Drug Treatment for Diabetes* Flashcards
what are drugs that treat diabetes known as?
Hypoglycaemic Agents
what is insulin?
what is it regulated by?
secreted by beta cells of the islets on Langerhans in pancreas
action –> lower blood glucose
Insulin section is regulated by:
- Glucose (most important)
- Glucagon
- GI hormones - due to eating – Incretins
- Products of digestion e.g. amino acids and fatty acids.
- Somatostatin hormone inhibits insulin secretion
- Parasympathetic/sympathetic nerve stimulation
what is the mechanism of secretion of insulin?
- Glucose enters Beta cells via transporter molecules
- Glucose metabolism increases intracellular ATP concentration => inhibits the activity of ATP sensitive K+ channels (KATP)
- KATP: a complex made up of a K+ channel & sulphonylurea receptor (SUR)
- This results in depolarisation of the cell as K+ efflux is reduced
- Depolarisation causes voltage gated Ca2+ channels to open
- Rise in intracellular Ca2+ causes insulin secretion via exocytosis
- (Diacylglycerol) DAG regulates insulin secretion by controlling the pathway that vesicles are secreted.
how is insulin released in the body?
t=0 => Glucose injection
Normal Person:
First rapid phase of insulin secretion (via exocytosis ),
Second phase (promoted by enzyme action) - slower in order to normalise blood sugar levels over a long term
Lack of both first and second phase in T1 DM
lack of first rapid phase of insulin secretion T2 DM
describe the structure of and Insulin receptor (in liver, muscle & fat) = RTK (tyrosine kinase)
Heterodimer:
- 2 alpha subunits forming the extracellular binding domains
- 2 beta subunits forming transmembrane tyrosine kinases
- Because 2 alpha subunits & 2 insulin molecules have to bind for a response
- Binding of insulin molecules causes phosphorylation of insulin receptor substrate proteins (IRS proteins) by tyrosine kinase
- This produces a cascade causing enzyme activation & gene transcription
- Increase expression of Glut-4 (glucose transporter) results in increased glucose uptake
Increased glycogen synthesis
define onset, peak and duration in the context of insulin
Onset – How quickly insulin lowers your blood sugar.
Peak Time – When insulin is at maximum strength.
Duration – How long insulin works to lower your blood sugar.
what is insulin therapy?
insulin is a peptide hormone so it administered parenterally (non-orally - subcutaneous pump, intramuscularly; intravenously)
Insulin has a short half-life: T1/2 = 5 mins
Medical insulin is produced from recombinant DNA being inserted into bacteria (although some = porcine – pigs pancreas)
what is the duration of action of insulin?
Duration of insulin action is determined by controlling the rate of insulin absorption into blood once injected into tissue
Short acting (pre-meal):
Onset: 30min; peak: 1-2 hrs
Short acting insulin is absorbed faster into the blood
Types: Soluble insulin or Insulin Lispro
Insulin lispro faster as it is less likely to aggregate (insulin molecules have tendency to bind together)
Long acting:
onset: 1-2 hrs; peak: 4-12 hrs
Type: Insulin complex or insulin glargine
Insulin Complex: when insulin is combined with protamine or zinc, => allows slower absorption of insulin into blood
Insulin Glargine = insulin molecules bind to each other forming micro-precipitates => allows for slower absorption into blood
what are the 3 different Insulin dose regimes?
- Short acting (x3 a day) - before each meal and then Intermediate/long acting (x1-2 a day).
This is known as the basal-bolus regime - You can also get pre-mixed short acting with intermediate/long acting insulins (x1-2 a day)
This reduces the number of injections required per day - Continuous Insulin infusion (Insulin pump therapy): This delivery method mimics nondiabetic insulin delivery - delivers a slow basal rate throughout the 24 h with patient-activated boosts at mealtimes. This could be very helpful for people with uncontrolled diabetes.
what are some Insulin Therapy Complications?
Hypoglycaemia (symptoms hard to detect in elderly)
Allergies to insulin
Lipodystrophy – wasting or synthesis of adipose tissue at the injection site. Therefore the site is regularly altered by diabetics to avoid this
what is type 2 diabetes mellitus?
- Linked to Obesity, hypertension, hyperlipidaemia (abnormally high levels of fats (lipids) in the blood)
- Usually initially developed in patients older than 25
- Less severe than T1 DM (Glucose levels don’t get as high as type 1)
- Loss of 1st phase of insulin secretion (rapid secretion)
- Higher basal insulin compared to non-diabetic (however still insufficient due to insensitivity)
- Insulin resistance of tissue is the main problem
- Insulin resistance is associated with inflammation in adipose tissue
what are the different Oral Hypoglycaemic Agents? (MATMIS)
Metformin
Sulphonylureas (SU)
Meglitinides
Thiazolidinediones (TZD)
Acarbose
Drugs based on Incretin Actions
what is metformin?
Used to manage T2 DM but can be given to T1 DM.
Mechanism - requires insulin to be taken alongside it
Work at the Liver/muscle
Decreased gluconeogenesis at the liver. This is done via the activation of AMP-activated protein kinase. This decreases gene expression for genes involved in gluconeogenesis
It also results in increased glucose uptake by the muscles
what are the side effects of metformin?
Side effects:
no hypoglycaemia
no increased appetite
cause lactic acidosis - occurs when lactic acid production exceeds lactic acid clearance (reversible once drug stopped)
It is used by obese diabetics in combination with other drugs
GMC recommends metformin as first line treatment following failure to control T2 DM via lifestyle changes
what are Sulphonylureas (SU)?
i.e. tolbutamide, glibenclamide, gliclazide
Used in Type 2 diabetics, ineffective in T1 DM
Mechanism:
Act on B cells => bind to SU receptor component of KATP => binding causes channel to close (similar to effect of increased ATP) 🡪 depolarisation => increased insulin secretion
Secondary effect => increased tissue sensitivity to insulin (effective for type 2 diabetics)
Duration of action (variations due to half-life)
Long i.e. glibenclamide => it is an active metabolite of the breakdown of the drug, so longer lasting (1x a day)
Short i.e. tolbutamide (3 x a day)
