Small intestinal glucose absorption in cystic fibrosis: a study in human and transgenic ΔF508 cystic fibrosis mouse tissues

Abstract

Intestinal transport is disturbed in cystic fibrosis (CF), with both defective Cl- secretion and changes in absorption being reported. We have examined the effects of the disease on Na(+)-dependent glucose absorption by the small intestine. Active glucose absorption was monitored as changes in short-circuit current (SCC) in intact and stripped intestinal sheets from normal (Swiss) and transgenic CF (Cftr(tm1Eur) and Cftr(tm2Cam)) mice with the DeltaF508 mutation, and in jejunal biopsies from children with CF and normal controls. Na(+)-dependent glucose uptake at the luminal membrane was measured in brush-border membrane vesicles (BBMVs). Intact and stripped sheets of jejunum and midintestine from Swiss mice exhibited a concentration-dependent increase in SCC with glucose. Apparent Km values were similar in the two preparations, but the apparent Vmax was greater in stripped sheets. This difference was not due to a loss of neural activity in stripped sheets as tetrodotoxin did not influence the glucose-induced SCC in intact sheets. Similar results were observed in stripped sheets of jejunum and mid-intestine from wild-type Cftr(tm1Eur) mice, but in tissues from CF mice the apparent Vmax value was reduced significantly. A lower Vmax was also obtained in intact sheets of mid-intestine from CF (Cftr(tm2Cam)) mice. Jejunal biopsies from CF patients however, exhibited an enhanced glucose-dependent rise in SCC. Na(+)-dependent uptake by BBMVs from CF (Cftr(tm1Eur)) mice was not reduced compared with wild-type and Swiss BBMVs. It was concluded that, in contrast to human intestine, intestinal glucose absorption was reduced in transgenic mouse models of CF with the DeltaF508 mutation, but that this could not be detected in an isolated preparation of brush-border membranes. Transgenic mouse models of CF may not accurately reflect all aspects of intestinal dysfunction in the human disease.

The ΔF508 Mutation in the Cystic Fibrosis Transmembrane Conductance Regulator Is Associated With Progressive Insulin Resistance and Decreased Functional β-Cell Mass in Mice

“…3 ). This can be due to reduced intestinal absorption of glucose ( 43 ), improved insulin secretion, and/or enhanced insulin sensitivity. Insulin tolerance tests ( Fig.…”

Decreased Expression of Enterocyte Nutrient Assimilation Genes and Proteins in the Small Intestine of Cystic Fibrosis Mouse

“…Evidence for abnormal enterocyte nutrient assimilation protein levels in patients with CF has been reported, but the data are conflicting, (20)(21)(22)(23), perhaps because of comorbidities such as celiac disease (24)(25)(26).…”

“…A healthy microbiota is required for multiple aspects of normal gut physiology, including maturation of enterocytes, as measured by the expression of nutrient assimilation genes/proteins (eg, brush border enzymes and transporters), which can be negatively affected when dysbiosis occurs (17)(18)(19). Evidence for abnormal enterocyte nutrient assimilation protein levels in patients with CF has been reported, but the data are conflicting, (20)(21)(22)(23), perhaps because of comorbidities such as celiac disease (24)(25)(26).…”

Status of Fluid and Electrolyte Absorption in Cystic Fibrosis

“…In contrast to human intestine, intestinal glucose absorption seems reduced in transgenic mouse models of CF with the DF508 mutation. Therefore, it was suggested that the transgenic mouse models of CF might not accurately reflect all aspects of intestinal dysfunction in the human disease (Hardcastle et al 2004). It was further reported that the Cftr-null mice lacking one or both copies of the NHE3 (Na þ /H þ exchanger) gene exhibited increased fluidity of their intestinal contents, which prevented the formation of obstructions and increased survival (Bradford et al 2009), indicating that salt absorption in the face of reduced secretions caused by CFTR mutations plays a significant role in the development of intestinal pathology in CF mice.…”