Diabetes Pharm/Phys Flashcards
3 classic signs of type 1 diabetes
polyuria (volume of urine )
polydypsia (thirst)
Polyphagia (increased appetie )
how is Insulin synthesized
- Measured using C-peptide ELISA
- mRNA = preproinsulin
- RER= Proinsulin A,C, B, chain produced
- Golgi =>A+B chains disulphide bonds =INSULIN
- C chain = USED TO make Cell membrane protein
You have to measure C protein to measure insulin levels as insulin doesn’t stay around long!
How is insulin secreted
-Rapid 1st phase trigger = increased glucose level
-Slow sustained release of vesicles triggered
=pulsatile release
1) GLUT2
2) ATP made using glucokinase
3) The change in ADP/ATP ratio causes ATP sensitive K+ channels to close! K+ stays in a cell, less K+ is lost
4) B cell depolarises, Ca2+ enters the cell
5) This triggers insulin release
Adverse effects of insulin administration
-Too much insulin = hypoglycaemia, coma, brain damage
(Drink sugary drink to fix this, or use glucagon kit )
-Allergic reactions
-Lipodystrophy
-lipo hypertrophy (fat on site of injection)
-Serum K+ levels (insulin causes K+ INTO cell = positive cells = fewer K+ in serum, can cause diabetic ketoacidosis )
How can DKA occur in Diabetes ?
4
- stopped insulin = High blood sugar
- Body uses fats for energy
- Fatty acids => beta-oxidation = if the acetyl CoA doesn’t bind to Oxaloacetate = KETONES = Diabetic Ketoacidosis
How does insulin stimulate glucose uptake?
1-Insulin receptor (TRK) 2-Signal transduction caused GLUT4 to open (inducible transporter ) 3-Causes glucose utilisation 4-Glycogen /lipid /protein synthesis
Effects of insulin Liver
4
LIVER :
- Decreased gluconeogenesis, glycogenolysis
= Increases storage of Glycogen in the liver (reducing Glucose in the blood)
- GLUT2
Effects of insulin on skeletal tissue
4
1-Increases GLUT4
2-Glycogen synthesis
3-Glycolysis increases ( break down of glucose)
4-Increases AA acid up take, protein uptake = anabolic
Effect of Insulin on adipose tissue
1-Increases GLUT4
2-increases glycerol ..>this increases TRG
The storage form of glycogen for situations when no food is around
Insulin preparations for Type 1 Diabetes
1) Insulin pen = short-acting
2) Insulin Zn suspension = intermediate-acting = insulin in circulation for a longer time
3) Crystalised insulin zinc (Ultralente) suspension = lONG acting for the whole day
4) Insulin Glargine (Lantus ) = long-acting insulin , always being secreted from site
Best treatment = Short + medium-lasting insulin subcutaneouslty by patient
Insulin pumps are new treatments
differentiate between type 1 and type 2 diabetes
4
1) Type 1: diagnosed childhood puberty, frequently malnourished, 10% x cases, moderate genetic predisposition, B cell insulin defect = Risk of DKA
Your body attacks the cells in your pancreas which means it cannot make any insulin.
2)TYPE 2= over 35, frequently obese, 90% of cases, Very strong genetic predisposition, Insulin resistance
Your body is unable to make enough insulin or the insulin you do make doesn’t work properly.
What is the role of HbA1C in the diagnosis of Diabetes?
**
-DO NOT USE IN TYPE 1
-HbA1C of 42-47 mmol/mol = risk of developing diabetes
-Set target for patients
HbA1c is what’s known as glycated haemoglobin. This is something that’s made when the glucose (sugar) in your body sticks to your red blood cells.
Your body can’t use the sugar properly, so more of it sticks to your blood cells and builds up in your blood.
Red blood cells are active for around 2-3 months, which is why the reading is taken quarterly.
A high HbA1c means you have too much sugar in your blood. This means you’re more likely to develop diabetes complications, like serious problems with your eyes and feet.
Classifications of diabetes
1) Gestational diabetes (at time of pregnancy)
2) Steroid-induced Diabetes
3) LADA= Latent Autoimmune diabetes in adulthood (autoimmune disease )
4) MODY= Maturity Onset Diabetes Of the young = rare form
Nonpharmacological management of Diabetes
What areas of the body does Diabetes affect?
KEVIN
1-Education 2-Diet 3-Lifestyle 4-Foot care 5-Retinal Photography
Kidney Eyes Vascular Infections Neuropathy Skin
Treatment of diabetes = drugs
4 main
overview of mechanism of action
(8)
1) Biguanides = MetFORMIN = stops gluconeogenesis in liver
2) Sulfonyureas (Gliclazide )= Sulfonylureas bind to and close ATP-sensitive K+ (KATP) channels on the cell membrane of pancreatic beta cells, which depolarizes the cell by preventing potassium from exiting. This depolarization opens voltage-gated Ca2+ channels= increased insulin release
3) Glucagon-like peptide=GLP (Liraglutide)
GLP-1 = enhance insulin secretion and inhibit glucagon secretion from pancreatic islet cells.
4) Dipeptidylpeptidase IV inhibitors (SitaGLIPTIN) Sitagliptin works by increasing the amount of insulin that your body makes.
USED TO GET Hb1AC down to target
Metformin case study
- First line, along with lifestyle intervention
- Activated the liver AMP-kinase reducing liver glucose output
- Increases liver, muscle, fat cell sensitivity to insulin
- Peripheral tissues can act on the insulin
- Causes weight loss
- GI adverse effects
- Rare = lactic acidosis, most common in kidney impairment
Sulfonylureas(SU) case study: Gliclazide
1-Binds to sulfonylureas Receptor= closes ATP-K+ channels = decrease K+ leaving the cell .K+ stays in the cell!
2-This means Ca2+ enters the cell
3-Causes BETA CELL depolarisation
(Beta cell squeezes out more insulin )
-Only works on patients with beta cells= type 2
Side effect:
- Prolonged hypoglycemia
- Weight gain
- Hyponatraemia
- Oedema
- Hepatotoxicity
- Photosensitivity, allergy, rash
Incretin Hormones -Glucagon-like peptide-1 (GLP1) and DPP 4 inhibitors!
1-30 AA pp (L-cell in SI)
2-Stimulated by lipids, carbs
3-Binds to G-Protein on beta cell of the pancreas= insulin
4-It increases insulin synthesis, beta cells grow, Stops glucagon secretion
NORMALLY DPP 4= breaks down Incretin so we don’t have too much insulin
DPP4 INHIBITOR
We either make analogues= GLP-1
= promotes insulin signal longer ie: Liraglutide
OR
=Incretin Enhancers (DPP4 inhibitors ) so insulin continues being made=Gliptins ie: sitagliptin
outline the complication associated with pituitary adenomas, list causes of hypopituitarism
The most common cause of hypopituitarism is a nonfunctioning pituitary adenoma (40.5%),
- congenital causes (14.6%)
- prolactinomas
- GH-secreting adenomas equally (7.0% and 7.2%)
- craniopharyngiomas (5.9%)
What is it called when :
a) Too many glucocorticoids
b) You have an over active thyroid= too much T3,T4
c) Too much aldosterone
a) Cushing’s disease
b) Grave’s Disease
c) Conn’s Disease
Sodium-glucose Co-Transporter -2 Inhibitors (SGLT)-2
Dapagliflozin, Canagliflozin,Empagliflozin
when is it used?
Mechanism of action
Side effects
contraindications
(10)
TYPE 2 DIABETES:
Decrease Blood glucose (they cause the kidney to secrete glucose into the urine)
PCT =>glucose active reabsorbed here with Na+, but the SGLT2 INHIBITOR = blocks receptor and so glucose stays in urine
- Low plasma glucose
- Polyuria
- Weight loss
- Low Blood pressure
- Diabetic Ketoacidosis
- Risk of acute kidney injury
- UTI risk
- Acute kidney injury
- Osteoporosis
In order for these to work, you need a functioning kidney ( don’t use if eGFR <45mL/min)
Drug interactions: (diuretics,ACE,ARBs,NSAIDs)
Add on to metformin to have the best result
How is insulin used in TYPE 2 diabetes?
Normally just add insulin to oral therapies such as metformin (reduces the weight gain and offers CV protection)
When to use:
-Hyperglycaemia at presentation= Insulin required ( sugars, weight not controlled)
-Introduced before surgery or when they are ill, pregnant, allergies to other agents
First line = NPH intermediate-acting insulin
Second line= Long-acting insulin (insulin Determir, Insulin glargine)
= Hollistic response to their lifestyle
Case study Thiazolidinediones (insulin resistance reducers)
1) They bind avidly to peroxisome proliferator-activated receptor-gamma (PPAR) in adipocytes to promote adipogenesis and fatty acid uptake, and this forms a dimer with the Retinoid X receptor for the insulin .
2) This dimer causes insulins effect to be brought around =>
- Lipoprotein lipase ( breaks down fatty acids, lowers FFA)
- GLUT4 receptor (adipose, skeletal, cardiac muscle, more insulin sensitivity )
- Fatty acid transporters ( so TRG are stored )
This all leads to enhanced uptake of glucose /fatty acids = reduction in blood glucose level, and blood pressure
1) Causes Liver damage
2) Risk of bladder cancer
3) Weight gain
4) Heart failure
How can statins treat type 2 diabetes
2
Statins are cholesterol-lowering drugs that are frequently used as part of diabetes care due to the knowledge that people with diabetes face a greater likelihood of heart attack and stroke.
Acarbose case study?
mechanism of action
side effects
1) Intestinal disaccharidase Enzyme Inhibitors
(Alpha-glucosidase, Alpha-amylase)
2)Inhibits the carbohydrates being absorbed in the Small intestine
-Abdominal pain
-Diarrhoea
-Gas
-IBS
Meglitinide, Repaglinide , Nateglinide
2
Causes closure of ATP-Dependant K+ channel
GLP1 receptor agonist
What drugs cause gyncomastia
Some drugs create awesome Kicks
Spironolactone Digitalis Cimetidine (H2- receptor blocker) Alcohol Ketaconazole
