Carbohydrate metabolism-IPAP

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Secreted in response to the movement of gastric acid.

Secretin
-stimulates the liver, pancreas, gastric and intestinal cells to secrete HCO3 and H2O

Breaks down plant starches and glycogen into Maltose, maltitriose, and alpha dextrins (limit-dextrins) in the mouth

alpha-amylase

Breaks down amylase, amylopectin, glycogen, and maltose into glucose

B-glucoamylase

Breaks down alpha dextrins, sucrose, maltotriose, and maltose into glucose and fructose

Sucrase-Isomaltase
(dextrinase)

Breaks down sugar from mushrooms, algae, fungi, and insects into glucose

Trehalase
(trehalose sugar)

Breaks down lactose and glycolipids into glucose and galactose

B-gylcosidase
(Lactase)

Sodium Dependent Transporters
-Membrane Protein transporter
-allows glucose and galactose and Na
-Found in Renal and Intestinal cells

SGLT1

Membrane Protein Transporter-absorbs Fructose only

GLUT 5
(found in intestines, testes, brain, liver, kidneys)

Insulin Sensitive Membrane Protein Transporter

GLUT 4
(found in adipose, skeletal muscle, heart, brain-neurons and astrocytes)

Membrane Protein Transporter for cell types with barrier functions. High Affinity Glucose

GLUT 1
(most cells, human erythrocyte, BBB, BRB, BPB, BTB, Brain (astrocytes/glial))

Membrane Protein Transporter
-high capaciity, bidirectional . Transports Glucose, Galactose, and Fructose

GLUT 2
(found in Liver, Kidneys, Pancreatic B-cell, Serosal Intestine mucosa cells)

Membrane Protein Transporter in the ER of liver

GLUT 7

Membrane Protein Transporter-newly discovered

GLUT 8
(found in brain-neurons, testes, adipose, muscle)

Major Membrane Protein Transporter in the CNS

GLUT 3
-Brain-neurons

Fructose will be linked to ___ in the fed state and __ in the fasting.

Glycolysis-fed

Gluconeogenesis-fasting

Galactose is used to produce:

-glucose
-lactose
-glycogen
-glucuronides
-glycolipids
-glycoproteins

What pathway is used to convert Galactose into Glucose in the liver and intestinal cells?
What enzymes are used?

Lenoir Pathway

-Galactokinase
-Galacotse-1-Phosphate Uridyltransferase
-Phosphoglucomutase
-Glucose-6-Phosphatase

Where are the highest concentrations of galactose found in a lab test?

Urine
-10 x more
-what is not metabolized in liver or intestine

In Classical Galactosemia, ______enzyme is deficient leading up to build up of _____ and _____.

Galacotse-1-Phosphate Uridyltransferase
-Galactose and
-Galactose 1-Phosphate
(common in infants)

This Galactose metabolism disorder affecting mostly RBCs and WBCs from a deficiency of _______ enzyme.

UDP-galactose-4-epimerase

Deficient ____enzyme will cause a buildup of Galactose in the blood.

Galactokinase

What are some test results that confirm the diagnosis of Classical Galactosemia?

-Impaired liver function
-Elevated blood galactose levels
-Hyperchloremic metabolic acidosis
-Hyperaminoaciduria (high AA)
-High galacticol excretion in urine
-Increased Galactose-1-Phosphate inside RBCs

A buildup of Galactose caused by Galactokinase Deficiency can cause _____.

Galactosemic cataracts
-fail to develop social smile
-fail to visually track moving objects
-same labs as others (look for enzyme in blood level)

How and why does Galactose get converted to Galactitol in neural tissue and lens of the eye?

-too much galactose in circulation
-Aldose Reductase (w/NADPH) converts to Galacticol
-cannot complete Polylol Pathway

What lab tests should be done to confirm galactose disorders in newborns?

-Blood test-from heel
-Urine-check for 3 enzymes:
1. Galactokinase
2. Galacto-1-phosphate unidyltransferase
3. UDP-galactose-4-epimerase

How to treat galactose disorders

-Eliminate lactose from diet
-Use Soy based formula
-Surgical removal of cataracts(only persistent ones)

Why is fructose used in gatorade?

-immediate source of energy
-active in both fed and fasting states

When does hexokinase convert fructose into fructo-6-phosphate to join glycolysis?

When there is not enough Glucose
-has higher affinity for Glucose

What cycle does fructose enter in the fasting state?

Gluconeogenesis

What enzyme is deficient in Fructose Intolerance?

Aldolase B
-inhibits connection of fructose-1-phosphate to glycolysis
(in fed state)

How does fructose intolerance affect the fasting state?

It causes an accumulation of:
-glyceraldehyde-3-phoshate and
dihydroxyacetone phosphate

-inhibits gluconeogenesis
-traps phosphates

What is affected if phosphates are trapped?

-ATP, GTP synthesis
-enzyme activation
-glyconeogenesis, glycolysis, glycogenolysis
-leads to cell death

How will blood tests confirm fructose intolerance

-Hypoglycemia
-Hyperuricemia
-Liver fxn panel fail
-Bleeding tendency

How do you treat fructose intolerance

-Elimination of Fructose and Sucrose from diet
-may not prevent progressive liver disease

What is fructose malabsorption?

GLUT 5 in deficient
-fructose is digested by flora in gut

What do the flora produce after consumption of fructose?

-short chain FA
-H+, CH4, CO2

What is a consequence of fructose malabsorption?

-promotes bio-film in gut
-decreased tryptophan, folic acid,and zinc in blood
-decreased absorption of some nutrients

What lab tests are run to diagnose fructose malabsorption?

Hydrogen breath test(adults)

Stool acidity test (infants)

How will urine tests confirm fructose intolerance?

-Positive for reducing sugars (high levels of sugars)
-Aminoaciduria
-Increased salts
Also...Liver Biopsy

What is fructosuria?

Deficiency of hepatic fructokinase
-cannot convert fructose to fructose-1-phosphate
-excess fructose excreted in urine
-benign

Where is glycogen stored?

Mainly in Liver and Muscle cells

What is the two unit subunit enzyme that initiates glycogen synthesis?

Glycogenin

-macromolecules (proeoglycans)
-free in fasting state-liver
-tyrosine residues

What is the substrate for the active site of glycogenin?

UDP-glucose
-made from galactose
-converted from glucose

What is a glycogen primer?

8-12 glucose molecules attached to the glycogenin
-alpha 1,4 linkage

What enzyme transfers a glucose molecule from UDP-glucose to the terminal residue of a glycogen primer?

Glycogen synthase

What enzyme breaks 5-8 glucose residues from the chain to make a branch?

Branching enzyme
(amylo (a-1-4, a1-6) transglycosylase

The globular structure of glycogen contains how many concentric rings?

12
-@30k glucose units

What is an advantage of the ring structure?

-Increased solubility
-exposed carbon makes easy degradation/synthesis

In the fed state, what does insulin do?

-activates:
-GLUT 4
-glucose to glycogen
-glucose to TG
-enzymes for carb metabolism
-inhibits glycogenolysis enzymes

What is a type 0 glycogen disorder?
Enzyme?
Consequences?

Lewis
-Glycogen synthase
-hypoglycemia
-hyperketonemia
-failure to thrive
-early death

What is a type 4 glycogen disorder?
Enzyme?
Consequences?

Anderson's
-branching enzyme
-altered glycogen structure
-enlarged liver
-fatal

What does the polyol pathway do?

converts glucose to sorbitol to fructose

What happens when there is too much sorbitol in the lens of the eye?

Diabetic cataracts

Why is sorbitol not converted to fructose to limit cell damage?

Sorbitol is produced faster than it can convert to fructose.
(diabetics)
-cannot leave cell-toxic
-leads to cell lysis and loss of function
-peripheral tissue cells
-peripheral nerves
-blood vessel cells
-pancreas
-kidneys

What tissue uses lactate for energy?

-Liver-50%
-Kidneys
-Muscles
-neurons
(provided from RBCs, seritoli cells, astrocytes,muscles)

Glycogenolysis is the breakdown of _____.

Glycogen
-fasting state
-muscle contraction

What enzyme starts the breakdown of glycogen by breaking the a-1,4 bonds

Glycogen Phosphorolase
-pyridoxal (b6) cofactor

What product is initially made when glycogen is split?

Two glucose-1-phosphate molecules

What enzyme goes into effect during glycogenolysis when there are only four glucose molecules left on a branch?

Debranching enzyme
(4:4 transferase), then
(a-1,6-amyloglucosidase)

What enzyme converts G-1-P to G-6-P during the last stage of glycogenolysis?

phosphoglucomutase

Where do the G-6-P molecules end up after glycogenolysis?

-Glycolyic Pathway
-Pentose Phosphate Pathway
-Gluconeogenesis

What three hormones regulate glycogenolysis in the liver?

Glucagon, cortisol, and epinephrine
-released due to hypoglycemia
-fasting, low carb diet, sleep, exercise
-stress on the body

What binds to B Receptors and magnifies the effect of Glucagon?

Epinephrine

What is inactivated when glucagon enters the liver and muscle?

Glycogen synthase

-glycogenesis

What is activated when glucagon enters the liver and muscle?

Glycogen phosphorylase

-glycogenolysis

What hormone counters the effect of insulin and stimulates gluconeogenesis to increase blood sugar levels?

Cortisol

-with glucagon

What is affected in Type 1 VonGlerke's glycogen disorder

Glucose-6-Phosphatase
-stops conversion to glucose
-severe hypoglycemia
-lactic acidemia
-hyperlipidemia

What is affected in Type III Cori's glycogen disorder?

Debranching Enzyme
-no free glucose
-altered glycogen structure
-hypoglycemia

What is affected in Type V McArdle's glycogen disorder?

Muscle Phosphorylase
-no breaking of glycogen
-cramps
-no energy

What is affected in Type VI Hers' glycogen disorder?

Liver phosphorylase
-hypoglycemia
-no glucose to brain
-breaks down AA/FA

What is lactogenesis and where does it occur?

production of Lactose
-mammary glands in females
-uses both glucose and galactose

What hormone stimulates lactogenesis?

Prolactin
-other hormones levels drop after childbirth leaving high levels of prolactin
-or suckling of infant

What enzyme converts UDP glucose to UDP galactose?

4-epimerase

What enzymes are synthesized in response to prolactin and cortisol?

A-lactalbumin and galactosyltransferase
-increases production of lactose

What enzyme removes galactose from UDP galactose and bonds with glucose to create lactose?

Galactosyltransferase

-enhanced by A-lactalbumin

What is the first milk a breastfed baby receives?
What is special about it?

Colostrum

-high amounts of WBCs, and Antibodies
(more than mature milk)

What does IgA do for a newborn?

coats lining of intestines
-fights germs
-prevents food allergies

What is in mature breast milk?

-80% water
-proteins
-carbs (lactose)
-fats
-minerals
-enzymes
-hormones(growth, etc.)
-Ig

What glucose/galactose pathway creates no ATP, makes macromolecules for other functions in the body,and connects to the pentose phosphate pathway?

Uronic Acid Pathway
-AKA Glucuronic Acid Pathway

What is the clinical significance of glucuronides?

eliminates insoluble(non polar) substances from body
-out in urine and bile
-facilitates transport of insoluble drugs in body

What is the synthesis of glucuronides called and where does it take place?

Glucuronidation

-mainly in liver
-other-H,K,spleen, adrenal glands, thymus

What enzyme catalyzes glucuronidation?

UDP-glucuronate transferase
-AKA UDP glucuronyltransferase

Non polar substances that are transported by glucuronides

morphine, sleep drugs, cancer drugs
-Steroids,Thyroid hormones (T3 and T4)
-pollutants
-fatty acid derivatives
-bile acids

What compounds can help control the progression of cancer by increasing the rate of glucuronidation reactions?

- D-gluraco-1
- 4-lactone
- D-glucaric acid

-lung, skin, liver, breast, colon, bladder, and prostate cancer

How do the "anti-cancer" compounds work?

- inhibit the enzyme B-glucuronidase
- suppress cell proliferation and inflammation

How is 80% of Bilirubin produced?

Degradation of Hb in RBCs
-20%-myoglobin, cytochrome p450

How is Bilirubin transported in circulation?

-Bound to Albumin
(unconjugated/indirect)
-transported to liver

What happens to unconjugated Bilirubin in the liver?

undergoes glucuronidation
-makes conjugated Bilirubin
-water soluble

Where does conjugated bilirubin go after the liver?

-most to intestines
-some in plasma-to urine

What do intestinal bacteria do with conjugated bilirubin?

Make urobilinogen
-90% converted to stercobilin/urobilin
-color of poo
-10% liver-bile/plasma-urine

What enzymes convert Heme to bilirubin?

Microsomal heme oxygenase
-biliverdin + Fe
-Fe stored as Ferritin

Biliverdin Reductase

What is Jaundice or Icterus?

Excess unconjugated, conjugated, or urobilinogen in circulation or urine

What are the causes of Jaundice

-Too much unconjugated bilirubin-liver cannot conjugate all
-Hepatic disease-liver can't conjugate
-Liver disease-cannot reabsorb or re-excrete urobilinogen
-duct obstruction-backup of conjugated bilirubin

Prehepatic Jaundice

-over-abundance of u-b in blood
-increase u-b
-increase urine urobilinogen
-increase fecal urobilinogen
-no conjugated
-normal AST, ALT, ALP
-no urine bilirubin

Intrahepatic (hepatitis)

-Increase c-b
-Increase AST and ALT
-Increase urine urobilirubin
-urine bilirubin present (dark)
-normal ALP
-decrease fecal urobilirubin

Intrahepatic (Neonatal) <30 days old

Immature liver cells
-increase U-B
-no C-B
-no Urine-B
-no Urine urobilinogen
-no fecal urobilinogen

Post Hepatic Jaundice (obstructive)

-increase C-B
-increase ALP
-urine bilirubin present (dark)
-no fecal urobilinogen (blocked)
-no U-B
-no urine urobilinogen
-normal PT
-normal AST, ALT

Causes and signs of liver disease

hepatitis exposure, transfusions, IV drug use, alcohol use, some meds, or family history
-increase AST
-prolonged PT
-blood test will specify

How to treat jaundice caused by sickle cell anemia

-increase iron in diet or supplements

Tests to run to diagnose Jaundice

-CBC
-plasma bilirubin-conjugated and total
-Liver Panel-AST, ALT, ALP, GGT
-measurement of coagulation time (PT)

What disease is marked by a unconjugated bilirubin level that rarely exceeds 50?

Gilbert's
-low UDP-glucuronyltransferase
-enzyme for conjugation
-inherited

Causes of Intra-hepatic Jaundice in Newborns

-Immature Liver Cells-can't conjugate or might leak into intestine
-unconjugation in intestine by B-glucuronidase -re-enters bloodstream
-RBC destruction - maternal IgG problems or conversion to adult Hb

What is the most common type of neonatal jaundice?

Physiological

What is the most severe form of Jaundice in newborns?

Pathological(Kernicterus)
serum>300 of U-B
-no C-B in urine
-U-B and no uribilinogen in Meconium

What are some causes of post-hepatic obstructive jaundice?

Intra-hepatic
-Drugs
-Cholangitis

Extra-hepatic
-Cancer-mass closes lumen
-Gall Stones (>60yrs)
-Liver Flukes

Possible treatments for neonatal jaundice

Phototherapy/Bili Lights
-takes care of skin color
IVIG-due to blood group incapatabilities
-exchange transfer of blood

How are gall stones treated?

Surgically by removing gall bladder
cholecystectomy

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