D-mannose

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Mannose Utilization in Man

Author:

Wood FC and GF Cahill, JR

Year:

1963

Bibliographic source:

J. Clin.Invest., 43(8):1300-1312

Materials and methods

Study type:

study with volunteers

Endpoint addressed:

basic toxicokinetics

Principles of method if other than guideline:

Intravenous infusions of mannose and glucose were given to human subjects. A series of experiments were done to look at rapid infusion as well as prolonged infusion. One experiment also looked at effects following oral administration.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

D-mannose

EC Number:

222-392-4

EC Name:

D-mannose

Cas Number:

3458-28-4

Molecular formula:

C6H12O6

IUPAC Name:

D-mannose

Details on test material:

Purity: not reported

Method

Subjects:

Subjects included 7 normal men, 2 normal women, 4 mildly maturity-onset diabetic subjects on no treatment, and one severe, ketosis-prone diabetic subject whose last insulin dose was 24 hours before.

Ethical approval:

not specified

Route of exposure:

other: intravenous infusions

Reason of exposure:

intentional

Details on exposure:

Glucose or mannose was administered at 0.5 g/kg into an antecubital vein as a 25% solution in water in 3-5 minutes. Venous blood samples were collected every 10 minutes for one hour starting 10 minutes after the end of infusion. The samples were gently mixed in tubes containing 25 mg potassium oxalate and 25 mg sodium fluoride, and frozen until hexose assay. Additional blood samples were similarly collected for the determination of FFA concentration in the supernatant plasma after centrifugation. In one experiment on a normal subject, portions of the supernatant fluid, after precipitation of protein from blood samples, were deionized by passage through a mixed-bed resin, lyophilized and chromatographed. Similar chromatographs were run with glucose and mannose standards and their glucose and mannose determined by reduction before and after intubation with glucose oxidase. This procedure verified mannose as the primary reducing substance in blood not removed by glucose oxidase at all intervals after infusion of mannose.

Other studies included iv administration of either crystalline zinc insulin or sodium tolbutamide immediately before the glucose or mannose infusions. Blood was collected every 5 minutes. The effect of insulin on mannose disappearance rate was studied in a normal person both with the normal concomitant fall in blood glucose, and also with this fall prevented by glucose infusion. All studies were performed with the subject supine after an overnight fast. The subjects had not been restricting calories or losing weight. Successive studies in a single subject were always separated by at least one week.

In another set of experiments, mannose was administered for several hours (5 or 10 hours) at a rate of 0.5 g/kg per hour, and plasma concentration and urinary excretion were determined. Subjects included 2 normal subjects, one mild diabetic subject, and one severe, ketosis-prone diabetic subject, both of whom received no insulin for 24 hours before the test. In one of the normal subjects, insulin was also infused, and plasma and urine levels were determined in order to characterize the mechanism of renal excretion of mannose.

A single normal subject received 0.5 g/kg of mannose by mouth as a 20% solution. Blood and urine samples were collected for 2 hours, when he experienced marked abdominal cramps followed by sudden diarrhea. Further studies on oral absorption were not performed.

Results and discussion

Outcome of incidence:

The studies suggest that glucose and mannose are removed from the blood at similar rates by peripheral tissues in man. Mannose administered intravenously to normal or diabetic subjects was metabolized in each at rates proportionate to glucose. In man, mannose does not stimulate pancreatic release of insulin, not is it actively absorbed from the abdominal tract, not does there appear to be a significant active reabsorption of mannose by the kidney.

Any other information on results incl. tables

Glucose and mannose are removed from the blood at similar rates by peripheral tissues in man.

 

In man, mannose does not stimulate pancreatic release of insulin. It is not actively absorbed from the abdominal tract. There does not appear to be a significant active reabsorption of mannose by the kidney.

 

Rapid Infusion Results

Mannose administered intravenously to normal or diabetic subjects was metabolized in each at rates proportionate to glucose. Acceleration of both glucose and mannose disappearance rates was achieved with both hypoglycemic agents (crystalline zinc insulin and sodium tolbutamide). A characteristic decrease in FFA concentrations in plasma were observed with both glucose and mannose administration. Insulin accelerated mannose disappearance to a similar degree whether the blood glucose was allowed to fall or whether it was sustained by glucose infusion, thus showing that insulin stimulated mannose disappearance primarily, and not secondarily by removal of a competitor. In all the mannose and glucose infusions, no subjective or objective symptoms or signs were noted by the subjects or observers, except for an occasional temporary flushing of the face after the start of the infusions.

 

Prolonged Infusion Results

Normal subjects given mannose or glucose infusions for 10 hours, urinary loss of mannose was proportionate to the plasma concentration, without evidence of a threshold. At the end of the infusion, the first subject felt fatigued and anorectic. These symptoms were thought to be related to immobility and mild phlebitis at the infusion site. The second subject felt more uncomfortable and 36 hours after infusion noted malaise, anorexia, scleral icterus, and urine deeply orange in color. Hepatic function tests indicated a rise in indirect-reacting bilirubin. The two diabetic subjects given mannose or glucose infusions for 5 hours showed twice the level of blood mannose concentration than the normal subjects. Neither diabetic subject experienced any subjective change, either during or after the infusions.

 

Oral Test Results

The oral mannose test clearly demonstrated poor gastrointestinal absorption.

Applicant's summary and conclusion

Conclusions:

The studies suggest that glucose and mannose are removed from the blood at similar rates by peripheral tissues in man. Mannose administered intravenously to normal or diabetic subjects was metabolized in each at rates proportionate to glucose. In man, mannose does not stimulate pancreatic release of insulin, not is it actively absorbed from the abdominal tract, not does there appear to be a significant active reabsorption of mannose by the kidney.

Executive summary:

Intravenous infusions of mannose and glucose were given to human subjects. A series of experiments were done to look at rapid infusion as well as prolonged infusion. One experiment also looked at effects following oral administration. Mannose administered intravenously to normal or diabetic subjects was metabolized in each at rates proportionate to glucose. In man, mannose does not stimulate pancreatic release of insulin, not is it actively absorbed from the abdominal tract, not does there appear to be a significant active reabsorption of mannose by the kidney.