Lecture 8: Glucose, Glucagon, Insulin, Diabetes Pathogenesis Flashcards
1
Q
Describe the pathway of glucose from the GI tract to the tissues?
A
- GI tract -> circulation -> tissues
2
Q
True/False: Brain can only use glucose and not fatty acids
A
True
3
Q
Where is excess glucose normally stored and in what form?
A
- Excess glucose stored in liver and muscle
- Stored as glycogen
4
Q
What happens to glucose during meals & what is the normal circulating blood glucose concentration?
A
- Between means glucose absorption is minimal
- Circulation doesnt allow glucose to go below 5mmol for brain
- Degrades glycogen into glucose
5
Q
What type of glands is the pancreas made from and what are the functions of each?
A
- Exocrine and Endocrine glands
- Exocrine glands release digestive enzymes
- Endocrine glands contains small groups of cells called islets of langerhans
- 3 main cell types of IoL : a = glucagon, b = insulin, delta = somatostatin
6
Q
What is insulin secreted as and what is the process that makes it active?
A
- Secreted as a polypeptide in B cell
- Chain is processed in golgi into pro insulin = inactive
- Pro insulin activated by pro hormone convertase 1 and 2 which removes 33 amino acids = C chain
- Stored in secretory granules before needed
7
Q
What is the structure of insulin?
A
- 2 Polypeptide chains held by disulphide bridges
8
Q
What are the 2 phases of insulin secretion after a meal?
A
- Glucose is eaten and absorbed
- 1st Phase: High glucose: Release of insulin from secretory granules: rapid, acute response
- 2nd phase: Synthesis/secretion of new insulin: maintains blood sugar when levels are elevated
9
Q
What is used to measure insulin secretion?
A
- C Chain
- It is released w/ insulin and is more stable. Insulin half life = 6 min
10
Q
What is the process of insulin secretion in the B cell of pancreas ?
A
- B cells express GLUT 2 transporters on membrane , hormone insensitive (always active) & glucose enters
- B cells metabolise glucose & produce ATP which closes ATP sensitive K+ channels
- Causes depolarisation (as K+ stays in cell & positive membrane potential
- Activates Ca2+ channels increases membrane permeability: promotes release of secretory vesicles
11
Q
What can the liver do with glucose w/ out insulin?
A
- Glucose can enter through GLUT 2 transporters on liver
- Releases stored glucose
- Makes new glucose through gluconeogenesis
12
Q
What organ is exposed to glucose first?
A
- The liver from small intestine through hepatic portal vein
- Pancreas also detects the glucose
13
Q
What is the vein called that insulin from pancreas secretes into?
A
- The portal vein
- The portal vein carries blood from the pancreas, intestines, and stomach to the liver
14
Q
What is the process of insulin evoking responses in target cells
A
- Insulin binds to the receptor (has a alpha subunit and beta subunit) and promotes dimerisation, the 2 subunits phophorylate eachother at multiple tyrosine residues
- Active receptors phosphorylate IRS-1 which activates P13K
- P13K stimulates cellular responses to insulin
15
Q
Name the 6 key functions of insulin?
A
- Insulin promotes glucose uptake by liver and skeletal muscle
- Glycogen synthesis by activating glycogen synthase
- Mediates effects when glycogen reserves are full
- Fat release from adipocytes
- Insulin promotes synthesis of new proteins
16
Q
How does insulin promote glucose uptake by liver?
A
- Insulin binds to insulin receptor on liver
- Activates IRS-1, P13K then protein kinase B
- PKB induces translocation of GLUT 4 to plasma membrane thus allows glucose uptake into hepatocyte
17
Q
What are the 2 main sites for glucose storage?
A
- Muscle
- Liver
18
Q
What is glucose used for in cells?
A
- Metabolism/respiration
- Metabolied to give ATP for energy and H2O, CO2
19
Q
How does insulin promote deposits of fat in adipocytes?
A
- Insulin stimulates glucose entry via GLUT 4 transporters and glucose metabolised to glycerol in the cell. This binds with FFA = triglyceride
- Insulin inactivates lipase (this normally breaks down fats to glycerol and fatty acids)
- Glucose is metabolised to glycerol and excess fatty acids enter = fat and is stored
20
Q
What is stored in secretory granules of beta cells?
A
- Insulin along with some pro-insulin and c-peptidde (c-chain)
21
Q
How does insulin promote protein synthesis of new proteins?
A
- Incr amino acids promote insulin release
- Insulin receptors activate a 2nd P13K dependent kinase’- Insulin R -> P13K -> TORC1 (central regulator of protein synthesis) -.> Protein syntheis
- When AA = high, insulin stimulates incorporation into proteins
22
Q
How is insulin degraded after its function?
A
- Insulinase degrades insulin once done to avoid hypoglycaemia
- Found in liver, kidneys and muscles
23
Q
What enzyme degrades insulin and where?
A
- Degraded by insulinase mainly in the liver but also in the muscle and kidney
24
Q
What is the half-life of insulin?
A
- 6 mins so its effects on tissues are rapidly reversible
25
Where are GLUT4 transporters found in unstimulated cells of the liver?
- In the intracellular membrane vesicles and not the plasma membrane
26
What are the causes of glucagon release?
- Hypoglycaemia
- vigorous excercise
- increase in amino acids indirectly
27
What cell secretes glucagon and what is its structure?
- Pancreatic alpha cells
- Single chain of 29 amino acids also stored in secretory granule
28
How does insulin promote glycogen synthesis?
- Insulin activates PKb which inhibits GSK by phosphorylating it
- This prevents glycogen synthase A inhibition as the enzyme remains dephosphorylated
- Therefore is active and glycogen is synthesised
29
What happens when glycogen reserves in the liver are full and theres no more space to store glucose as glycogen?
- Glucose can still enter the liver via the GLUT4 transporters, however they are then metabolised into fatty acids which are released into circulation and stored as fat eventually
30
Why are people with type 1 diabetes likely to lose weight?
- In the absence of insulin, the body uses free fatty acids for energy
- However, with insulin body can uptake glucose therefore FFA arent used and are stored
31
How are fatty acids released from adipocyte cells/ tissues?
- Glucose doesnt enter the cell due to a lack of insulin
- This causes the hormone-sensitive lipase to breakdown the lipid into free fatty acid and 1 glycerol
- Fatty acids are then released to fuel metabolic processes
32
What are the main functions of glucagon?
- Glycogen -> glucose
- through G-protein coupled receptor cAMP/PKA pathway. It activates AC
- Opposes insulins effects on fat cells: Activates lipase due to low glucose permeability
33
What hormone can activate the glucagon pathway to promoting glucose release from liver, and what receptor is activated this way?
- Adrenaline via B adrenoceptors
34
What happens when insulin and glucagon are released due to high amino acid levels?
- Insulin secretion promotes increase in amino acid uptake by cells but also promotes a reduction in plasma glucose
- Glucagon secretion due to insulin lowering BG promotes an increase in plasma glucose but glucagon has no effect on amino acid uptake
35
Once glycogen stores are depleted what happens to meet the demand for glucose?
- Glucagon stimulates the formation of glucose from lipids and amino acids via a complex metabolic process in kidneys and liver
- Gluconeogenesis
36
How can urine help to see if a patient is diabetic?
- If sugar is present in urine, indicates diabetes
37
What is gestational diabetes and how does it occur?
- High blood glucose that develops during pregnancy and tends to disappear after birth
- When beta cells cant produce enough insulin to meet the extra needs of pregnancy
38
What trimester does gestational diabetes tend to occur in?
- 2nd or 3rd
39
What are the possible consequences of gestational diabetes?
- Baby growing larger
- Premature birth (before 37th)
- Pre-eclampsia: HTN which can lead to complications in preg
- Jaundice after birth
- Increased risk for type 2 in future
40
What are some symptoms of diabetes due to lack of insulin?
- Tissues cant accumulate and store glucose
- Cant use glucose as a metabolic fuel so use proteins and fatty acids resulting in weight loss
- Body cant store excess energy as fat therefore weight loss
- Reduced synthesis of protein
- Formation of ketones resulting in metabolic acidosis - acidotic coma
- Hyperglycaemia
41
What are some signs of hyperglycaemia?
- Weak, tired
- Frequent urination
- Thirst
- Reduced appetite
- Blurry vision
- Fruity breath: later stage
42
What are some signs of hypoglycaemia?
- Nervous
- Shakey
- Dizzy
- Confused
- Headache
43
How does hyperglycaemia affect the kidneys to cause dehydration?
- High glucose enters glomerular filtrate and overwhelms absorbing capacity of the proximal convoluted tubule
- Increased fluid osmolarity in the tubules
- More water is secreted from cells into PCT
- Increased urine flow - diuresis - reduced water absorption: dehydration, urine production
44
How does insulin injection cause lipohypertrophy?
- Insulin promotes the deposition of fat therefore cells close to site of injection are exposed to high insulin
- If used all the time - promotes fat deposition around injection site
45
What is the problem with lipohypertrophy?
- Leads to unpredictable rate of insulin absorption
- Poor glycaemic control and patients could experience hypo/hyper events
- Important to change site of injection frequently
46
What are the 3 forms of insulin used in therapy?
- Animal insulin
- Human insulin
- Human insulin analogue
47
What are the 3 types of human insulin?
- Soluble insulin - rapid and short lived
- Isophane insulin - immediate acting forms precipitates
- Insulin zinc suspension: Long acting, forms precipitates
48
What are the 2 types of insulin analogues?
- Insulin lispro
- Insulin glargine
49
How is insulin lispro obtained and how long does it last?
- Obtained by switching a lysine and proline residue
- Very rapid and very short lived, taken before meals
50
How is insulin glargine obtained and how long does it last?
- Obtained by mutating Asn21 in Gly and by adding 2Arg at the end of the B chain
- Long acting so normally taking before a meal in combo with short acting
51
What 4 factors of obesity cause insulin resistance?
- Free fatty acids
- Adipokines
- Inflammation
- PPARy
52
How are AGEs formed?
- Sugar + protein -> schiff base
- Schiff base --> Amadori products
- Amadori products --> AGEs
53
What are the biological effects of AGEs?
- CVD
- Diabetes
- Kidney disease
- Sarcopenia
- RA
- Alzheimers disease
54
How do AGEs cause blood vessel damage?
- AGEs crosslink with collagen inside BVs
- The basal membrane of the endothelium thickens
- The thickened endothelium traps LDL and IgGs
- Oxidation, complement activation and inflammation
- Blood vessel damage
55
What is AGEs receptor binding like?
- AGE binds to RAGE receptors -> generates reactive oxygen species and inflammation
- If binds to AGE-R1 = protective role by reducing AGE accumulation (promotes AGE degradation and reduces RAGE expression)
56
What are microvascular diseases?
- Retinopathy
- Nephropathy
- Neuropathy
- Formed from damage to small blood vessels
57
What are macrovascular diseases?
- Damage to medium to large blood vessels
- Coronary artery disease
- Cerebrovascular disease
- Peripheral vascular disease
