Lecture 25: Physiology of whole body metabolism Flashcards
Impotance of Glucose?
Brain consumes 80% of NIMGU (non-insulin mediated glucose uptake) and acutely can only use glucose
Blood cells and kidneys use the other 20%
Blood levels are controlled by insulin
through gluconeogenesis (new) and gylcogenolysis (from stores)
What are the Islets of langerhans?
Make up 1-2% of the pancrease by mass but have 20% of the blood flow.
Islands of tissue in the pancrease within the exocrine tissue. Neurovascular bundles enter each islet throgh beta cell core.
Paracrine interaction with venous effluent to portal vein and liver
Delta cells produce somatostatin involved with production of GH
Beta cells produce insulin
Alpha cells produce glucago “downstream from beta cells”
Two major glucose transporters?
GLUT transporters and also Na-Glu linked transporters
Location of these GLUT transporters? After absorption?
GLUT 1 - RBC and brain - NIMGU
GLUT2 - Pancreas and Liver
GLUT 3 - Neurons (placenta)
GLUT 4 - Fat and Muscles - insulin mediated and present in vesicles (also exercise induced)
After absorption it enters the beta cells by NIMGU and GLUT 2 and is changed by glycolysis to form ATP
Pathway into cells - errors with this?
- GLUT 2 transporter allows glucose to enter beta cell
- Glucokinase in an enzyme involved in GLUT2
Deficiency of glucokinase causes Type II diabetes as they are not breaking glucose down to ATP properly and so can’t/don’t signal insulin release as readily.
- ATP is produced that closes a K+ channel causing a +ve charge opening a Ca2+ channel allowing Ca2+ to flow in and cause Insulin release
Suphonylureas bind to calcium channel allowing insulin release in type 1 diabetes. Patients ‘born’ with type 1 diabetes actually have a receptor fault with the K+ channel not allowing closing.
Insulin production/formation?
Produced in a long chain that is made of preproinsulin that is broken down to pro-insulin that is then activated to insulin being released as A and B chain. The C peptide is broken off and can be measured (helps differentiate between T1 and 2)
If someone is injecting insulin they won’t have C chains so can be ‘caught’ if they shouldn’t be.
Insulin regulation?
Basal secretion is pulsatile 9-14 minutes
Major regulator is glucose with acute phase release and then slower second phase
Other regulators are AA, glucagon, incretins = all increase
somatostatin = decreases
Process following ingestion of sugar containing food?
Incretin gut hormones GLP-1 and some GIP is released from the GI tract. These act on the pancrease and:
- Reduce the glucagon levels decreasing hepatic glucose output
- Makes Insulin levels rise and drives glucose into muscle and fat via GLUT-4
All in a glucose dependent manner and will turn off when the BLS comes down to a normal level or 4-5.
Insulin actions on carbs?
Liver: Inhibits glycogenolysis and gluconeogenesis
Muscle : increae glucose transport and glycolysis -(for muscles to use)
Adipose tissue: increase glucose transport and glycolysis
Insulin actions on fats?
Increases triglyceride storage and inhibits lipolysis (decreases hormone sensitive lipase) and FFA production and therefore,
Inhibits ketone production
Insulin effects on protein?
Anabolic by increasing transport of AA into liver and muscle
Energy storage?
Fat accounts for around 20-30% of body weight but is 70-80% of stored energy
Lipolysis - FFA and (from oxidation by the liver)- Ketones
Glycerol goes diretly to the Krebs cycle
Protein (20% stored energy) is hydrolysed releasing AA
Carbs (1-2%) of energy store but is rapidly available - abut 1300calories = 5500kJ
Krebs cycle does what? where?
In all cells with mitochondria (so not RBC - these just steal ATP from elsewhere)
Liver:
- Glycogen stores - glycogenolysis - glucose as easy as that
- to make energy we gotta go to pyruvate and then Krebs cyce
Muscle
- Doesn’t have glucose-6-phosphatase so can’t produce glucose so just makes lactate that then goes to the liver and circulates in the krebs cycle - Chori cycle
- Alanine (AA) can go straight to krebs to produce glucose
Fat
- broken down to glycerol that is broken down to that goes straight into krebs cycle
- also to FFA that are oxidised in the liver to Ketones
Ketogenesis?
Oxidation of FFA to :
- Aceto acetate
- Acetone
- Beta hydroxybutyrate (MOST common measurable in blood, urine and breath)
Fuel for muscle and liver but NOT acutely for brain or RBC (but can if chronic)
Insulin shortage results in the hormone sensitve lipase being unchecked = uncontrolled gluconeogenesis and protein hydolysis. GLUT4 inactive
= Diabetic ketoacidosis (fatal if untreated)
Diabetic ketoacidosis summary?
If insulin is insufficient then no glucose being uptaken via GLUT 4 and so muscles begin to undergo massive amount of glycogenolysis producing lactate going to the liver.
Glucose can’t be taken up to fat so uncontrolled glycolysis
Glycerol goes from Krebs cycle as well as NEFAs to the liver and oxidised to ketones
Protein hydrolysis produces AA that go into krebs
uncontrolled ketone production and glucose production
- veru very sick, abdoniman pain, vomiting = 10% require ICU
Anion gap as well = diabetic ketoacidosis
