Flashcards in Lecture 5 - Glucose Control in Health and Disease Deck (55):
What is the normal blood glucose concentration?
Around 4.5 mM
aka 60-90 mg/100mL
Describe what happens to the body at the various concentrations of blood glucose
4.5 - 5.6 mM: normal range
• Glucagon release
• Adrenaline release
• Corticol release
• Sweating, trembling
Very very low:
• Permanent brain damage
Resting blood glucose:
• 4.5-5.6: normal
• 5.6-7: intermediate
• > 7: elevated
Describe the source of blood glucose
• Glucose taken up from the digested food in the intestine into the blood
Describe the absorption of the various nutrients found in food
Glucose: into blood
Amino acids: into blood
• Packaged into Chylomicrons
• Lacteals → Lymphatics → Blood
Describe the mechanism resulting in insulin secretion
1. Blood glucose conc. rises
2. ↑ ATP production through metabolism of glucose in β islets cells
3. ATP inhibits ATP-gated K+ channel; K+ sequestered in the cell
4. Plasma membrane is depolarised (build up of +ve charge inside the cell)
5. A voltage gated Ca2+ channel opens (in response to +ve charge in cell)
6. Ca2+ enters β islet cell, as well as being released from intracellular stores in the ER
7. ↑ intracellular Ca2+ triggers insulin release by exocytosis of insulin granules from the secretory pathway
What are the outcomes of insulin secretion?
• Uptake of glucose from the blood (through GLUT deposition in membranes)
• Storage of fuels (glycogenesis)
• ↑ glucose metabolism
• ↑ synthesis of TAGs
( • Synthesis of proteins
• -ve regulation of gluconeogenesis in liver
• -ve regulation of glycogenolysis)
Describe the structure of insulin
Preproinsulin → Proinsulin → Mature insulin
• Two chains:
• A and B chain
• A, B and C chain
• 2x Disulphide bonds between A and B chains
• Disulphide bond one A chain
• A, B and C chain + Signal sequence
• No disulphide bonds
Describe the features of GLUT molecules
• Transmembrane proteins
• 12 alpha helical ™ domains
• N and C termini are intracellular
• Different isoforms in different tissues
• Chain loops outside the cell
• Domains arranged such that they create a polar pore (through which glucose can move)
( • 14 different isoforms)
Which GLUT is found in myocytes?
Describe how glucose gains access to cells
1. Glucose binds GLUT externally
2. GLUT undergoes a conformational change
3. GLUT opens on the intracellular side
4. Glc moves into the cell
Which tissue takes up most of the blood glucose in response to insulin?
Muscle tissue (around 90%)
Why is transport of glucose into the cell so important?
It is the rate limiting step of the use of glucose by the cell
Failure of GLUT4 transport to the plasma membrane is an early features of insulin resistance
Describe the regulation of GLUT4 in myocytes
1. GLUT "stored" within cells in membrane vesicles
2. Insulin signalling → vesicles to move to surface, fuse with plasma membrane, depositing the GLUT in the membrane
3. Drop in insulin levels → GLUT4 removed from the plasma membrane by endocytosis to form small vesicles
4. Smaller vesicles fuse with larger endosome
5. Patches of the endosome enriched with GLUT4 bud off to become small vesicles (ready to again return to the surface)
Describe the mechanism of release and action of glucagon
1. Decreased blood glucose conc.
2. Detected by hypothalamus: activation of K+/ATP channels
3. Autonomic nerve signalling to α cells of islets
4. Release of glucagon from α islet cellsLiver is main target tissue, as well as adipose tissue
5. Glucagon binds to cell surface receptors in liver & adipose tissue, activation of cell signalling pathways
Describe the structure of glucagon
A peptide (like insulin)
Where are glucagon and insulin produced?
Glucagon: α cells
Insulin: β cells
of the Islets of Langerhans in the pancreas
List the outcomes of glucagon signalling
↑ Mobilisation of fatty acids
Regulation of which enzyme alters glycogenesis?
Regulation of which enzyme alters glycolysis?
Regulation of which enzyme alters gluconeogenesis?
Regulation of which enzyme alters glycogenolysis?
Regulation of which enzyme alters fatty acid mobilisation?
On which tissues can glucagon act?
• Adipose tissue
Receptors also found in:
• Intestinal smooth muscle
Describe the main features of IDDM:
Type I Diabetes
Absolute lack of insulin due to autoimmune destruction of β cells
• Specific CTL killing of β cells
• Th1 involvement: cytokines & chemokines that destroy cells
(IFN-γ, IL-3, GM-CSF, TNF-β)
Certain HLA molecules:
• HLA DR3-DQ2
• HLA DR4-DQ8
• Self-monitoring of blood glucose
• Insulin therapy (injection)
Symptoms: (if uncontrolled)
• Frequent urination
• Extreme thirst
• Sudden weight loss
• Lack of energy
• Blurred vision
Compare β cell mass in:
• Healthy people
Healthy people: 100%
i.e. Loss of β cells is greater in T1DM
What is responsible for the loss of β cells in DM?
Pro-inflammatory cytokines (IL-1, *)
Especially in IDDM
Describe the basis of T2DM (NIDDM)
How does the disease progress?
What are the symptoms of T2DM?
• Varying levels of insulin production and release from the pancreas
• Varying levels of insulin resistance in the target tissues (liver, adipose, muscle)
Progressive destruction of β islet cells → increasing glucose intolerance and requirement for insulin therapy
Symptoms are very similar to T1DM
Describe metabolism in T1DM of:
• Adipose tissue
-- Glucose --
1. Failure of glucose uptake
• Glycogenesis inhibited
• Glycogen stores become depleted
-- Protein --
1. Inhibition of uptake of amino acids and protein
2. Loss of normal inhibition of protein degradation
3. Degradation of muscle
4. ↑ transport of nitrogen to the liver (as Alanine)
5. Gluconeogenesis in liver
6. Worsening of hyperglycaemia
-- Adipose tissue --
1. Failure of glucose uptake by GLUTs
2. ↑ lipolysis of TAGs
3. ↑ levels of circulating FFAs
4. Transfer of FFAs to liver for use as fuel (instead of glucose)
What are TAGs?
Describe liver glucose metabolism in T1DM
1. ↑ Glycogenolysis
• Loss of activation of glycogen synthase by insulin
• Loss of inhibition of glycogen phosphorylase
2. ↑ Blood glucose conc. due to
3. ↑ FA oxidation → ketone body formation
4. ↑ ketone bodies + ↑ blood glucose → diabetic ketoacidosis
What leads to the development of 'Diabetic Ketoacidosis'?
↑ Ketone bodies
• Due to ↑ FA oxidation in liver
↑ Blood glucose
• Due to failure of glucose uptake, and ↑ glycogenolysis in liver
Why is there muscle breakdown in T1DM?
AAs not taken up by muscle
Loss of inhibition of protein degradation in muscle cells
Why is dehydration seen in DM?
1. Raised blood glucose conc.
2. Blood glucose levels exceed the ability of the kidneys to retain glucose
3. Glucose appears in urine, taking water with it
Describe the effect of insulin resistance in the various tissues that are effected
What is the hypothesised basis of insulin resistance?
Occurs in T2DM (in conjunction w/ death and/or dysfunction of β islet cells
• Adipose tissue
• Skeletal muscle
Insulin effects are 'subnormal'
• Less glucose disposal into muscle
• Less suppression of endogenous glucose production in liver
• Though to be disruption of insulin receptor signalling pathways
Outline the three phases in the development of T2DM
Describe blood glucose conc. and insulin conc. in the three phases
• Tissues develop insulin resistance
• Pancreatic insulin increases to compensate: Hyperinsulinaemia
• Normal BG conc.
• High insulin levels
• Hyperglycaemia occurs despite elevated insulin
• Glucose tolerance is impaired
• Insulin secretion declines, probably due to death of β islet cells
• High fasting blood glucose conc. (=diabetes)
What is hyperinsulinaemia, and why / when does it occur?
↑ insulin in the blood
This occurs early in T2DM, when the β islet cells of the pancreas secrete increased amounts of insulin to compensate for the developing insulin resistance in the tissues
What is the definition of impaired glucose tolerance?
Glucose levels of 7.8 to 11.0 mM 2hrs after a 75g oral glucose tolerance test
Describe the lipotoxicity model of insulin resistance
1. When caloric intake is excessive, adipocytes store increasing amounts of TAG until they can store no more
2. Enlarged, pro-inflammatory adipocytes secrete MCP-1
3. Macrophages infiltrate adipose tissue in response to MCP-1
4. Macrophages in adipose tissue produce TNF-α
5. TNF-α favours the export of fatty acids
6. Adipocytes export FAs to muscle, where ectopic lipid deposits form
7. Ectopic lipid interferes with GLUT4 movement to the myocyte surface
8. Insulin resistance
What is MCP-1?
Monocyte chemotaxis protein 1
Secreted by enlarged adipocytes (i.e. in overweight individuals)
Describe the structure of IR
IR: Insulin receptor
Receptor tyrosine kinase (RTK)
Two membrane bound subunits (dimerise when insulin binds)
Each subunit furthermore formed from two subunits:
• α: insulin binding, extracellular
• β: transmembrane
• Joined by disulphide bonds
Tyrosine residues on the intracellular tail of β subunits
Describe signalling through the IR
1. 2x Insulin molecules bind α subunits
2. Dimerisation of β subunits
3. Trans-autophosphorylation of tyrosine residues on intracellular tails of β subunits
4. Recruitment of intracellular signalling proteins
5. pYs of IR interact with conserved domains of recruited signalling proteins (e.g. IRS1)
6. Initiation of signalling events
Describe the activity of protein tyrosine kinases
A family of enzymes that transfer the γ-phosphate of ATP to specific Tyr residues of the protein substrate
Phosphorylation is an example of ...
What is IRS1?
Insulin receptor substrate 1
i.e. one of the intracellular signalling proteins recruited by IR after trans-autophosphorylation
Contains SH3 domain that interacts with pYs on intracellular tails of beta subunits of IR
Describe the down-stream signalling events of the IR
1. IRS1 interacts w/ pY
2a. Grb2 interacts with IRS1
4a. MAPK pathway
5a. Changes in gene expression
6a. Translation elongation
2b. p85 of PI3K interacts w/ IRS1
3b. PI3K signalling pathway
4b. Cell survival
5b. Translation initiation
6a. Translation elongation
Why is blood glucose levels so critical and tightly regulated?
Because the brain requires a constant supply of glucose
What is the term for high blood glucose concentration?
What type of hormones are glucagon and insulin?
What is the purpose of the signal sequence?
Targets preproinsulin to the granules in the beta islet cells
Describe disulphide bonds
Two cysteine residues covalently bonded
Which is the GLUT on pancreatic beta cells?
Where are TAGs stored?
Describe where TAGs come from
-- Glycolysis --
2. Acetyl CoA
Compare alpha and beta cells detecting glucose levels to release their respective hormones
• Directly detect high blood glucose to release insulin
• Low blood glucose conc. detected first by hypothalamus
• Autonomic nerve signalling then stimulates the alpha cells to release glucagon