Diabetes Flashcards
Roles of insulin
Increased glucose uptake
Increased glycogen synthesis
Reduced gluconeogenesis
Reduced glycogenolysis
Counter regulatory hormones and actions
Glucagon - increased glycogenolysis and gluconeogenesis
Adrenaline - increased glycogenolysis
Glucocorticoids - reduced glucose uptake and increased gluconeogenesis
Growth hormone - reduced glucose uptake
Synthesis of insulin
Preproinsulin synthesised in RER
Transported to Golgi aperatus and undergoes proteolytic cleavage to proinsulin
Proteolytic cleavage to insulin and C peptide
Both are stored in granules in B cells
Excreted by exocytosis
How is insulin release triggered in B cells?
Glucose bathes B cell and is transported via GLUT2 (facilitated diffusion)
Intracellular glucose rises and is metabolised to ATP
Blocks ATP sensitive K+ channel and intracellular K+ rises
Depolarisation opens VOCC and Ca2+ triggers insulin release
Describe the insulin receptor and effect caused
It is a tyrosine kinase linked receptor and the phosphorylation cascade increases GLUT4 expression. Insulin and its receptor are destroyed.
Describe the non pharmacological management of type 2 diabetes
Reduce BP, weight and cholesterol: Dietary management - limit fats, salts and sugar Exercise Smoking cessation Alcohol cessation Foot care - clean feet, fitting shoes Eye test
Insulin profile
Indications - type 1 diabetes, type 2 diabetes not controlled by diet/hypoglycaemics, hyperglycaemic emergencies, emergency hyperkalaemia
Mechanism - analogue of endogenous insulin
Pharmacokinetics - administered SC (IV emergency). Half life varies, can be short acting (lispro), intermediate (isophane) or long acting (glargine)
Pharmacodynamics - reduces plasma glucose
ADRs - hypoglycaemia leading to brain damage (treat with sugary snack/drink or IV glucose
DDIs - none
Monitoring - patients should self monitor using finger prick tests
Describe the typical regimes for insulin management in type 1 diabetes
Short acting insulin before meals and intermediate/long lasting twice daily
Pre mixed insulin with short and intermediate/long acting component
What are the main classes of oral hypoglycaemics? Give examples
Biguanides - Metformin
Sulfonureas - Tolbutamide, Gliclazide
Meglitinides - Repaglinidine, Nateglinide
Thiazolidinediones - Pioglitazone, Rostiglitazone
A-glucosidase inhibitors - Acrabose
Glipyins - Stiagliptin
GLP-1 analogues - Exenatide
Biguanides - Metformin profile
Indications - type 2 diabetes not controlled by lifestyle
Contraindications - renal impairment (lactic acidosis)
Mechanism - unknown but reduces gluconeogenesis (liver) and increases sensitivity to insulin so there is increased glucose uptake into skeletal muscle and adipocytes
Pharmacokinetics - oral before meals, half life of 3 hours
ADRs - DOES NOT CAUSE HYPOGLYCAEMIA, lactic acidosis, nausea, diarrhoea
DDIs - excretion reduced by Cimetidine
Sulfonureas - Gliclazide, Tolbutamide profile
Indications - added to regimen if type 2 diabetes is not controlled with Metformin, instead of insulin following MI
Contraindications - pregnancy, renal impairment (hypoglycaemia)
Mechanism - bind to and block K+ATP channels on B cells thus causing depolarisation, Ca2+ entry and more insulin released
Pharmacokinetics - oral once daily, varied half lives
Pharmacodynamics - insulin release stimulant
ADRs - HYPOGLYCAEMIA, stimulates appetite
DDIs - NSAIDs, alcohol, MOAIs, warfarin compete for binding so can lead to hypoglycaemia. Thiazides diuretics and glucocorticoids can decrease action
What are Meglitidines?
These have the same mechanism as sulfonureas but are selective to B cell K+ channels (avoiding action on CVS) and there is less weight gain.
Glitazones (Thiazolidinediones) - Pioglitazone, Rostiglitazone
Indications - additional treatment for type 2 diabetes
Contraindications - heart failure, pregnancy, previous bladder cancer
Mechanism - PPARy complexes with RXR and binds to DNA to promote transcription of genes for insulin signalling e.g. Lipogenesis, fatty acid uptake. Glitazones are an agonist for PPARy
Pharmacokinetics - oral once daily, half life 7 hours (24 for metabolites), metabolised by CYP34A and 2C
Pharmacodynamics - enhances the effect of endogenous insulin
ADRs - DO NOT CAUSE HYPOGLYCAEMIA, weight gain, fluid retention (worsens heart failure), increased risk of fractures, increased risk of bladder cancer
DDIs - may increase risk of heart disease if used with insulin
GLP-1 analogue profile
Indications - additional treatment for type 2 diabetes
Contraindications - ketoacidosis, pregnancy
Mechanism - glucagon like peptide 1 is released from the gut to stimulate insulin release before absorbed glucose reaches islet cells.
Pharmacokinetics - SC twice daily or modified release formula
Pharmacodynamics - increases insulin release and reduces glucagon release
ADRs - hypoglycaemia, nausea, pancreatitis
Glipyins profile
Indications - additional treatment for type 2 diabetes
Contraindications - ketoacidosis, pregnancy
Mechanism - inhibits DDP4 which breaks down GLP-1 this stimulates insulin secretion
ADRs - does not cause weight gain, nausea, oedema
Describe the pharmaceutical treatment for type 2 diabetes
Start on Metformin
If HbA1c remains raised add Sulphonurea
If HbA1c remains raised consider insulin, Glitazone, Meglitidine, GLP-1 analogue
Describe the insulin regimes used to manage type 2 diabetes
Long acting insulin once daily before bed
Biphasic - pre mixed twice daily
Retain Metformin
How would you monitor blood glucose?
Finger prick if type 1 or on insulin type 2
HbA1c
Renal, hepatic, cardiovascular, neurological function to monitor microvascular disease
Describe a trial concerning HbA1cb and monotherapy
1998 UKPDSG-UK carried out a prospective study showing initial reduction in HbA1c was 1% in the first year of monotherapy but after the initial drop it increased requiring multiple drugs.
Name 2 anti-obesity drugs
Orlistat
Sibutramine
What is Orlistat? How does it work? What are the ADRs?
Anti-obesity drug
Pancreatic lipase inhibitor preventing the breakdown of fat to fatty acid and glycerol so reduces absorption
ADRs - soft fatty stools, flatus, faecal discharge
What is Sibutramine? How does it work? What are the ADRs?
Anti-obesity drug
Noradrenaline and serotonin reuptake inhibitor that suppresses appetite
ADRs - increased HR and BP
Why might you not want to give an obese patient a Sulphonurea or a Glitazone? What drug would you consider instead?
ADR of weight gain
Consider Gliptin (DDP4 inhibitor)
