpha-Glucosidase inhibitor-inhibitable increases in total intestinal absorptive capacity for sugars were due to carbohydrate-induced increases in V(max) of glucose transport. Clearly, one potential mechanism by which AGIs blunt postprandial glycemic excursions and lower fasting blood glucose concentrations in individuals consuming carbohydrate-containing diets is by preventing carbohydrate-induced increases in intestinal sugar transport.

Role of the small intestine in postpartum weight retention in mice.

BACKGROUND: Approximately 25% of women retain 5 kg of the weight gained during pregnancy, but the physiologic factors underlying excessive postpartum weight gain are not known. OBJECTIVE: The objective of the study was to determine whether pregnancy-related adaptive increases in intestinal nutrient transport are retained after parturition and therefore contribute to postpartum weight gain. DESIGN: We measured body weight and intestinal nutrient transport in virgin (V, control), primiparous (P, one pregnancy), and multiparous (M, 3 pregnancies) mice at parturition (day 1), during lactation (days 14 and 21), at weaning (day 28), after weaning (day 40), and during aging (days 70, 120, 200, and 300). RESULTS: In M and P mice, body weight and the weight and length of the small intestine were greatest during lactation; they then decreased but did not return to prepregnancy values until 300 d after parturition. Intestinal villus heights were maximal at lactation and remained high < or = 200 d after parturition. Total intestinal transport capacity for D-glucose, D-fructose, and L-proline was also greatest during lactation, and the lactation-enhanced transport capacity was retained < or = 70 d after parturition. M mice retained more body weight and intestinal transport capacity postpartum than did P mice. Aging per se had little or no effect on body weight or intestinal weight, length, and nutrient transport. The dramatic, lactation-related increases in intestinal nutrient transport capacity were due mainly to increases in intestinal mass. CONCLUSIONS: Postpartum retention of pregnancy- and lactation-related increases in intestinal nutrient uptake capacity may play a significant role in postpartum body weight retention. These adaptive increases may be cumulative and may result in greater weight retention in mice with multiple pregnancies.

Luminal fructose inhibits rat intestinal sodium-phosphate cotransporter gene expression and phosphate uptake.

BACKGROUND: While searching by microarray for sugar-responsive genes, we inadvertently discovered that sodium-phosphate cotransporter 2B (NaPi-2b) mRNA concentrations were much lower in fructose-perfused than in glucose-perfused intestines of neonatal rats. Changes in NaPi-2b mRNA abundance by sugars were accompanied by similar changes in NaPi-2b protein abundance and in rates of inorganic phosphate (Pi) uptake. OBJECTIVE: We tested the hypothesis that luminal fructose regulates NaPi-2b. DESIGN: We perfused into the intestine fructose, glucose, and nonmetabolizable or poorly transported glucose analogs as well as phlorizin. RESULTS: NaPi-2b mRNA concentrations and Pi uptake rates in fructose-perfused intestines were approximately 30% of those in glucose and its analogs. NaPi-2b inhibition by fructose is specific because the mRNA abundance and activity of the fructose transporter GLUT5 (glucose transporter 5) increased with fructose perfusion, whereas those of other transporters were independent of the perfusate. Plasma Pi after 4 h of perfusion was independent of the perfusate, probably because normal kidneys can maintain normophosphatemia. Inhibiting glucose-6-phosphatase, another fructose-responsive gene, with tungstate or vanadate nonspecifically inhibited NaPi-2b mRNA expression and Pi uptake in both glucose- or fructose-perfused intestines. The AMP kinase (AMPK)-activator AICAR (5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) enhanced and the fatty acid synthase-AMPK inhibitor C75 (3-carboxy-4-octyl-2-methylenebutyrolactone trans-4-carboxy-5-octyl-3-methylenebutyrolactone) prevented fructose inhibition of NaPi-2b but had no effect on expression of other transporters. NaPi-2b expression decreased markedly with age and was inhibited by fructose in all age groups. CONCLUSIONS: Energy levels in enterocytes may play a role in NaPi-2b inhibition by luminal fructose. Consumption of fructose that supplies approximately 10% of caloric intake by Americans clearly affects absorption of Pi and may promote Pi homeostasis in patients with impaired renal function.