W. F. Caspary

Increase of intestinal brush border hydrolases in mucosa of streptozotocin-diabetic rats

SummaryExperimental diabetes mellitus in rats was induced by streptozotocin. Five days after administration of streptozotocin intestinal brush border hydrolases (maltase, sucrase, trehalase, lactase) and alkaline phosphatase were markedly elevated at all levels of the small intestine as measured in the total homogenate and in the isolated brush border preparation. Insulin treatment beginning 15 h after administration of streptozotocin was able to decrease the increased disaccharidase activity due to streptozotocin diabetes. In experimental diabetes mellitus of rats trransport as well as digestive functions of the intestinal mucosa are stimulated.

Alteration of bile acid metabolism and vitamin-B12-absorption in diabetics on biguanides

SummarySince vitamin B12malabsorption has been described in diabetics on biguanides and inhibition of bile acid absorption found in rat ileum the effect of treatment with different biguanides (phenformin, buformin, metformin) on bile acid metabolism and vitamin B12 absorption was assessed in maturity onset diabetics. Biguanides did not alter faecal weight or faecal fat excretion, but they decreased faecal bile acid excretion. All biguanides tested increased deconjugation of glycocholic acid, as determined by a simple breath test technique. Vitamin B12 malabsorption was most prominent in patients on metformin. Discontinuation of biguanide treatment, or administration of antibiotics, normalized or improved the increased deconjugation of bile acids and the Schilling test. Decreased faecal bile acid excretion, positive14C-glycocholate breath tests, pathological Schilling tests and the reversal of pathological tests by antibiotic treatment suggest that small intestinal bacterial overgrowth, leading to binding of the intrinsic-factor-vitamin B12-complex to bacteria, is responsible for the previously observed pathological Schilling tests in diabetics on biguanides. Bile acid malabsorption, possibly responsible for the cholesterol-lowering effect of biguanides, does not occur in diabetics on biguanides. Whether qualitative changes in small intestinal bile acid composition might affect cholesterol metabolism remains to be determined.

Inhibition of intestinal amino acid transport by blood sugar lowering biguanides

SummaryThe effect of blood-glucose lowering biguanides (phenethyl- and butylbiguanide) on active intestinal transport of different amino acids has been tested in hamster small intestinein vitro. —.Biguanides inhibited active transport of all amino acids tested. The inhibitory effect of biguanides increased with incubation time, was more pronounced after preincubation of intestinal tissue and was found to be non-competitive. The minimal inhibitory concentration of phenethylbiguanide on amino acid transport was 5×10−4 M. —14C-butylbiguanide was found to be transported into hamster small intestine by a concentration-independent, energy-independent uptake mechanism and was accumulated in intestinal tissue against a concentration gradient. — In accord with earlier results on the inhibitory effect of biguanides on active intestinal hexose transport it is concluded that biguanides do not act as specific inhibitors for glucose transport, but rather affect active, energy-requiring intestinal transport mechanisms in general (hexose-, amino acid-, calcium- and myo-inositol transport), most likely due to their known inhibitory effect on mitochondrial respiration, thus depriving mucosal cells of ATP required to translocate substrates against a concentration gradient.

In vitro Inhibition of Rat Intestinal Surface Hydrolysis of Disaccharides and Dipeptides by Guaran

The effect of guaran on intestinal surface hydrolases was studied in everted jejunal segments by measuring the hydrolysis of maltose and phenylalanylglycine. On the basis of kinetic experiments, guaran was found to inhibit competitively the hydrolysis of these substrates only if the cleavage was performed with intact tissue. Hydrolysis in mucosal homogenates was not affected by guaran, indicating that this polysaccharide may increase the diffusion barrier overlaying the mucosa and thus may retard final digestion of carbohydrates and peptides.

14C-D-Galactose Breath Test for Evaluation of Liver Function in Patients with Chronic Liver Disease

D-Galactose metabolism and demethylation of aminopyrine by healthy controls and patients with chronic active hepatitis (CAH) and cirrhosis (Ci), were assessed by a breath analysis technique measuring 14CO2 exhalation after oral ingestion of 14C-D-galactose or 14C-aminopyrine. Patients with CAH and Ci exhibited decreased 14CO2-exhalation rates following 14C-D-galactose or 14C-aminopyrine. D-Galactose oxidation capacity of the liver can be assessed by a breath analysis technique in analogy to the demethylating function for aminopyrine. The ordinary oral D-galactose tolerance test seems, however, superior in comparison to the 14C-D-galactose tolerance test, in discriminating between healthy controls and patients with chronic liver disease.

Effects of Chenodeoxy- and Ursodeoxycholic Acid on Absorption, Secretion and Permeability in Rat Colon and Small Intestine

The effect of equimolar concentrations of chenodeoxycholic (CDCA) and ursodeoxycholic acid (UDCA) on the colonic absorption of water, sodium and oxalate, and on the transmural potential difference was examined in the rat colon by an open perfusion technique. In addition, the ileal absorption of D-glucose, oxalate, water and sodium was measured in the presence and absence of CDCA and UDCA. CDCA reversed the absorption of water and sodium into secretion more effectively than UDCA Oxalate absorption and permeability of the colon measured by the disappearance of D-mannitol were enhanced by CDCA, but to a lesser extent by UDCA. The ileal absorption of water and sodium was nearly abolished by CDCA and inhibited to a lesser extent by UDCA in the presence of D-glucose in the perfusate. At equimolar concentrations, CDCA induced a more marked inhibitory effect on colonic function than UDCA. This quantitative difference may account for the less frequent side-effects of diarrhoea in cholelitholytic treatment with UDCA compared to CDCA.

Inhibition of bile salt absorption by blood-sugar lowering biguanides

SummaryThe effect of blood sugar lowering biguanides (phenethyl-, butyl- and dimethylbiguanide) upon jejunal and ileal transport of bile salts (tauro- and glycocholate) was tested in rat small intestine by an in vitro technique. Biguanides inhibited active transport of bile salts in the ileum, but did not affect diffusional absorption of bile salts in the jejunum. The inhibitory effect was time-dependent and not reversible under in vitro incubation conditions, suggesting that biguanides must enter intestinal mucosal cells in order to exert their inhibitory action on active transport of glucose analogues, amino acids, calcium and bile salts. Since biguanides achieve high tissue concentrations in the small intestine even after parenteral administration, inhibition of ileal bile salt reabsorption by biguanides could possibly explain the lipid- and cholesterol-lowering effect of these oral antidiabetic drugs.

In vitro inhibition of rat small intestinal absorption by lipophilic organic cations

Cationic, lipid-soluble organic compounds may interfere with cation-mediated membrane transport processes. Thus, small intestinal absorption may be influenced by lipophilic organic cations. Therefore a series of arylalkylamines was studied in the concentration range from 0.5 to 20 mmol/l for their effect on the transport of various monosaccharides and leucine in the rat small intestine in vitro by means of the tissue accumulation technique. Whereas the monophenyl substituted monoamines (e.g. benzylamine, 2-phenylethylamine, 3-phenylpropylamine) did not show a significant effect on the active transport, the corresponding omega,omega-diphenyl derivatives exhibited a strong inhibition of the active transport of the sugars and the amino acid. These monoamines and drugs of similar structure (e.g. benzoctamine, diphenydramine) exhibited a mixed or non-competitive type of inhibition which correlated quite well with their octanol-water partition coefficients. In contrast, di- or triamines (e.g. harmaline, imipramine, pyrilamine) revealed a rather pure competitive type of inhibition. These findings tentatively suggest a different mode of action on the active transport by lipid-soluble organic amines according to the molecular charge distribution. In addition, membrane vesicles were used to examine the effect of the different amines on the sucrase activity. Regarding the cation-dependent hydrolysis of sucrose, however, no distinct pattern developed.

Influence of Short- and Long-Term Feeding of an α-Amylase Inhibitor (BAY e 4609) on the Exocrine Pancreas of the Rat

The effect of feeding an alpha-amylase inhibitor (BAY e 4609, 700 mg/100 g food) for 20 or 90 days on the enzymes of the exocrine pancreas of the rat was investigated. The amylase inhibitor-fed rats gained significantly less weight despite a higher food intake than control rats on a standard diet. Fecal weight increased threefold. Pancreatic wet weight, pancreatic DNA, protein and insulin concentrations were not influenced. The amylase content of the pancreas was significantly diminished compared with controls. The trypsin level increased and the changes in the amount of lipase were not significant. Also in response to an infusion of 15 or 60 IU CCK/kg/h combined with 0.5 clinical units of secretin/kg/h amylase secretion was significantly diminished after both feeding periods compared with controls, while trypsin output increased as did the output of lipase to a lesser extent. The enzyme pattern of the pancreatic juice reverted to normal when the animals consumed the control diet again. Gut weight and length increased significantly in the experimental animals. It is concluded that the changes in the pancreatic enzymes are induced by altered food intake. The amylase inhibitor prevents the digestion of starch and by this carbohydrate absorption. As a consequence, hyperphagia develops resulting in an increased protein and fat intake. Unlike trypsin a negative feedback regulation does not exist between alpha-amylase concentration in the gut and pancreatic enzyme secretion.

Intestinal brush border enzyme activity in juvenile and maturity onset diabetes mellitus

SummarySmall intestinal enzymatic activities of disaccharidases, alkaline phosphatase and peptide hydrolases have been measured in small bowel biopsy material of healthy controls and patients with maturity and juvenile onset diabetes. In contrast to increased digestive enzymatic activities in experimental diabetes mellitus, juvenile and maturity onset diabetics did have normal digestive activities for hydrolysis of disaccharides and oligopeptides.