Clinical Aspects

Impairment of the Pentose Phosphate Pathway Leads to Erythrocyte Hemolysis

Genetic deficiency of glucose-6-phosphate dehydrogenase, with consequent impairment of the generation of NADPH, is common in populations of Mediterranean and Afro-Caribbean origin. The defect is manifested as red cell hemolysis (hemolytic anemia) when susceptible individuals are subjected to oxidants, such as the an-timalarial primaquine, aspirin, or sulfonamides or when

Glucose

UDPGlc

HEXOKINASE

UDPGlc PYROPHOSPHORYLASE

PHOSPHOGLUCOMUTASE

NAD+

UDPGal

URIDINE DIPHOSPHOGALACTOSE 4-EPIMERASE

LACTOSE SYNTHASE

UDPGal

LACTOSE SYNTHASE

Lactose

Glucose

Lactose

Glucose 6-phosphate

Glucose 1-phosphate

Glucose

Figure20-6. Pathway of conversion of (A) galactose to glucose in the liver and (B) glucose to lactose in the lactating mammary gland.

they have eaten fava beans (Vicia fava—hence the term favism). Glutathione peroxidase is dependent upon a supply of NADPH, which in erythrocytes can be formed only via the pentose phosphate pathway. It reduces organic peroxides and H2O2 as part of the body's defense against lipid peroxidation (Figure 14-21). Measurement of erythrocyte transketolase and its activation by thiamin diphosphate is used to assess thiamin nutritional status (Chapter 45).

Disruption of the Uronic Acid Pathway Is Caused by Enzyme Defects & Some Drugs

In the rare hereditary disease essential pentosuria, considerable quantities of L-xylulose appear in the urine because of absence of the enzyme necessary to reduce l-xylulose to xylitol. Parenteral administration of xylitol may lead to oxalosis, involving calcium oxalate deposition in brain and kidneys (Figure 20-4). Various drugs markedly increase the rate at which glucose enters the uronic acid pathway. For example, administration of barbital or of chlorobutanol to rats results in a significant increase in the conversion of glucose to glu-curonate, l-gulonate, and ascorbate.

Loading of the Liver With Fructose May Potentiate Hyperlipidemia & Hyperuricemia

In the liver, fructose increases triacylglycerol synthesis and VLDL secretion, leading to hypertriacylglyc-erolemia—and increased LDL cholesterol—which can be regarded as potentially atherogenic (Chapter 26). In addition, acute loading of the liver with fructose, as can occur with intravenous infusion or following very high fructose intakes, causes sequestration of inorganic phosphate in fructose 1-phosphate and diminished ATP synthesis. As a result there is less inhibition of de novo purine synthesis by ATP and uric acid formation is in-

-Glycogen-

Glucose 1-phosphate-*^

ATP ADP

Fructose 6-phosphate

Glutamine

Glucosamine

ATP ADP

Glucosamine

N-Acetyl-glucosamine

Acetyl-CoA ATP ADP

ATP ADP

Acetyl-CoA ATP ADP

Glucosamine

Glutamate

6-phosphate f*- Acetyl-CoA

AMIDOTRANSFERASE

Glutamate

6-phosphate

PHOSPHOGLUCO-MUTASE

Glucosamine 1-phosphate

f*- Acetyl-CoA

N-Acetyl-glucosamine 6-phosphate

N-Acetyl-glucosamine 1-phosphate

N-Acetyl-mannosamine 6-phosphate r

UDP-

N-acetylglucosamine*

Phosphoenolpyruvate

NAD+

Glycosaminoglycans (eg, heparin)

Glycosaminoglycans (hyaluronic acid), glycoproteins

N-Acetyl-neuraminic acid 9-phosphate

UDP-

N-acetylgalactosamine*

A/wwww\a> Inhibiting — allosteric effect

Sialic acid, gangliosides, glycoproteins

Glycosaminoglycans (chondroitins), glycoproteins

Figure 20-7. Summary of the interrelationships in metabolism of amino sugars. (At asterisk: Analogous to UDPGlc.) Other purine or pyrimidine nucleotides may be similarly linked to sugars or amino sugars. Examples are thymidine diphosphate (TDP)-glucosamine and TDP-W-acetylglucosamine.

EPIMERASE

EPIMERASE

creased, causing hyperuricemia, which is a cause of gout (Chapter 34).

Defects in Fructose Metabolism Cause Disease (Figure 20-5)

Lack of hepatic fructokinase causes essential fructo-suria, and absence of hepatic aldolase B, which cleaves fructose 1-phosphate, leads to hereditary fructose intolerance. Diets low in fructose, sorbitol, and sucrose are beneficial for both conditions. One consequence of hereditary fructose intolerance and of another condition due to fructose-1,6-bisphosphatase deficiency is fructose-induced hypoglycemia despite the presence of high glycogen reserves. The accumulation of fructose 1-phosphate and fructose 1,6-bisphosphate allosterically inhibits the activity of liver phosphorylase. The sequestration of inorganic phosphate also leads to depletion of ATP and hyperuricemia.

Fructose & Sorbitol in the Lens Are Associated With Diabetic Cataract

Both fructose and sorbitol are found in the lens of the eye in increased concentrations in diabetes mellitus and may be involved in the pathogenesis of diabetic cataract. The sorbitol (polyol) pathway (not found in liver) is responsible for fructose formation from glucose (Figure 20-5) and increases in activity as the glucose concentration rises in diabetes in those tissues that are not insulin-sensitive, ie, the lens, peripheral nerves, and renal glomeruli. Glucose is reduced to sorbitol by aldose reductase, followed by oxidation of sorbitol to fructose in the presence of NAD+ and sorbitol dehydrogenase (polyol dehydrogenase). Sorbitol does not diffuse through cell membranes easily and accumulates, causing osmotic damage. Simultaneously, myoinositol levels fall. Sorbitol accumulation, myoinositol depletion, and diabetic cataract can be prevented by aldose reductase inhibitors in diabetic rats, and promising results have been obtained in clinical trials.

When sorbitol is administered intravenously, it is converted to fructose rather than to glucose. It is poorly absorbed in the small intestine, and much is fermented by colonic bacteria to short-chain fatty acids, CO2, and H2, leading to abdominal pain and diarrhea (sorbitol intolerance).

Enzyme Deficiencies in the Galactose Pathway Cause Galactosemia

Inability to metabolize galactose occurs in the galactosemias, which may be caused by inherited defects in galactokinase, uridyl transferase, or 4-epimerase (Figure 20-6A), though a deficiency in uridyl transferase is the best known cause. The galactose concentration in the blood and in the eye is reduced by aldose reductase to galactitol, which accumulates, causing cataract. In uridyl transferase deficiency, galactose 1-phosphate accumulates and depletes the liver of inorganic phosphate. Ultimately, liver failure and mental deterioration result. As the epimerase is present in adequate amounts, the galactosemic individual can still form UDPGal from glucose, and normal growth and development can occur regardless of the galactose-free diets used to control the symptoms of the disease.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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