L18 Insulin and Type 1 Diabetes Flashcards
What is insulin?
What does it promote?
What does it inhibit?
- Insulin is a peptide hormone involved in blood glucose regulation
- It promotes glucose uptake from the bloodstream into adipose tissue and skeletal muscle
- It inhibits hepatic glucose production
What does insulin stimulate?
Cell growth and differentiation - increased synthesis of glycogen, proteins and triglycerides
Where and why is insulin synthesised?
Synthesised by pancreatic beta cells in response to elevated blood glucose concentrations
What is considered normal BGL?
3.6-5.8mM
At what BGL are beta islet cells most sensitive?
5.5-6.0mM
Does glucose enter beta islet cells actively or passively?
Passively
What is insulin called when it is first synthesised?
Preproinsulin
What is the composition of preproinsulin?
A single polypeptide containing signal peptide, A-chain, C peptide and B-chain
How is insulin synthesised?
- Initially as preproinsulin
- Signal
How is insulin synthesised? (4 steps)
- Initially as preproinsulin
- Signal peptide cleaved in the ER making proinsulin
- C peptide cleaved in Golgi complex
- A-chain and B-chain linked to form mature insulin
What type of bond links A- chain and B-chain in mature insulin?
Two disulphide bonds
How is insulin secreted? (5 complex steps)
- Glucose enters beta cell through GLUT2 and is phosphorylated to G-6-P
- G-6-P enters the citric acid cycle, increasing the production of ATP
- High intracellular ATP closes K+ channels, depolarising the cell membrane
- Voltage-gated Ca++ open and Ca++ enters the cell
- Ca++ increase causes exocytosis of insulin storage vesicles
What type of receptor is insulin receptor?
Type of tyrosine kinase receptor
What is activated when insulin binds to the insulin receptor? (2)
- Phosphorylation of insulin receptor substrate (IRS)
- Activation of PI3K signalling pathway and activation of GLUT4
Where are GLUT1 transporters found? (5)
- Brain
- Kidney
- Colon
- Placenta
- Erythrocyte
Where are GLUT2 transporters found? (4)
- Liver
- Pancreatic beta cells
- Small intestine
- Kidneys
Where are GLUT3 transporters found? (3)
- Brain
- Kidney
- Placenta
Where are GLUT4 transporters found? (3)
- Heart
- Skeletal muscle
- Adipose tissue
Where are GLUT5 transporters found? (1)
- Small intestine
What glucose transporter is insulin independent?
GLUT2
What glucose transporter is insulin dependant?
GLUT4
GLUT2 transporters have a ___ capacity for glucose but a ___ affinity
GLUT2 transporters have a high capacity for glucose but a low affinity
What does insulin and GLUT4 do in adipose tissue and how?
- Insulin stimulates glucose uptake and its storage as fat (TGs)
- Glycolysis to pyruvate to acetyl CoA
What does insulin and GLUT4 do in skeletal muscle tissue?
- Insulin stimulates glucose uptake and use, or storage as glycogen
How does insulin stimulate glycogen synthesis in skeletal muscle?
Activation of glycogen synthase
How dues insulin inhibit glycogen breakdown?
Inactivation of glycogen phosphorylase
What effects does insulin have on protein? (3)
- Stimulates amino acid uptake
- Increases net protein synthesis
- Inhibits protein catabolism
What effects does insulin have on fats? (1) What enzyme is affected in particular? (1)
- Insulin prevents inappropriate mobilisation of stored fat
- Insulin inhibits lipolysis by suppressing Hormone Sensitive Lipase (HSL)
What is Hormone Sensitive Lipase and what does it do?
HSL is an enzyme that catalyses hydrolysis of stored TGs therefore a key factor in lipid metabolism
What are ketone bodies? Where are they produced and when?
Metabolites derived from fatty acids, produced in the liver during energy restriction
What are three examples of ketone bodies?
- Acetoacetate
- B-hydroxybutyrate
- Acetone
When is it considered ‘normal’ for ketone bodies to be present
During prolonged fasting
What hormone promotes ketone bodies?
Glucagon
Explain ketogenesis (4)
- Stimulation of lipolysis - breakdown of TGs
- FFAs and glycerol enter the blood stream and are taken up by the liver
- Liver makes ketone bodies from acetyl CoA
- Once made they re-enter the bloodstream and used for energy production
What is ketogenesis?
A metabolic pathway that produces ketone bodies as an alternate energy source for the body
What pancreatic cells secrete glucagon?
Alpha cells
What effects does glucagon have on the body? (3)
- Increased breakdown of glycogen to glucose
- Increased breakdown of fats to fatty acids
- Increased synthesis and release of glucose
What are some characteristics of T1DM? (6)
- ~10% total diabetic cases
- Insulin dependant
- Common in children and adolescents
- Beta cells of pancreatic islets gradually destroyed causing an absolute insulin deficiency
- Autoimmune (genetic + environmental)
- Dependant on insulin administration
- Severe symptoms if untreated - DKA
What are some characteristics of T2DM? (7)
- ~85% diabetic cases
- Insulin resistant, non insulin dependant (NIDDM)
- Decreased insulin sensitivity and impaired insulin signalling
- Generally middle to old age and overweight
- Milder initial symptoms than T1DM
- Responsive to dietary changes, weight loss and hypoglycaemics
- Can develop into T1DM if left untreated over a long time
What causes T1DM? (4)
- Genetics
- Exposure to certain viruses
- Body’s own immune system attacking Beta pancreatic cells
- No insulin to let glucose into cells
What happens when there is no insulin? (3 steps)
- Body thinks it is starving due to no peripheral nutrient uptake
- Gluconeogenesis occurs
- System flooded with glucose and FFA
What tissues are most affected by insulin deficiency and why?
Adipose and muscle tissue as they have GLUT4 mediated glucose uptake which is insulin dependant
What are some symptoms of diabetes? (10)
- Polydipsia
- Polyphagia
- Lethargy
- Blurred vision
- Acetone breath
- Weight loss
- GI upset
- Kussmaul breathing
- Polyuria
- Glycosuria
What affects does hyperglycaemia have on the kidneys? (2)
- Glucose in filtrate causes osmotic diuresis = polyuria
- Increased urine output = dehydration
How much glucose is normally reabsorbed in the proximal convoluted tubules of the kidneys?
100%
What is ‘Hyperglycaemic Hyperosmolar State’?
What is it caused by in diabetics?
Very high blood glucose levels - blood becomes hyperosmolar with a high viscosity
Caused due to kidneys overwhelmed by excessive glucose
What does insulin deficiency do in muscle? (2)
- Increases protein degradation
- Release of amino acids to be used for gluconeogenesis and ketogenesis
