L 26 Pharmacology of T2DM Flashcards
What is T2DM?
Dysregulated glucose associated with impaired insulin secretion and action
This is a metabolic disorder
How is blood glucose normally regulated?
Pancreatic B cells precisely adjust the amount of insulin secreted to promote glucose uptake AFTER meals.
Pancreatic ‘Beta cells’ produce glucagon to increase glucose output from cells when fasting.
How Insulin is released under FASTING conditions?
In a pulsatile manner every 10-14 minutes However,(insulin is almost consistently released in healthy individuals)
Where does insulin act? and what does this do?
On a plasma membrane receptor. It activates a cascade of signalling events
What is the half life of insulin?
It is a hormone.it reaches in peak within 3-5 mins and remember it has very short half life like 10 minutes.
Where does insulin work?
It activates a cascade on a plasma membrane receptor through signalling events.
What does insulin do?
Insulin has various effects on our body like uptake use and storage of glucose lipids and amino acids.
It stimulates Glycogenesis, lipogenesis, and protein synthesis.
Inhibits glycogenolysis, lipolysis and proteolysis.
They promote translocation of proteins between cellular compartments, regulates action of specific enzymes and controls gene transcription and mRNA translation.
So what usually happens when a patient has Type 2DM?
Insufficient insulin can not maintain plasma glucose concentration within normal range thus dramatically increasing sugar level in blood.
The sensitivity of Beta cell to glucose is impaired.
What occurs to glucose during (untreated) T2DM?
Blood glucose rises dramatically after meals.
Failure to restrain liver glucose release during fasting.
Higher rate of lipolysis and release of fatty acids into circulation thus increase dyslipidaemia.
What is insulin resistance?
Reduced production of insulin and the amount of glucose produced which been cleared all amount of insulin ti muscle and fat or in blood stream.
Effects of insulin resistance
- Reduced amount of glucose taken up by cells
- No restraint(under control) on glucose production
- Higher rates of lipolysis into circulation
Drug treatment options for T2DM
- Insulin secretagogues (sulphonylureas, meglitinides, incretin/GLP-1 agonists, DPP4 inhibitors)
- Exogenous insulin
- Alpha glucosidase inhibitors
- Biguanides
- PPARy activators/glitazones
- SGLT2 inhibitors i.e. gliflozins
Therapeutic effects of exogenous insulin. Is it a first line treatment for T1 and T2?
First line for T1, usually last line for T2.
Gives an identical effect to endogenous insulin.
Given by SC injection
How many different types of exogenous insulin are in the market?
Very rapid acting
Short acting
Mixed(intermediate)
Long acting
Side effects of exogenous insulin treatment
Hypoglycaemia
Sometimes weight gain. Why? Because insulin stops (lipolysis) lipid breakdown.
Insulin secretagogues
sulphonylureas, meglitinides, GLP-1 agonists, and DPP-4 inhibitors
Therapeutic effects of sulfonylureas and meglitinides
Binding to B-cell K-ATP channel causes insulin release.
Examples of sulphonylureas (x3)
glipizide, gliclazide and glibenclamide
Example (x1) of meglitinide
Repaglinide
Side effects of sulphonylureas or meglitinides
Hypoglycaemia, Nausea, Vomiting, jaundice, initial weight gain with sulfonylureas
What is the Therapeutic effects of incretins/GLP-1 agonists?
Incretins (e.g GLP-1) are hormones naturally released after meals to stimulate/activate insulin secretion.
And GLP-1 receptor agonists activate GLP-1 receptors by B cells to produce insulin.
What is the Example of GLP-1 agonists?
Dulaglutide (injected)
What are the Side effects of GLP-1 agonists
GI disturbances, Nausea, Diarrhoea, decreased appetite (despite being injected)
What is the Therapeutic effects of DPP-4 inhibitors
DPP-4 inhibitors are enzymes. It is a serine protease, this is widely distributed throughout the body. It inactivates GLP-1.
Inhibiting DPP-4 causes Increased GLP-1 resulting in increased insulin synthesis and secretion.
Ex: Vildagliptin
What is an Example of DPP-4 inhibitor?
Vildagliptin
Side effects of DPP-4 inhibitors
Headache, dizziness, GI disturbances (esp when given w/ metformin)
Therapeutic effects of alpha glucosidase inhibitors
Reduce intestinal absorption of glucose but inhibiting x-glucosidase in the intestinal brush border. Ex: Acarbose
What are Examples of an alpha glucosidase inhibitor?
Acarbose
Side effects of alpha glucosidase inhibitors
Malabsorption, flatulence, diarrhoea, abdominal bloating.
What are the Therapeutic effects of biguanides?
Metformin reduces hepatic gluconeogenesis, activates AMP kinase by stimulating glucose uptake, fatty acid oxidation, reduction of lipogenesis and by reduction of the effects of glucagon.Ex: Metformin
What is an Example of biguanide?
Metformin
What are the main Side effects of biguanides?
GI effects (N,D, cramps, dyspepsia) Lactic acid build up
Therapeutic effects of PPARy activators. Other name for PPARy activators.
PPARy is a nuclear hormone receptor. It Promotes glucose uptake into muscle and adipose tissue, decreasing insulin resistance.
Also called thiazolidinediones.
Ex:Pioglitazone
What are Examples of PPARy activators?
Pioglitazone
What are the Side effects of PPARy’s?
Weight gain and edema. Potential Heart Failure may occur because of edema with long-term use.
What are the Therapeutic effects of SGLT2 inhibitors?
SGLT2 is a Na+/glucose transporter in the proximal portion of the renal tubule. Glucose moves against conc gradient from tubular tubular lumen through epithelial cells. Inhibition blocks glucose transport, therefore lowering blood glucose Ex: Empagliflozin
What is an example of SGLT2 inhibitor?
Ex: Empagliflozin
Side effects of SGLT2 inhibitors
Lower Urinary tract infection
Increase in genital infections
Mild diuresis/mild hypotension(reduces blood pressure) (vvi to remember)
When are SGLT2 inhibitors contraindicated?
In kidney disease
What are Examples of SGLT2 inhibitors?
Empagliflozin, dapagliflozin
Patients with reduced renal function should avoid
Sulphonylureas, meglitinides
Patients who are obese may not be offered
Sulphonylureas
Heart failure may be exacerbated by…
Glitazones/PPARy activators
