Insulin Flashcards
When do you used insulin treatment?
Insulin replacement in T1DM
- 30-50 units/day but this varies depending on weight, diet + activity. Long acting insulin (1 or 2 injections) + rapid or short acting insulin (injected with meals)
Control of blood glucose in T2DM when oral hypoglycaemic treatment is inadequate or poorly tolerated.
Diabetic emergencies (IV in diabetic ketoacidosis, hyperglycaemic hyperosmolar syndrome, perioperative glycaemic control) > IV fluids and K+ at a rate determine by blood glucose conc
Alongside glucose to treat hyperkalaemia while other measures are initiated.
How many phases of insulin release are there in response to constant glucose?
2
1st peak > rapid peak is release of ready-made insulin
2nd phase > slower release relies on synthesis of new insulin molecules.
Where is preproinsulin produced?
What happens to it then?
Rough endoplasmic reticulum
Processed in golgi system and its packed into vesicles.
Preproinsulin goes through proteolytic cleavage, chopped into proinsulin then insulin.
21+30 amino acid long chains/peptides linked together by disulfide bridges.
Describe the role of K-ATP channel in initiating insulin release
- an increase in [glucose] leads to increased metabolic flux
- increased metabolic flux increases [ATP]/[ADP]
- Increased [ATP]/[ADP] closes K-ATP channels
- Plasma membrane depolarises
- Voltage-dependent Ca2+ channels open
- Ca2+ influx leads to increased intracellular [Ca2+]
- Ca2+ triggers insulin secretion
What happens to insulin after its secretion?
Insulin will bind to insulin receptors in insulin sensitive tissues like muscle, liver, adipose tissues.
Higher density of receptors = higher sensitivity.
What family do insulin receptors belong to?
Insulin receptors belong to tyrosine kinase linked receptor family
Describe the structure of an insulin receptor
Insulin receptors have an extracellular ligand binding site for insulin.
Has 4 polypeptide chains linked by disulfide bridges.
Tyrosine kinase enzyme domain is inside cell. This enzyme can phosphorylate tyrosine residues on receptor + other proteins in cytosol.
how does insulin regulate metabolism? (3)
- Promotes synthesis and storage of carbohydrates, lipids and proteins while inhibits their degradation and release into circulation.
- stimulates uptake of glucose, amino acids and fatty acids into cells.
- increases the expression and activity of enzymes that catalyse glycogen synthesis while inhibiting the activity or expression of those that catalyse degradation.
Describe transduction in insulin action
- Insulin receptor is a tyrosine kinase that undergoes autophosphorylation and catalyses the phosphorylation of cellular proteins (IRS family, Shc, CbI).
- Upon tyrosine phosphorylation these proteins interact with signalling molecules through their SH2 domains resulting in the activation of diverse series of signalling pathways.
> immediate effect of stimulation of insulin receptors is that it will lead to insertion of glucose transporters into plasma membrane.
GLUT-4
What are the major sites of expression?
What is its characteristics?
- Skeletal and cardiac muscle
- the insulin-responsive glucose transporter. high affinity for glucose.
GLUt 4 is translocated from intracellular compartments into plasma membrane. Influx of glucose into cells.
GLUT-2
What are its major sites?
What is its characteristics?
- Liver, pancreatic, beta cells, small intestine, kidney
- Transports glucose, galactose and fructose.
A low affinity, high capacity glucose transporter; serves as a “glucose sensor” in pancreatic beta cells.
What are the metabolic effects of insulin in liver cells?
CARBOHYDRATE: > Decrease gluconeogenesis > Decrease glycogenolysis > Increase glycolysis > increase glycogenesis
FAT
> increase lipogenesis
> decrease lipolysis
PROTEIN
> decrease protein breakdown
What metabolic effect does insulin have in fat cells?
CARBOHYDRATE:
> glucose uptake
> glycerol synthesis
FAT
> incr triglyceride synthesis
> increase fatty acid synthesis
> decrease lipolysis
What metabolic effects does insulin have in muscle cells?
CARBOHYDRATE
> Incr glucose uptake
> incr glycolysis
> increase glycogenesis
PROTEIN
> increase amino acid uptake
> increase protein synthesis
What is glyconeogenesis?
glucose synthesis from non carbohydrate molecules (aa, lactate, glycerol)
What is glycolysis?
anaerobic conversion of glucose to lactate or pyruvate and energy (ATP)
What is glycogenesis?
glycogen synthesis from glucose
What is glycogenolysis?
Glycogen breakdown to glucose
What is lypogenesis?
Transformation of non-fat food materials into body fat
What is lipolysis?
lipid breakdown
What is the main action of insulin?
Main stimulus for secretion?
Main effect?
A) increase glucose uptake
increase glycogen synthesis (glycogenesis)
decrease glycogenolysis
decrease gluconeogenesis
b) moment-to-moment fluctuations in blood glucose
c) decrease blood glucose
What are the main actions of glucagon?
Main stimulus for secretion?
Main effect?
Increased glycogenolysis
Hypoglycaemia (blood glucose <3mM)
Increase blood glucose
What are the main actions of catecholamines?
Main stimulus for secretion?
Main effect?
a) increase glycogenolysis
decrease glucose uptake
b) hypoglycaemia (blood glucose <3 mM)
c) incr blood glucose
What are the main actions of glucocorticoids?
Main stimulus for secretion?
Main effect?
a) increase gluconeogenesis
glucose uptake and utilisation
b) hypoglycaemia (blood glucose <3 mM)
c) incr blood glucose
What are the main actions of Growth hormone?
Main stimulus for secretion?
Main effect?
a) Decrease glucose uptake
b) hypoglycaemia (blood glucose <3 mM)
c) incr blood glucose
What are the differences in treatment for IDDM (type I) and NIDDM (type II)?
IDDM (type I)
- insulin & diet
NIDDM (type 2)
- diet only
- diet & oral hypoglycaemic agents (biguanides e.g. metformin. sulphonylureas e.g. tolbutamide)
- diet & insulin (1/3 pts)
How do you monitor treatment of diabetes?
- Blood glucose measurement
- Glycated haemoglobin (HbA1c) > reliable representation of the mean blood glucose over the previous 6-12 weeks. healthy: 4-6%. Diabetes >7% HbA1c)
- Blood pressure
What are the types of insulin preparations? (usually sc, but iv or im in emergencies)
Short acting (peak action: 2-4 hrs)
Intermediate (peak action: 6-12 hrs)
Long acting (peak action: 14-24hrs)
(these can be used in combination to achieve good control of blood glucose levels)
What are insulin analogues?
insulin lispro (actos more rapidly but for a shorter time)
Insulin glargine (provides a constant basal level)
What are the unwanted effects of insulin?
- Hypoglycaemia
- Formation of anti-insulin antibodies causing insulin resistance
How does insulin decrease blood glucose?
1) increasing glucose uptake into muscle and fat via GLUT4
2) increasing glycogen synthesis
3) decreasing gluconeogenesis
4) decreasing glycogen breakdown
Glucagon is a fuel-mobilising hormone, stimulating: (4)
1) gluconeogenesis
2) glycogenolysis
3) lipolysis
4) proteolysis
