Lecture 10 - Diabetes Flashcards
What stimulates the release of insulin in the body?
Inc plasma glucose
Incretins like GLP1 and GIP
Parasympathetic activity (M3) receptors
What is the half life of insulin?
Short like 5mins
What inhibits the secretion of insulin in the body?
Dec plasma glucose
Cortisol
Sympathetic activity (a2 receptors)
What is the role of insulin in the body?
Reduces heptaic output of glucose by:
-inhibiting Gluconeogenesis
-inhibiting Glycogenolysis
Promotes uptake of of glucose into tissues (muscle and adipose by. Upregulating GLUT4)
Why is insulin secreted into the blood even during fasting?
Prevents receptor down regulation
What is the normally pattern of insulin release?
Biphasic pattern
What is meant by the biphasic pattern of insulin release?
Soon after eating, plasma insulin levels rapidly rise, then fall, the have a small rise again before falling
What are the 3 key clinical signs for diagnosing Type 1 diabetes Mellitus (T1DM)?
Polyuria (often wake up for the toilet iin night)
Polydipsia (thirst)
Weight loss
What are some symtpoms of Type 1 diabetes Mellitus?
Fatigue/lethary
Generalised weakness
Blurred vision
What are some classic investigation results for someone with Type 1 diabetes Mellitus?
Hyperglycaemia
Plasma or urine ketones
Elevated HbA1C
What is the difference between what plasma glucose levels and HbA1c are measuring?
Glucose = immediate measure of glucose in blood
HbA1c = perecentage of glycated haemoglobin which reflects the average blood sugar over the last 10-12 weeks
What is the biochemical triad for diabetic ketoacidosis?
(DKA)
Hyperglycaemia
Ketonaemia
Acidosis
What is the metabolic pathway for developing diabetic ketoacidosis?
Insulin normally regulates lipid metabolism by down regulating it
If insulin is absent (T1DM) then uncontrolled lipid metabolism occurs since glucose cant be moved into cells for metabolism
This leads to the lipolysis of lipids leading to production of many fatty acids protruding ketone bodies which are Acidic
What are some reasons you may suspect DKA?
Blood glucose> 11mmol/L AND:
-polyuria
-Polydipsia
-abdominal pain
-vomitting and diarrhoea
-fruity acetonic breath
-visual disturbances
What do you test for in DKA?
Ketones in urine
Blood in urine
Venous blood pH <7.3
HCO3-< 15mmol/L
What are the precipating factors for DKA?
Infection
Trauma
Non adherence to insulin treatment
Drug-drug interactions
How is DKA treated?
IV fluids
Then IV soluble insulin
The fluids correcting K+
How is human insulin made/
Recombinant DNA from bacteria or yeast
Or
Enzymatic modification of porcine
What method must insulin be administered in and why?
Paraentrally
Since insulin is a protein so needs to not be digested in the gut
What is the normally formulation for insulin?
100units/mL
With insulin resistnace and obesity can give
300 or 500units/mL
What is pharmacokinetics?
What is pharmacodynamics?
Pharmacokinetics = the ability for the drug to be absorbed and distributed in the body
Pharmacodynamics = the way that the drug works
What is the normal way that insulin is delivered?
Subcutaneous injection (can be by pump)
Like upper arms, thighs, buttocks and abdomen
When is insulin delivered via IV?
Emergencies like DKA
What are some ways that we can slow absorption of an insulin preparation?
Soluble insulin forms hexameter delaying absorption from site of injection
Insulin analogues (alter a couple amino acids to change the pharmacokinetics)
What does the site of administration of insulin injection need to be rotated?
Reduce risk of lipodystrophy
What is an example of rapid acting insulin?
Insulin aspart
What is an example of short acting insulin?
Regular soluble insulin
What is an example of an intermediate length insulin?
NPH
What is an example of a long lasting insulin?
Insulin glargine
What are the different types of insulin and their length of action?
Insulin Aspart = rapid
Soluble insulin = short
NPH = intermediate
Insulin glargine = long
What is basal-bolus dosing?
Where several different insulins are given at different times in the day
Why is insulin considered a TIME CRITICAL MEDICATION?
If people don’t have it at the time they need it it can be detrimental
Insulin:
1.) What are the adverse effects?
2.) contraindications?
3.) drug-drug interactions?
1.) Lipodystrophy (lipohpertropgy and lipoatrophy)
Hypoglycaemia
2.) renal impairment (hypoglycaemic risk)
3.) dose needs increasing with systemic steroid
Other hypoglycaemic agents
Go to page 14 what signs are are being seen?
Lipodystrophy
What is the basal-bolus dosing method for giving insulin?
Give rapid acting insulin bolus like aspart
Then long acting insulin basal like glargine
What is diabulimia?
A mental health condition where a type 1 diabetic stops or reduces their insulin intake to control their weight
Normally is young T1Diabetics
What is type 2 diabetes?
Where a patient has insulin resistance
Insulin into cell reduced due to cellular resistance associated with obesity
What happens do insulin receptors and GLP1 secretion in repsonse to oral glucose at beta cells in T2DM?
Why?
Reduced insulin receptors
Reduced GLP1 (incretin)
Since body has become sensitised to the high levels of glucose all the time
What is the management for Type 2 Diabetes Mellitus?
Lifestyle changes
Education
Weight loss (bariatric surgery)
Initially non insulin therapies
Insulin used in later stage disease
Treat comorbidities
What is the problem with management of T2DM?
Hypoglycaemia and weight gain with some of the therapeutics makes adherence difficult
What is the first line drug for type 2 diabetes?
Metformin
Then another drug given like and SGLT2 inhibitor
1.) What type of drug is metformin?
2.) what is it used for?
3.) MoA?
4.) Adverse effects?
5.) Contra-indications?
6.) Drug-drug interaction?
1.) Biguanide
2.) Used for T2DM
3.) decreases hepatic glucose production inhibiting gluconeogensis and appetite suppressed
4.) GI upset, nausea, vomiting and diarrhoea
5.) excretion is unchanged by kidneys so need to stop if eGFR is less than 30mL/min, alcohol intoxication
6.) ACEi, diuretics, NSAIDS since can impair renal function
Loop and thiazide like diuretics inc glucose so can reduce metformin action
How can GI upset by metformin be reduced?
Modified release metformin
What are sulfonylureas used to treat?
What are their mechanism of action?
T2DM
Blocks the K+ ATP sensitive channels leading to K+ building up in the beta cell leading to membrane depolarisation opening VG Ca2+ channels
Ca2+ influx causes insulin secretion
What is an example of a sulfonylurea?
Gliclazide
1.) What type of drug is gliclazide?
2.) what is it used for?
3.) MoA?
4.) Adverse effects?
5.) Contra-indications?
6.) Drug-drug interaction?
1.) sulfonylurea
2.) T2DM
3.) blocks K+ ATP sensitive channels at B cell, causes depolarisation cuz K+ builds up, VG Ca2+ open causing Ca2+ influx leading to vesicles releasing insulin
4.) Mild GI upset - nausea, vomiting, diarrhoea, Hypoglycaemia (since gliclazide works at low glucose concentrations too)
5.) heptaic and renal disease, careful in those at risk of hypoglycaemia
6.) other hypoglycaemic agents, loop and thiazide diuretics since they inc glucose
What are some examples of glitazones?
Pioglitazone
Rosiglitazone
What is the mechanism of action for the glitazones?
They activate PPAR-gamma which leads to gene transcription which works to convert glucose to triglycerides
Also decreases hepatic glucose output
Why does weight gain often occur when using glitazones?
Fat cell differentiation (glucose to triglycerides)
1.) What type of drug is pioglitazone and rosiglitazone?
2.) what is it used for?
3.) MoA?
4.) Adverse effects?
5.) Contra-indications?
6.) Drug-drug interaction?
1.) glitazones
2.) T2DM
3.) activates the PPAR-gamma gene transcriptor leading to glucose to triglyceride conversion
4.) GI upset, bladder cancer, fluid retention
5.) Heart failure because of fluid retention
6.). Other hypoglycaemic agents
What are some examples of SGLT2 (sodium glucose cotransporter inhibitors)?
Dapagliflozin
Empagliflozin
How do SGLT2 inhibitors work to treat T2DM?
Inhibits the SGLT2 transporters in the PCT so more glucose excreted in the urine
1.) What type of drug is dapagliflozin and empagliflozin?
2.) what is it used for?
3.) MoA?
4.) Adverse effects?
5.) Contra-indications?
6.) Drug-drug interaction?
1.) SGLT2 inhibitor
2.) T2DM, HFrEF and HFpEF
3.) inhibits SGLT2 transporter in PCT increasing glucose excretion in urine
4.) UTI and genital infections (more glucose in urine), thirst and polyuria (pancreatitis unknown why)
5.) hypovolaemia
6.) anti-hypertensives and other hyperglycaemic agents
What produces incretins?
The small intestines after a meal has been consumed
What is the main incretin made by the small intestine?
GLP-1
What is the affect of incretins like GLP1 being made by the small intestine?
Essentially stimulates insulin production following a meal
Pancreas:
-inc insulin secretion
-dec glucagon secretion
-inc insulin biosynthesis
Brain:
-inc satiety
Muscle:
-inc glucose uptake
Liver:
-dec glucose production
What are some examples of dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors)?
Sitagliptin
Saxagliptin
How do DPP-4 inhibitors work to treat T2DM?
Prevent incretin degradation leading to increased plasma incretin levels which drives insulin synthesis
Why do DPP-4 inhibitors have a low hypoglycaemic risk?
Drives insulin synthesis so doesn’t stimulate insulin secretion at normal blood glucose levels
1.) What type of drug is sitagliptin and saxagliptin?
2.) what is it used for?
3.) MoA?
4.) Adverse effects?
5.) Contra-indications?
6.) Drug-drug interaction?
1.) Dipeptidyl peptidase-4 (DPP-4) inhibitor
2.) T2DM
3.) prevents incretin breakdown increasing plasma incretin levels. Its glucose dependant so doesn’t stimulate insulin secretion at normal blood glucose levels (low hypoglycaemic risk)
4.) GI upset, small pancreatitis risk
5.) avoid in pregnancy, history of pancreatitis
6.) other hypoglycaemic agents, drugs that inc glucose can oppose. DDP-4 action like thiazide like and loop diuretics
What are some glucagon-like peptide-1 (GLP-1) receptor agonists (incretin mimetics)?
Exantide
Liraglutide
Semaglutide
How do GLP-1 receptor agonists act to Treat T2DM?
Increases glucose dependant synthesis of insulin secretion from beta cells by activating the GLP1 receptors
Its resistant to degradation by DPP-4
How are GLP1 receptor agonists administered?
Subcutaneous injection mostly
1.) What type of drug is exanatide, liraglutide and semaglutide?
2.) what is it used for?
3.) MoA?
4.) Adverse effects?
5.) Contra-indications?
6.) Drug-drug interaction?
1.) GLP1 receptor agonists (incretin mimetics)
2.) T2DM
3.) activates GLP1 receptors leading to increased glucose dependant synthesis of insulin secreted from B cells
Also promotes SATIETY and WEIGHT LOSS
4..) GI upset, decreased appetite with weight loss
5.) renal impairment
6.) other hypoglycaemics
What is SNAC for oral insulin doses?
The outer protective coat that helps overcome some of the oral bioavailbity issues of the protien drug insulin
What type of metformin helps overcome GI upset issues?
Modified/extended release metformin (slower release changes PK properties)
Why do you have to swallow extended release tablets whole?
Ensures the extended release coating remains intact so pharmacokinetics stay the same
Why is it helpful having a combo of drugs in one tablet?
What is the disadvantage?
Improved adherence
Cant really change the dose of one of the drugs
