T1 L14: Drug treatment for T2 diabetes Flashcards
What is the effects of insulin on hepatic cells?
Decrease gluconeogenesis, glycogenolysis and ketogenesis (increases glycogen synthesis)
What is the effect of insulin on muscle cells?
- Increases GLUT-4 translocation to the membrane and hence increases glucose uptake, glucose oxidation, glycogen synthesis, amino acid uptake and protein synthesis
- Decreases glycogenolysis and amino acid release
What effect does insulin have on adipocytes?
- Increases glucose uptake and triglyceride synthesis
- Decreases FFA and Glycerol release
What is the net effect of insulin?
To cause hypoglycaemia and increase fuel storage in muscle, fat and liver cells
Gliclazide, Glipizide, and Glimepiride are example of which drug type?
Sulfonylureas
They are all orally active and all bound to plasma proteins so they have a long half life
How do Sulfonylureas work?
They bind to the ATP site of K+ transporter proteins to close the channel to cause a build up of Ca2+ inside the cell which will make the cell positive.
This process makes the cells release more insulin because Ca2+ is needed to release insulin
What are some secondary mechanisms of action of Sulfaonylureas?
- Sensitize B-cells to glucose
- Decrease lipolysis
- Decrease clearance of insulin by the liver
Why are Sulfonlyureases only used for T2 diabetes mellitus not T1?
Because the drugs target beta-cells to release more insulin but T1 diabetics don’t have sufficient beta-cells for this to be effective
What are some drug interactions of Sulfonylureases?
They potentiate Allopurinol, Aspirin, and alcohol
What is the gold standard for treating T2 diabtes?
Metformin - a biguanide
How do Biguanides work?
They target insulin resistance by increasing glucose uptake in muscle and decrease glucose production by the liver
They don’t stimulate insulin release or cause hypoglycaemia
What is the mechanism of action of Metformin?
Mechanism of action in unknown but involves primarily supressing hepatic glucose production through gluconeogenesis by lowering the levels of PEPCK and glucoe-6-phosphatase
It increases insulin sensitivity, enhances peripheral glucose uptake, increases fatty-acid oxidation, and decreases glucose absorption from the GI tract
How is Metformin excreted?
Through urine
Why doesn’t it matter that Metformin isn’t bound to plasma proteins?
Because it has it’s effects are in the liver so the hepatic first pass pass effect doesn’t affected it in a negative way
What are some adverse effects of Metformin?
- Rarely produces lactic academia mostly in patients with renal impairment
- Nausea
- Abdominal discomfort
- Diarrhoea
- Metallic taste
- Vitamin B12 and folate absorption decreased with chronic use
What are some contraindications of Metformin?
- Hepatic disease
- Past history of lactic acidosis
- Chronic hypoxic lung disease because it causes metabolic acidosis
What do Glitazones do?
They mimic insulin
- Decrease gluconeogenesis, glucose output, and triglyceride production in the liver
- Increase glucose uptake
- Cause differentiation of adipocytes
How is the drug Pioglitazone metabolised and excreted?
Metabolised in the liver and excreted in faeces (2/3) and in urine (1/3)
What are some adverse effects of using Glitazones?
- Fluid retention causing oedema
- Dose related weight gain because they increase the number of adipocytes
Don’t cause lactic acidosis. Liver damage patients need to be monitored
How do Glucagon-like peptide 1 (GLP-1) hormones work?
- Increase insulin secretion
- Decrease glucagon secretion and hepatic glucose output
- Decrease food intake
- Decrease plasma glucose levels
Give 2 examples of Glucagon-like peptide-1 analogs
Exenatide and Semaglutide
How do Dipeptidyl peptidase-4 (DPP-4) inhibitors work?
They increase the levels of incretins GLP-1 and GIP
What does GLP-1 do?
Works to:
- Stimulate glucose-dependent insulin release
- Supress hepatic glucose output by inhibiting hepatic glucagon secretion
- Inhibits gastric emptying
- Enhances B-cell proliferation
Where is Glucagon-like peptide-1 (GLP-1) produced?
In L cells of the ilium and colon
What does Glucose-dependent immunotropic polypeptide (GIP) do?
- Stimulates glucose-dependent insulin release
- Stimulates glucagon secretion
Where is GIP produced?
In K cells of the proximal gut
Is the drug Vildagliptin reversible?
Yes
Is the drug Sitagliptin reversible?
Yes
Is the drug Saxagliptin reversible?
No
Where are SGLT1 found?
In the small intestine and proximal straight tubule of the nephron
Where are SGLT2 found?
In the proximal convoluted tubule of the nephron
Give examples of 2 SGLT2 inhibitors
Dapagliflozin and Canagliflozin
What effects do SGLT2 inhibitor drugs have all around the body?
- They increase insulin sensitivity in muscles (increase GLUT4 translocation and insulin signalling)
- Increase insulin sensitivity in the liver (by decreasing glucose-6-phosphate)
- Decrease gluconeogenesis
- They improve beta-cell function
How do SGLT2 inhibitors reverse glucotoxicity?
They inhibit SGLT2 transporters and therefore reverse hyperglycaemia and this reverses the build up of glucose within the body
What are some adverse side effects of SGLT2 inhibitor drugs?
- Rapid weight loss
- Tiredness
- Osmotic diuretic dehydration
- Can worsen urinary tract infections and thrush
