Molecular analysis of the SGLT2 gene in patients with renal glucosuria.

The role of SGLT2 (the gene for a renal sodium-dependent glucose transporter) in renal glucosuria was evaluated. Therefore, its genomic sequence and its intron-exon organization were determined, and 23 families with index cases were analyzed for mutations. In 21 families, 21 different SGLT2 mutations were detected. Most of them were private; only a splice mutation was found in 5 families of different ethnic backgrounds, and a 12-bp deletion was found in two German families. Fourteen individuals (including the original patient with 'renal glucosuria type 0') were homozygous or compound heterozygous for an SGLT2 mutation resulting in glucosuria in the range of 14.6 to 202 g/1.73 m(2)/d (81 - 1120 mmol/1.73 m(2)/d). Some, but not all, of their heterozygous family members had an increased glucose excretion of up to 4.4 g/1.73 m(2)/d (24 mmol/1.73 m(2)/d). Likewise, in index cases with glucosuria below 10 g/1.73 m(2)/d (55 mmol/1.73 m(2)/d) an SGLT2 mutation, if present, was always detected in the heterozygous state. We conclude that SGLT2 plays an important role in renal tubular glucose reabsorption. Inheritance of renal glucosuria shows characteristics of a codominant trait with variable penetrance.

Intestinal glucose transport: evidence for a membrane traffic-based pathway in humans.

BACKGROUND & AIMS: The presence of glucose transporter 2 (GLUT2) molecules in the basolateral membrane of enterocytes has long been considered to be of major importance for intestinal glucose absorption. The aim of this study was to reevaluate the role of GLUT2 in a patient with congenital GLUT2 deficiency (Fanconi-Bickel syndrome, FBS). METHODS: Oral mono- and disaccharide tolerance tests including gaschromatographic determination of breath hydrogen concentrations were performed in an FBS patient. For comparison, a patient with a microsomal carbohydrate transport defect, glucose-6-phosphate translocase 1 (G6PT1) deficiency, and a control individual were investigated. RESULTS: No increase in breath hydrogen concentration was found in the GLUT2-deficient patient after a glucose load. In G6PT1 deficiency, basal hydrogen concentrations were repeatedly found to be elevated. CONCLUSIONS: From the fact that a GLUT2-deficient patient does not show any impairment of intestinal monosaccharide transport measurable by the hydrogen breath test, we conclude that mechanisms other than facilitative glucose transport by GLUT2 must be involved in the transport of monosaccharides at the basolateral membrane of enterocytes. When relating this observation to the high intestinal expression of human hexokinase, G6PT1, and glucose-6-phosphatase and to our results of oral carbohydrate tolerance tests in a G6PT1-deficient patient, there is evidence that a microsomal membrane traffic-based transport pathway, as recently suggested for GLUT2-deficient animals, also plays a major role in transcellular monosaccharide transport of the human intestine.

Feeding patterns in breast-fed and formula-fed infants.

AIM: The intention of this study performed in healthy breast- and formula-fed infants was to characterize physiological feeding patterns as a basis for counseling parents to feed their infants on demand. METHODS: Ingested milk volumes of 10 breast-fed and 14 formula-fed infants were measured during five 72-hour investigation periods during the 3rd, 6th, 9th, 13th, and 17th weeks of life. RESULTS: A comparable diurnal distribution of feeds was observed in both groups during the first 9 weeks of life, with a day-night asymmetry of feeding first observed at the age of 6 weeks. Thereafter, formula-fed infants showed a further decrease in their nightly milk intake. Within the investigation period, the milk volume per feed rose from 100 (range 40-200) g to 140 (range 30-300) g in the breast-fed group and from 100 (range 20-200) g to 200 (range 20-450) g in formula-fed infants. From the 6th week of life onwards, formula-fed infants had significantly higher feeding volumes. CONCLUSIONS: Parents should be informed about the variability of infant demands per feed and of feeding at night observed in breast-fed infants. The results suggest that feeding patterns similar to those of breast-fed infants are difficult to accomplish in formula-fed infants.

Supplemental feeding in the first days of life -- effects on the recipient infant.

AIM: Since clinical indications may necessitate the feeding of supplements to newborn infants, the effects of different supplemental feedings on the recipient infants were studied. METHODS: Two groups of healthy, term newborn infants (n = 64 in each group) were investigated. The mothers breast-fed their infants, and by indication the babies were additionally fed supplement A (supplementary neonatal formula, 78 kcal/dl) or the traditionally used supplement B (glucosaccharide solution, 100 kcal/dl). The differences in volume and energy intake, weight development and rate of hyperbilirubinemia were assessed in the hospital. The frequency of breast-feeding was evaluated using a structured telephone interview at the ages of 4 and 8 weeks. RESULTS: The energy intake of group B was higher prior to the 3rd day of study (p < 0.05). Afterwards a higher mean intake of human milk, a faster weight gain but a lower frequency of exclusive breast-feeding at discharge were observed in study group A. Hyperbilirubinemia was more frequent in the group B. Fifty-five percent (group A) and 52% (group B) of the participants were exclusively breast-fed at the age of 8 weeks. CONCLUSIONS: Despite differences in milk intake and weight gain in the early postpartum period, the breast-feeding patterns at 4 and 8 weeks were not significantly influenced by the use of different supplements.

The mutation spectrum of the facilitative glucose transporter gene SLC2A2 (GLUT2) in patients with Fanconi-Bickel syndrome.

We report a total of 23 novel mutations of the SLC2A2 ( GLUT2) gene in 49 patients with a clinical diagnosis of Fanconi-Bickel syndrome (FBS). Molecular genetic analysis has now been performed in more than 50% of the 109 FBS cases from 88 families that we have been able to locate world-wide since the original report in 1949. In these 49 patients, 33 different SLC2A2 mutations (9 missense, 7 nonsense, 10 frameshift, 7 splice-site) have been detected. Thus, our results confirm that mutations of SLC2A2 are the basic defect in patients with FBS. Mutations of SLC2A2 were detected in historical FBS patients in whom some of the characteristic clinical features (hepatorenal glycogen accumulation, glucose and galactose intolerance, fasting hypoglycemia, a characteristic tubular nephropathy) and the effect of therapy were described for the first time. Mutations were also found in patients with atypical clinical signs such as intestinal malabsorption, failure to thrive, the absence of hepatomegaly, or renal hyperfiltration. No single prevalent SLC2A2 mutation was responsible for a significant number of cases. In a high percentage (74%) of FBS patients, the mutation is homozygous, so we conclude that the prevalence of SLC2A2 mutations is relatively low in most populations. No mutational hot spots within SLC2A2 or even within homologous sequences among the genes for facilitative glucose transporters were detected.