Liver Metabolism 1: Blood Glucose Regulation Flashcards
Acute liver disease clinical presentation
Male breast enlargement
Poor gonadal function
Loss of body hair
Testicular atrophy
Ankle swelling/fluid retention
Jaundice
Bruises
Stretch marks
Enlarged liver
Abdominal swelling
Dilated esophageal veins
note: can present with asymptomatic
Common lab findings in acute liver disease
Lower than normal:
- glucose
- urea
- albumin
High than normal
- bilirubin (20x upper limit)
- ammonia (20x upper limit)
- Prothrombin time (5x upper limit)
- ALK (5x upper limit)
- ALT = upper limit
Primary liver functions
1) synthesis and secretion of bile and plasma proteins
2) metabolism and storage of:
- DEAK vitamins
- Vitamin B12
- copper and iron minerals
3) metabolism of:
- carbs
- lipids
- Nitrogen compounds
4) detoxification of:
- alcohol
- drugs and toxin metabolism
What are normal blood glucose levels?
Fasting = 74-106 mg/dL
2h postprandial = <120 mg/dL
Insulin production stops at 85 mg/dL
epinephrine and glucagon production increases at 68 mg/dL
growth hormone and cortisol production increases at 65 and 60 mg/dL respectively
adrenergic symptoms of hypoglycemia begin at 55 mg/dL (includes anxiety, palpatiations, tremors, sweating)
neuroglycopenia symptoms begin at 50mg/dL (includes: headaches, confusion, slurred speech, seizures, coma, death)
Glucose regulation in hepatocytes
1) gets uptakes by GLUT 2 receptors and immediately attached to a phosphate group and forms glucose-6-P
2) then either goes to HMP shunt, glycogenesis, or glycolysis
3) if needing glucose, goes reversed steps 2 -> 1 with glycogenolysis
Why is liver glycogenolysis a fast process?
There are multiple branches of glycogen that can be degraded simultaneously in the liver compared to other organs
Main ways of getting blood glucose with respect to time
4 hrs after immediately eating a meal = ingested glucose
4 -16 hrs = liver glycogenolysis
16 hrs - empty = gluconeogenesis
- does via liver and kidney
How does percentage of Gluconeogenesis change based on fasting?
Overnight fast:
- 90% in liver
- 10% in kidney
Prolonged fast:
- 60% in liver
- 40% in kidney
Glucokinase (GCK)
Is also called hexokinase 4 and is only found in hepatocytes and pancreatic B-cells
- is the prime enzyme for adding phosphate groups to glucose molecules
Is inhibited in the presence of glucose-6-P**
Has a low affinity (high Km) for glucose But fast action (high Vmax)
- this keeps glucose levels normal in the blood (since it doesnt activate except in the presence of high glucose levels) but if blood glucose gets too high, it excels at storing glucose fast (since it has a high Vmax)
insulin activates, glucagon inhibits
Maturity-onset diabetes of the young-2 (MODY2)
Very rare autosomal dominant form of diabetes that is caused by mutations in the glucokinase gene
Results in mild and stable fasting hyperglycemia and doesn’t require treatment
Glucokinase regulatory protein (GKRP)
Nuclear protein that’s reversibly binds to glucokinase and keeps it inactive within the nucleus of the cell.
Is inhibited by glucose levels (promotes glucokinase activity by releasing it)
- there is high glucose in the blood and we need to get it inside the liver
Is activated by fructose-6P (inhibits glucokinase by binding to it more)
- there is already a lot of glucose in glycolysis so we dont need more
Phosphofructokinase-1 (PFK-1)
Irreversible rate-limiting and committed step within liver glycolysis
- **most important control point for glycolysis
Converts fructose 6-P -> fructose (1,6)
Inhibited by = ATP and citrate
Activated by = fructose 2,6 biphosphate and insulin
Pyruvate kinase
Irreversible step in glycolysis
- converts PEP -> pyruvate
Inhibited by = ATP and glucagon
Activated by = fructose (1,6)
Steps of liver gluconeogenesis that occurs to get lactate -> PEP
1) carbon dioxide from bicarbonate is activated and transferred by pyruvate carboxylase to its biotin prosthetic group
2) CO2 is then transferred to pyruvate generating oxaloacetate (OAA)
3) OAA cannot cross the mitochondrial membrane and it is reduced to malate in the hepatocyte
4) malate is reoxidized to OAA, which is oxidatively decarbopxylated to phosphoenolpyruvate by PEP carboxylic are
Fructose 1,6 biphosphatase
Enzyme that dephosphorylates Fructose (1,6) bisphosphate into F-6-phosphate
- 2nd to last step in gluconeogenesis
Inhibited by AMP, F-2,6 bisP, glucagon
Activators by ATP
