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Objectives: Anorexia nervosa (AN) is an eating disorder accompanied by a low body mass index and (self-) restricted food intake. Nutritional limitations can cause complaints of the digestive system, because of a disturbed absorption of food components. The absorption of carbohydrates may be seriously affected and reduced to a minimum. On this basis, a possible connection between AN, and the prevalence of gastrointestinal symptoms due to malabsorption was examined. Methods: For the systematic literature research with the aim of a better understanding of the topic the databases PubMed, Web of Science, Cochrane Library, Livivo and Google Scholar were used. Results: After the manual selection process of 2215 retrieved studies, 89 full texts were read and according to the predetermined eligibility criteria, finally 2 studies on the monosaccharide fructose and disaccharide lactose were included in this review. Conclusion: Malabsorption is often observed in patients with AN. It may contribute to the gastrointestinal complaints reported by patients and hamper body weight regain. Among others, mucosal atrophy and duodenal transporter dysfunction are discussed as main reasons. In the future more studies on carbohydrate malabsorption related to low body weight as observed in AN are warranted and may be conducted rather in an outpatient setting. Plain English summary: People with anorexia nervosa (AN) may experience a preference for foods containing fewer calories but more carbohydrates, e.g. fruits and vegetables. The consequences of this food restriction and selection may include malabsorption of sugars such as fructose and lactose, the mechanism of which is incompletely understood. This may contribute to symptoms similar to those seen in people with lactose intolerance, e.g. bloating, and make it harder for people to eat recommended foods. This paper presents a comprehensive literature search for research on this topic. However, only two studies were identified which highlights that further investigation is needed to explore this clinically relevant field. [ABSTRACT FROM AUTHOR]

During preclinical development of canagliflozin, an SGLT2 inhibitor, treatment-related pheochromocytomas, renal tubular tumors (RTT), and testicular Leydig cell tumors were reported in the 2-year rat toxicology study. In a previous 6-month rat mechanistic study, feeding a glucose free diet prevented canagliflozin effects on carbohydrate malabsorption as well as the increase in cell proliferation in adrenal medulla and kidneys, implicating carbohydrate malabsorption as the mechanism for tumor formation. In this chronic study male Sprague-Dawley rats were dosed orally with canagliflozin at high dose-levels (65 or 100 mg/kg/day) for 15 months and received either a standard diet or a glucose-free diet. Canagliflozin-dosed rats on standard diet showed presence of basophilic renal tubular tumors (6/90) and an increased incidence of adrenal medullary hyperplasia (35/90), which was fully prevented by feeding a glucose-free diet (no RTT's; adrenal medullary hyperplasia in ≤5/90). These data further confirm that kidney and adrenal medullary tumors in the 2-year rat study were secondary to carbohydrate (glucose) malabsorption and were not due to a direct effect of canagliflozin on these target tissues. [ABSTRACT FROM AUTHOR]

Background & aims Congenital sucrase-isomaltase deficiency (CSID) is a genetic disorder associated with mutations in the sucrase-isomaltase ( SI ) gene. The diagnosis of congenital diarrheal disorders like CSID is difficult due to unspecific symptoms and usually requires invasive biopsy sampling of the intestine. Sequencing of the SI gene and molecular analysis of the resulting potentially pathogenic SI protein variants may facilitate a diagnosis in the future. This study aimed to categorize SI mutations based on their functional consequences. Methods cDNAs encoding 13 SI mutants were expressed in COS-1 cells. The molecular pathogenicity of the resulting SI mutants was defined by analyzing their biosynthesis, cellular localization, structure and enzymatic functions. Results Three biosynthetic phenotypes for the novel SI mutations were identified. The first biosynthetic phenotype was defined by mutants that are intracellularly transported in a fashion similar to wild type SI and with normal, but varying, levels of enzymatic activity. The second biosynthetic phenotype was defined by mutants with delayed maturation and trafficking kinetics and reduced activity. The third group of mutants is entirely transport incompetent and functionally inactive. Conclusions The current study unraveled CSID as a multifaceted malabsorption disorder that comprises three major classes of functional and trafficking mutants of SI and established a gradient of mild to severe functional deficits in the enzymatic functions of the enzyme. General significance This novel concept and the existence of mild consequences in a number of SI mutants strongly propose that CSID is an underdiagnosed and a more common intestinal disease than currently known. [ABSTRACT FROM AUTHOR]

Patients with the rare autosomal recessive disorder congenital lactase deficiency (CLD) present with severe, potentially life-threatening symptoms shortly after birth. Several variants have been characterized within the gene for lactase-phlorizin hydrolase (LCT) that are associated with CLD. Here, we analyze at the biochemical and cellular levels LCT mutants harboring the genetic variants p.Y1390*, p.E1612*, p.S1150Pfs*19, p.S1121L, p.R1587H, and p.S688P. Our data unequivocally demonstrate that these mutants are absolutely transport incompetent, some of which are readily degraded, and are enzymatically inactive. The current study contributes to and expands our understanding on the pathogenesis of CLD at the molecular level. [ABSTRACT FROM AUTHOR]

Background: Congenital lactase deficiency (CLD) is a rare severe autosomal recessive disorder, with symptoms like watery diarrhea, meteorism and malnutrition, which start a few days after birth by the onset of nursing. The most common rationales identified for this disorder are missense mutations or premature stop codons in the coding region of the lactase-phlorizin hydrolase (LPH) gene. Recently, two heterozygous mutations, c.4419C > G (p.Y1473X) in exon 10 and c.5387delA (p.D1796fs) in exon 16, have been identified within the coding region of LPH in a Japanese infant with CLD. Methods: Here, we investigate the influence of these mutations on the structure, biosynthesis and function of LPH. Therefore the mutant genes were transiently expressed in COS-1 cells. Results: We show that both mutant proteins are mannose-rich glycosylated proteins that are not capable of exiting the endoplasmic reticulum. These mutant proteins are misfolded and turnover studies show that they are ultimately degraded. The enzymatic activities of these mutant forms are not detectable, despite the presence of lactase and phlorizin active sites in the polypeptide backbone of LPH-D1796fs and LPH-Y1473X respectively. Interestingly, wild type LPH retains its complete enzymatic activity and intracellular transport competence in the presence of the pathogenic mutants suggesting that heterozygote carriers presumably do not show symptoms related to CLD. Conclusions: Our study strongly suggests that the onset of severe forms of CLD is elicited by mutations in the LPH gene that occur in either a compound heterozygous or homozygous pattern of inheritance. [ABSTRACT FROM AUTHOR]

Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has been developed for the treatment of adults with type 2 diabetes mellitus (T2DM). During the phase 3 program, treatment-related pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors were reported in the 2-year rat toxicology study. Treatment-related tumors were not seen in the 2-year mouse study. A cross-functional, mechanism-based approach was undertaken to determine whether the mechanisms responsible for tumorigenesis in the rat were of relevance to humans. Based on findings from nonclinical and clinical studies, the treatment-related tumors observed in rats were not deemed to be of clinical relevance. Here, we describe the scientific and regulatory journey from learning of the 2-year rat study findings to the approval of canagliflozin for the treatment of T2DM. [ABSTRACT FROM PUBLISHER]

Canagliflozin is an SGLT2 inhibitor used for the treatment of type 2 diabetes mellitus. Studies were conducted to investigate the mechanism responsible for renal tubular tumors and pheochromocytomas observed at the high dose in a 2-year carcinogenicity study in rats. At the high dose (100 mg/kg) in rats, canagliflozin caused carbohydrate malabsorption evidenced by inhibition of intestinal glucose uptake, decreased intestinal pH and increased urinary calcium excretion. In a 6-month mechanistic study utilization of a glucose-free diet prevented carbohydrate malabsorption and its sequelae, including increased calcium absorption and urinary calcium excretion, and hyperostosis. Cell proliferation in the kidney and adrenal medulla was increased in rats maintained on standard diet and administered canagliflozin (100 mg/kg), and in addition an increase in the renal injury biomarker KIM-1 was observed. Increased cell proliferation is considered as a proximal event in carcinogenesis. Effects on cell proliferation, KIM-1 and calcium excretion were inhibited in rats maintained on the glucose-free diet, indicating they are secondary to carbohydrate malabsorption and are not direct effects of canagliflozin. [ABSTRACT FROM AUTHOR]

Carbohydrate malabsorption such as in lactose intolerance or enteric infection causes symptoms that include abdominal pain. Because this digestive disorder increases intracolonic osmolarity and acidity by accumulation of undigested carbohydrates and fermented products, we tested whether these two factors (hypertonicity and acidity) would modulate colorectal afferents in association with colorectal nociception and hypersensitivity. In mouse colorectum-pelvic nerve preparations in vitro, afferent activities were monitored after application of acidic hypertonic saline (AHS; pH 6.0, 800 mosM). In other experiments, AHS was instilled intracolonically to mice and behavioral responses to colorectal distension (CRD) measured. Application of AHS in vitro excited 80% of serosal and 42% of mechanically-insensitive colorectal afferents (MIAs), sensitizing a proportion of MIAs to become mechanically sensitive and reversibly inhibiting stretch-sensitive afferents. Acute intracolonic AHS significantly increased expression of the neuronal activation marker pERK in colon sensory neurons and augmented noxious CRD-induced behavioral responses. After three consecutive daily intracolonic AHS treatments, mice were hypersensitive to CRD 4-15 days after the first treatment. In complementary single fiber recordings in vitro, the proportion of serosal class afferents increased at day 4; the proportion of MIAs decreased, and muscular class stretch-sensitive afferents were sensitized at days 11-15 in mice receiving AHS. These results indicate that luminal hypertonicity and acidity, two outcomes of carbohydrate malabsorption, can induce colorectal hypersensitivity to distension by altering the excitability and relative proportions of colorectal afferents, suggesting the potential involvement of these factors in the development of abdominal pain. [ABSTRACT FROM AUTHOR]