D-mannose

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Type of information:

other: review article

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

Objective of study:

metabolism

Principles of method if other than guideline:

Mannose chemistry, metabolism and metabolomics in cells, tissues, and mammals are summarized with emphasis on studies utilizing mannose therapies.

GLP compliance:

no

Type:

metabolism

Results:

Stringent regulation of metabolites such as Man-6-P is crucial: deficiency or excess can be detrimental for the cell and the physiology of the whole organism.

Human plasma normally contains approximately 50 µM mannose. Mannose absorbed through the intestine undergoes metabolism. A bolus dose of 200 mg/kg body weight increased the blood mannose concentration by three-fold. The clearance half-life was approximately 4 hours and did not alter glucose concentration. Excess mannose is excreted in urine.  Studies of mannose therapies underscore the variable phenotypic impact of disrupting mannose metabolism supplying different pathways and in different cell types. It suggests that glycosylation load and metabolic flux must play critical roles in determining the outcome.

The plasma concentration of endogenous mannose in rats is approximately 80 µM. Treatment of rats and mice with radiolabeled mannose gave clearance results similar to humans. Most of the label is metabolized and excreted with a low percentage incorporated into glycoproteins of all tissues. Long term mannose supplementation using 1-20% mannose in the drinking water for 5 months had no obvious side effects. Mannose fed pregnant mice had normal litter size and survival to weaning and all mice given mannose supplements had normal weight gain, organ function, physiology, and behavior.

Conclusions:

Stringent regulation of metabolites such as Man-6-P is crucial: deficiency or excess can be detrimental for the cell and the physiology of the whole organism. Steady state levels and metabolic flux of the metabolites depend on both the substrates and the relevant enzymes, which in turn, determine normal vs disease states. Mannose can be therapeutic, but indiscriminate use can have adverse effects.

Executive summary:

Both diet- and glucose-derived mannose contribute to the mannose pool, which is directly used ofr glycoconjugate synthesis. Stringent regulation of metabolites such as Man-6-P is crucial: deficiency or excess can be detrimental for the cell and the physiology of the whole organism. Steady state levels and metabolic flux of the metabolites depend on both the substrates and the relevant enzymes, which in turn, determine normal vs disease states. Mannose can be therapeutic, but indiscriminate use can have adverse effects.

Reference 2

Endpoint:

basic toxicokinetics, other

Type of information:

other: review article

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

Principles of method if other than guideline:

Article is a summary of the known information on mannose metabolism.

Type:

metabolism

Results:

Mannose is involved in an extensive series of metabolic transformations being incorporated into glycoproteins and glycolipids or formed into fucose that is then incorporated into glycoproteins. 

Metabolites identified:

yes

Details on metabolites:

Mannose is involved in an extensive series of metabolic transformations being incorporated into glycoproteins and glycolipids or formed into fucose that is then incorporated into glycoproteins. The primary source of mannose is glucose. Mannose is generated in the form of mannose-6-phosphate (M-6-P) from fructose-6-phosphate (F-6-P). Mannose is phosphorylated by hexokinase to M-6-P. M-6-P is transformed to mannose-1-phosphate (M-1-P). M-1-P reacts with guanosine triphosphate (GTP) to form guanosine diphosphomannose (GDP-mannose) and pyrophosphate (PP1). GDP-mannose is a mannose donor for the incorporation of mannose into glycoproteins and glycolipids and is transformed into guanosine diphosphate fucose (GDP-fucose), which is the future donor for the incorporation of fucose into glycoproteins and glycolipids.

Conclusions:

Mannose is involved in an extensive series of metabolic transformations being incorporated into glycoproteins and glycolipids or formed into fucose that is then incorporated into glycoproteins. 

Executive summary:

Mannose is involved in an extensive series of metabolic transformations being incorporated into glycoproteins and glycolipids or formed into fucose that is then incorporated into glycoproteins. This article describes and discusses this metabolic pathway in detail.

Reference 3

Endpoint:

basic toxicokinetics in vivo

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

Objective of study:

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

The effect of mannose ingestion was investigated to determine the effect on blood sugar. Concentrations of blood mannose or glucose were followed over periods of 4-10 hours after mannose or glucose administration and total urinary excretion was measured in periods for 24 to 36 hours after the start of the experiment. Three phases of experiments were carried out on 5 different rabbits. In five of these experiments, differential glucose and mannose determinations were run on each blood sample.

Species:

rabbit

Strain:

not specified

Sex:

not specified

Route of administration:

oral: gavage

Dose / conc.:

2 other: g/kg

Dose / conc.:

5 other: g/kg

Details on study design:

In first phase experiments, rabbits were fasted 36 to 48 hours and placed in metabolism cages. Control blood samples were taken and mannose was given by gavage in dosages of 2 to 5 g/kg in 10% solution in water. Blood samples were subsequently taken at 30 or 60 minute intervals for the duration of the experiment. Differential sugar determinations were conducted.

In second phase, experiments were conducted in fasted rabbits to determine effect of mannose on blood lactic acid. These animals were maintained in a state of mild sedation. A 2 to 3-hour control period was allowed before the animal received mannose in order to come to a steady state as far as blood sugar and blood lactate levels. Sugars were given in dosages of 2 g/kg and blood samples were taken at hourly intervals over periods of 3-6 hours. In some experiments mannose was administered via the i.p. route.

In third phase experiments, the effect of mannose administration on liver glycogen in fasted rabbits. Rabbits were anesthetized and operated on. After a sample was taken from the right liver lobe, the wound was closed, the sugar was given and the animals was kept in a metabolism cage for the duration of the experiment. After a period of at 6, 10, and 12 hours, the animal was anesthetized, reopened, and samples of the right and left liver lobes were taken for analysis. The animal was then sacrificed. Total sugar excretion was measured in the urines collected during the period of the experiment.

Type:

absorption

Results:

Mannose is fairly slowly absorbed from the gut, well utilized, and convertible to glucose in the intact rabbit.

Experiments on carbohydrate balance showed an average retention of 90% of the mannose dose when the sugar was administered orally or intraperiotenally. The results indicate a high degree of utilization of mannose by the rabbit. 

Mannose appeared in the peripheral venous blood and produced an elevation of blood glucose in all animals tested after mannose ingestion.  No fructose was found in any blood sample from animals tested during the hyperglycemia following mannose administration.

An increase in lactic acid was observed after mannose administration. These increases were similar to increases seen after glucose administration in that they paralleled increases in total blood sugar.

Amounts of liver glycogen found at 6, 10, and 12 hours after mannose administration were approximately in the same order as those found after glucose administration at the same dosage level when these sugars were given parenterally to animals previously fasted for 24 hours.

Conclusions:

Mannose is fairly slowly absorbed from the gut, well utilized, and convertible to glucose in the intact rabbit. A possible mechanism for the metabolic conversion of mannose to glucose was suggested to be by way of lactic acid and liver glycogen.

Executive summary:

The effect of mannose ingestion was investigated to determine the effect on blood sugar. Concentrations of blood mannose or glucose were followed over periods of 4-10 hours after mannose or glucose administration and total urinary excretion was measured in periods for 24 to 36 hours after the start of the experiment. Three phases of experiments were carried out on 5 different rabbits. In five of these experiments, differential glucose and mannose determinations were run on each blood sample. Mannose is fairly slowly absorbed from the gut, well utilized, and convertible to glucose in the intact rabbit. A possible mechanism for the metabolic conversion of mannose to glucose was suggested to be by way of lactic acid and liver glycogen.

Description of key information

The test substance (D-Mannose) is a non-essential six-carbon sugar that can be interconverted with glucose. The test substance is important for the post-translational processing of proteins by N-linked glycosylation (N-glycans). The digestion of glycoproteins and polysaccharides yield the test substance which can then be phosphorylated and enter the glycolytic or gluconeogenic pathways in hepatocytes. Human plasma normally contains approximately 50 µM mannose. Mannose absorbed through the intestine undergoes metabolism. A bolus dose of 200 mg/kg body weight increased the blood mannose concentration by three-fold. The clearance half-life was approximately 4 hours and did not alter glucose concentration. Excess mannose is excreted in urine. The plasma concentration of endogenous mannose in rats is approximately 80 µM. Treatment of rats and mice with radiolabeled mannose gave clearance results similar to humans. Most of the label is metabolized and excreted with a low percentage incorporated into glycoproteins of all tissues.

The effect of mannose ingestion was investigated to determine the effect on blood sugar (Bailey and Roe, 1994).  Concentrations of blood mannose or glucose were followed over periods of 4-10 hours after mannose or glucose administration and total urinary excretion was measured in periods for 24 to 36 hours after the start of the experiment. Three phases of experiments were carried out on 5 different rabbits. In five of these experiments, differential glucose and mannose determinations were run on each blood sample. Mannose is fairly slowly absorbed from the gut, well utilized, and convertible to glucose in the intact rabbit. A possible mechanism for the metabolic conversion of mannose to glucose was suggested to be by way of lactic acid and liver glycogen.

Intravenous infusions of mannose and glucose were given to human subjects (Wood and Cahill, 1963). 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.

A review article on mannose metabolism suggests that mannose is involved in an extensive series of metabolic transformations being incorporated into glycoproteins and glycolipids or formed into fucose that is then incorporated into glycoproteins (Herman, 1971). The primary source of mannose is glucose.  Mannose is generated in the form of mannose-6-phosphate (M-6-P) from fructose-6-phosphate (F-6-P). Mannose is phosphorylated by hexokinase to M-6-P. M-6-P is transformed to mannose-1-phosphate (M-1-P). M-1-P reacts with guanosine triphosphate (GTP) to form guanosine diphosphomannose (GDP-mannose) and pyrophosphate (PP1). GDP-mannose is a mannose donor for the incorporation of mannose into glycoproteins and glycolipids and is transformed into guanosine diphosphate fucose (GDP-fucose), which is the future donor for the incorporation of fucose into glycoproteins and glycolipids.

Normal subjects and CDGS patients who ingested mannose were evaluated to determine blood mannose concentrations would be elevated (Alton et al., 1997). The positive results support the feasibility of using mannose as a potential therapeutic dietary supplement for CDGS type I patients. The results of this study show that mannose was rapidly taken up following oral ingestion. The peak blood mannose level was observed approximately 90 minutes following oral ingestion. Blood mannose concentrations rose in a dose dependent fashion for all subjects and a peak concentration of 447 μM had no deleterious symptoms on one individual. At oral doses exceeding 200 mg/kg body weight, approximately half the subject reported some mild gastrointestinal distress. The clearance half-life was approximately 4 hours. Bilirubin, chosen as a marker for hepatic function, showed no significant alterations in concentrations in the blood following mannose ingestion. Additionally, no change in blood glucose was observed, indicating that neither liver function nor glucose homeostasis was perturbed by the dosages of mannose used in this study.