Liver and Adipose Carbohydrate Regulation Flashcards
GLUT 2
- GLUT-2 in intestinal cells facilitates movement of these sugars from the interior of the cell to the blood.
- GLUT-2 also accounts for most glucose uptake by both liver and pancreatic βcells.
- The GLUT-2 transporter is characterized by a low affinity but high capacity for glucose.
Glucose Concentration and Uptake
•The GLUT-2 transporter is characterized by a low affinity but high capacity for glucose.
- Thus following food deprivation, uptake of glucose by liver and pancreatic β-cells is limited by the lower blood glucose concentration.
- This characteristic provides regulation at the cell surface by virtue of the kinetic parameters of the transporter.
- Following a meal, the low affinity is overcome by intake of dietary glucose.
- The high capacity ensures the rapid removal by liver cells of glucose from the portal circulation and from the peripheral circulation by the pancreatic β-cells.
- Since glucose reaches the liver before signaling the pancreas to release insulin, it is important that the liver transporter function independently of insulin.
-This situation prevents hyperglycemia (excess blood glucose) after ingestion of sugar.
•In the pancreatic β-cells, it is essential that uptake of glucose is limited to only when glucose is at a high concentration; otherwise insulin secretion could cause hypoglycemia.
GLUT 4
- Uptake of glucose into adipose and muscle cells by GLUT-4 transporter is insulin-regulated to ensure uptake occurs only when glucose is abundant.
- Insulin-dependent transport of glucose by these cells occurs subsequent to pancreatic release of insulin in response to elevated blood glucose.
- Therefore, the GLUT-4 transporter in these tissues will not take up much glucose following food deprivation because of the low circulating concentration of insulin.
- GLUT-4 proteins stored in the cell are moved to the plasma membrane after insulin binds to its cell surface receptor.
- In this way the total number of transport proteins in the membrane increases markedly and in a dose-dependent manner.
Insulin Resistance and Muscle Cells
- As insulin resistance develops in the metabolic syndrome and type 2 diabetes, muscle cells are affected first as they seem particularly sensitive to decreased insulin responsiveness.
- This diminished effect of insulin on the muscle GLUT-4 transporter is an initial cause of the hyperglycemia associated with these pathological states.
- As the resistance worsens, fat cells become similarly affected and this exacerbates the hyperglycemia.
Fructose Disorders
- Essential fructosuria
- Hereditary fructose intolerance
Essential Fructosuria
- Essential fructosuria, an autosomal recessive disorder is a consequence of a deficiency/defect in fructokinase.
- Because fructose cannot be phosphorylated in the liver, due to the relative lack of hexokinase in this organ, dietary fructose is poorly metabolized primarily leading to excessive excretion of fructose in the urine.
- Often the disorder is asymptomatic because fructose does not enter the cells and fructose intake is insufficient to cause polyuria.
Hereditary Fructose Intolerance
- Hereditary fructose intolerance is caused by a deficiency/defect of aldolase B.
- These patients must eliminate fructose, as well as sucrose (disaccharide of glucose and fructose), from their diets.
- While aldolase B primarily catalyzes the cleavage of fructose-1-P, a defect in this enzyme also diminishes to some extent the cleavage of fructose-1,6-bisP.
- As a consequence of this defect, fructose-1-P accumulates in the cell.
- Large amounts of phosphate become ‘trapped’, making the phosphate unavailable for the formation of ATP and causing inhibition of both glycogenolysis and gluconeogenesis, energy-requiring pathways.
- Symptoms of this disorder include hypoglycemia, cirrhosis, jaundice and vomiting (when fructose consumption is attempted).
- Under conditions where there is insufficient dietary glucose, the liver produces glucose from its glycogen stores.
- However, in patients with an aldolase B defect, the accumulation of fructose-1-P and fructose-1,6-bisP inhibit the glycogen phosphorylase reaction, which is responsible for breaking down glycogen.
- Normally glucose-6-P inhibits glycogen phosphorylase and in high amounts fructose-1-P and fructose-1,6-bisP mimic this effect.
- Consequently, these fructose metabolic intermediates cause the breakdown of glycogen to decrease resulting in fructose-induced hypoglycemia that is coupled with a mild impairment of gluconeogenesis.
Galactose Disorders
- Galactokinase Deficiency
- Classic Galactosemia
Galactokinase Deficiency
- Galactokinase deficiency is autosomal recessive and leads to elevated concentration of galactose in the blood.
- When galactose is included in the diet, galactitol is formed by reduction of galactose by NADPH.
- Because galactitol diffuses poorly, an increase in osmotic pressure results in diffusion of water into the lens and infantile cataracts can develop.
- A low lactose diet is essential in such patients, as lactose is the primary dietary source of galactose.
Classic Galactosemia
- uridyl transferase deficiency
- Classic galactosemia also exhibits autosomal recessive inheritance.
- Accumulation of galactitol occurs leading to lens damage and infantile cataracts.
- Overall the condition is worse than galactokinase deficiency because, as with hereditary fructose intolerance, phosphate is trapped as galactose-1-P.
- Symptoms include liver damage with jaundice and hepatomegaly, as well as failure to thrive, and mental retardation.
Regulation of Carbohydrate Metabolism
- Regulation of Glucose Phosphorylation
- Regulation of Phosphofructokinase-1 and Fructose-1,6-bisphosphatase
- Liver Pyruvate Kinase
- inhibition by alanine
- allosteric activation by fructose 1,6bisP and PEP
- hormonal
Regulation by Glucose Phosphorylation
•Inhibition by alanine
-Alanine is the primary amino acid precursor for glucose synthesis. It is essential that glycolysis be diminished when the liver is synthesizing glucose. To accomplish this, in part, alanine allosterically inhibits pyruvate kinase
•Allosteric activation
-Activation of pyruvate kinase by fructose-1,6-bis P and phosphoenolpyruvate (PEP) ensures that the glycolytic intermediates between PFK-1 and pyruvate kinase are kept at a minimal concentration (Figure 7). As soon as flux through PFK-1 increases causing the concentration of fructose-1,6-bis P to increase, pyruvate kinase is activated in parallel.
- Activity of liver pyruvate kinase decreases following its phosphorylation by protein kinase A (PKA) in response to glucagon.
- In contrast, pyruvate kinase is active under conditions of high blood glucose because insulin promotes the dephosphorylation of the enzyme.
-Thus insulin (via protein phosphatase), as a signal of high blood glucose following a meal, coordinates an increased activity of liver glycolysis by causing the activation of both PFK1 (by raising fructose-2,6-bisP) and pyruvate kinase (by dephosphorylation).
•In starvation, glucagon reverses these effects on both enzymes.
Regulation of Pyruvate Carboxylase
- Pyruvate carboxylase is activated by acetyl CoA to accelerate the rate of gluconeogenesis.
- This effect coordinates with the increased beta-oxidation of fatty acids during food deprivation.
- Thus gluconeogenesis will not occur unless the liver has access to fatty acids to generate acetyl CoA.
- Consequently when fat stores become depleted with prolonged starvation, gluconeogenesis ceases.
Regulation of Phosphoenolpyruvate Carboxykinase
- Phosphoenolpyruvate carboxykinase, the rate-determining and committed step of gluconeogenesis, is induced by cortisol during starvation while its synthesis is antagonized by insulin in the fed state.
- This effect of cortisol coordinates with the ability of this hormone to mobilize amino acids, from muscle protein, to serve as precursors to gluconeogenesis.
