Lecture 10- Diabetes mellitus Flashcards
what sort of hormone is insulin
peptide
insulin is secreted by
Beta cells
beta cells secrete insulin in response to
- Increase [glucose] in plasma
- Incretins (GLP-1, GIP)- the incretin effect
- Parasympathetic activity (M3)
insulin secretion is inhibited by
- Low glucose
- Cortisol
- Sympathetic activity (alpha2)
insulin half life
5 mins in plasma
Function of insulin
- Decrease hepatic glucose output of gluconeogenesis and glycogenolysis- overall increasing glycogen stores
- Promotes uptake of glucose into tissues- muscles and adipose esp.
why is insulin secreted in the blood even during fasting
prevents insulin receptor down regulation
what sort of pattern is insulin released
biphasic
- Shortly after elevation of glucose conc,a transient stimulation of insulin secretion is observed ‘first phase secretion’
- This is later followed by gradually developing secondary stimulation ‘second phase secretion
- Spike in insulin conc
- Then second lower spike
Type 1 diabetic 7 day overlay- being treated
- Continual glucose monitoring (CGM)
- Erratic
- Even if being treated with insulin
Type 1 diabetes mellitus Diagnosis
- Fasting glucose >6.9 mml/L or random plasma glucose >11 mmol/L
- Plasma or urine ketones
- HbA1C >48 mmol/mol
- A single raised plasma glucose without symptoms not sufficient for diagnosis ( would need several blood tests in the absence of symptoms)
symptoms of Type 1 diabetes
- Rapid onset symptoms
- Polyuria (nocturia)
- Polydipsia (needing to wake at night for water)
- Weight loss
- Fatigue/lethargy
- Generalised weakness
- Blurred vision
measuring glucos vs HbA1c
- Glucose = an immediate measure of glucose levels in blood mmol/L
- HbA1C
- Haemoglobin A1c- glycated haemoglobin
- % of RBC with sugar coating
- Reflects average blood sugar over last 3 months (mmol or %)
what is the main treatment for T1DM
therapeutic insulin
therapeutic insulin types
- Historically bovine and porcine (immunogenicity concerns)
- Now use human insulin
- Recombinant DNA (bacteria/yeast)
why is insulin given parenterally
protein - avoids digestions
usual formation of insulins
- Due to obesity and insulin resistance there are higher doses (300 and 500 units/mL(
- NEVER abbreviate units or international units à dangerous mistake could be made
diabetic ketoacidosis is a biochemical triad of
- Hyperglycaemia
- Ketonemia
- Acidosis
who is DKA predominately found in
- T1DM
- Common in children on diagnosis
When to suspect DKA
- Blood glucose >11 mmol AND
- Polydipsia
- Polyuria
- Abdominal pain
- Acetonic breath
- Confusion
- Lethargy
- Visual disturbances
- Symptoms of shock
DKA- precipitating factors
- Infection
- Trauma
- Non-adherence to insulin treatment
- DDIs
Diagnosis of DKA
- Blood glucose >11mmol (may not always be present = euglycemia)
- Test for ketones in blood and urine
treatment of DKA (2 steps)
initial treatment- i.v.i (intravenous influsion) fluid with potassium
following initial treatment - i.v.i soluble insulin (fixed rate insulin)
delivery of insulin therapy
- Routine delivery= subcutaneous injection in upper arm, thighs, buttocks, abdomen
- Emergency e.g. DKA= i.v.i (IV infusion)
half life of insulin is only 5 minutes therefore we need to
slow absorption
how is absorption of insulin slowed
- For bovine and porcine insulins adding protamine and/or zin complex – used less now
- Soluble (neutral) insulin forms hexamers
- Insulin analogues
How does adding protamine/ or zince complex to bovine and porcine insulins slow absorption of insulin
- Delays dissolving
how does hexamer formation of soluble insulin delay aborption
- Delaying absorption from site of injection
- [plasma] insulin will be highest after 2-3 hours (dosing 15-30 min prior to meals)
Insulin analogues and slowing absorption
- Recombinant modifications- a few amino acid changes
- Changes PK and not PD
Methods of injecting insulin
- Syringes
- Pens
- Pumps
- Inhalers?
what class of drug is insulin
hormonal
uses of insulin
- Type 1 Diabetes
- Sometimes severe T2DM
Mode of action of insulin
- Insulin binds to insulin receptor
- Causes cascade of events which causes GLUT4 receptors to translocate from the cytoplasm to the membrane
- GLUT4 increases uptake of glucose into the cell lowering blood glucose
Adverse drug response: insulin
- Hypoglycaemia
- Lipodystrophy
- Lipohypertrophy or
- lipoatrophy
lipodystrophy
need to make sur einjection site is roated- otherwise will affect adherence
contraindications : insulin
- renal impairment- hypoglycaemia risk
Drug-drug interaction: Insulin
- dose needs increasing with systemic steroids
- caution with other hypoglycaemic agents
what is a common insulin dosing schedule for T1DM?
A common dosing schedule for young active TIDM patients which provides some flexibility if adherence is good
- Basal- long acting e.g. glargine
- Given once a day
- Bolus- rapid acting e.g. aspart
- Given before meals
emerging therapeutics for T1DM
- Immunotherapy- monoclonal antibodies for high risk group
- Delay progression
- Islet transplantation
- Islet cell regeneration
- Inhaled insulin
- Pharmaceutical challenge
- SGLT-2 inhibitors
- TI and TII DM and other CVDs
what is diabulimia
When a type 1 diabetic stops or reduces their insulin to control weight
name the oral hypoglycameic agents used to treat T2DM
Type 2 diabetes
- Slow progression of disease over many years
- Many asymptomatic early on
- Vast majority T2DM patients are overweight or obese
- Age profile of T2DM has decreased
Pathophysiology of T2DM
-
Insulin resistance
- Initially insulin resistance overcome by increased pancreatic insulin secretion
- However overtime there is a decrease in insulin receptor’s, and a decrease in GLP-1 secretion in response to oral glucose
- Response reduced in B cells and eventually insulin production reduced
- Lack of production of insulin
diagnosis of T2DM
Blood sugars rise slower than T1DM so variable symptoms- often diagnosed through midlife `MOT’
Management of T2DM
- Lifestyle
- Education
- Weight loss
- Initially non-insulin therapies
- May form part of treatment plan in poorly managed or later stage disease
- Treatment with hypoglycaemic agents
- Can cause weight gain- makes adherence to sustained successful therapy a challenge
- Treatment of comorbidities
NICE guidelines on T2DM
name a drug from the drug class Biguanides
Metformin
metformin uses
T2DM
Mode of action of metformin (biguanides)
- Reduces hepatic glucose production by inhibiting gluconeogenesis
- Some gluconegenic activity remains so hypoglycaemia risk reduced
- Also: suppresses appetite to limit weight gain
Adverse drug response: insulin
GI upset
- Nausea
- Vomiting
- diarrhoea
Contraindications: metformin
- eGFR <30 mL/min
- excreted unchanged by kidneys
- alcohol intoxication
Drug-drug interaction : metformin)
- ACEi (drugs which impair renal function)
- Diuretics (drugs which impair renal function)
- NSAIDs (drugs which impair renal function)
- Loop and thiazide like diuretics which increase glucose so can reduce metformin action
name a drug from the class Sulfonylureas
Gliclazide
use of glicazide (sulfonylureas)
- Typically in combination with other agents or a first line option if metformin contraindicated
Mode of action: Gliclazide (Sulfonylureas)
- Inhibit ATP-dependent K+ channels causing membrane depolarisation (consists of 4 sulfonylurea receptor 1 and 4 potassium channel)
- Causes calcium influx into B cell
- Stimulate insulin secretion
- NEED PANCREATIC FUNCTION TO WORK
Gliclazide (Sulfonylureas) affect on weight
- Can cause weight gain through anabolic effects of insulin
Adverse drug response: Glucazide (SU)
- Mild GI upset
- Nausea
- Vomiting
- Diarrhoea
- Hypoglycaemia (works at low [glucose])
Contraindications: Glucazide (SU)
- Hepatic disease
- Renal disease
- Caution of those at risk of hypoglycaemia
Drug-drug interaction: gliclazide (SU)
- Other hypoglycaemic agents
- Loop and thiazide like diuretics (increase glucose so can reduce SU action)
name a drug which comes under the drug class Thiazolidinediones (glitazones)
Pioglitazones, rosiglitazone
mode of action of pioglitazones and rosiglitazone
- Insulin sensitisation in muscle and adipose
- Decrease hepatic glucose output by activation of PPAR- Y –> gene transcription
- stimulates glucose –> triglyceride
- Half life not related to duration of action -6-8 weeks for benefit
pioglitazons and rosiglitazones affect on weight
- Can cause weight gain because of fat cell differentiation
- Used much less frequently than other agents
Adverse drug response: Pioglitazones and rosiglitazone
- GI upset
- Fluid retention
- Fracture risk
- Bladder cancer
Contraindications: Pioglitazones and rosiglitazone
Heart failure because of fluid retention
Drug-drug interaction: pioglitazones and rosiglitazone
Other hypoglycaemic agents
name a drug which comes under the drug class Sodium-glucose co-transporter (SGLT 2) inhibitors (gliflozins)
Dapagliflozin, canagliflozin
Uses of Sodium-glucose co-transporter (SGLT 2) inhibitors (gliflozins)
Drug name: Dapagliflozin, canagliflozin
- adjunct to insulin in T1DM (high BMI)
- T2DM as an add on therapy
Sodium-glucose co-transporter (SGLT 2) inhibitors (gliflozins) and weight
Modest weight loss, hypoglycaemic risk is low
Mode of action: SGLT inhibitors ( Dapagliflozin)
- Competitive reversible inhibition of SGLT-2 in PCT
- Decrease glucose absorption from tubular filtrate
- Increase glucose excretion
Adverse drug response: SGLT inhibitors
- UTI (sugar urine)
- Genital infections
- Thirst
- Polyuria
Contraindications: SGLT inhibitors
- Risk of DKA in T1DM
- Possible hypotension
drug-drug interaction: SGLT inhibitors
- Antihypertensives
- Other Hypoglycaemic agents
Physiological effect of GLP-1 (incretin hormone)
-
In the pancreas
- Increases insulin secretion
- Decrease glucagon secretion
- Increase insulin biosynthesis
Drugs which target GLP-1 (incretins) actions
- Dipeptidyl peptidase- 5 (DPP-4) inhibitors (Gliptins)
- Glucagon-like peptide-1 (GLP-1) receptor agonists (incretin mimetics)
name a drug which comes under the class Dipeptidyl peptidase- 5 (DPP-4) inhibitors (Gliptins)
Sitagliptin, Saxagliptin
uses of Sitagliptin, Saxagliptin (DPP-4 inhibitor)
when insulin (biguandides) and gliclazide (SU) are contraindacted/ or as an add on
Mode of action- gliptins (DDP-4i)
- Prevent incretin (GLP-1) degradation by inhibiting dipeptidyl peptidase- 4 (which usually breaks down GLP1) increasing plasma incretin levels
- Glucose dependent so postprandial action
- Will not stimulate insulin secretion at normal blood glucose- lower hypoglycaemic risk
DPP-4i (glipitins) affect on weight
Supress appetite- due to GLP-1 action in satiety
Weight neutral
Adverse drug response: Gliptin
- GI upset
- Small pancreatitis risk
Contraindications: gliptins
- Avoid in pregnancy
- History of pancreatitis
Drug-drug interaction : gliptins
- Other hypoglycaemic agents
- Drugs increase glucose can oppose gliptin action- thiazide like and loop diuretics
name a drug which comes under the class Glucagon-like peptide-1 (GLP-1) receptor agonists (incretin mimetics)
Drug name: exenatide, liraglutide
mode of action of GLP-1 receptor agonists (incretin memetics)
- Increase glucose dependent synthesis of insulin secretion from B cells by activating GLP-1 receptors (resistance to degradation by DPP-4)
- Subcutaneous injection
- Promotes satiety- possible weight loss
how are GLP-1 receptora gonists (incretin) delivered
subcutaenous injection (peptide so would be digested if taken enterally)
GLP-1 receptor agonists (incretin mimetics) affect on weight
Adverse drug response: GLP1 receptor agonists
- GI upset
- Decreased appetite with weight loss
Drug-drug interaction Glucagon-like peptide-1 (GLP-1) receptor agonists (incretin mimetics)
Other hypoglycaemic agents
how can GI upset by hypoglycaemic agents be avoided
- Modified/extended release (metformin, incretin mimetics) overcome GI upset, less frequent dosing
- Slower release changes PK properties
Why swallow extended-release tablet home (instead of chewing)?
- Slows down absorption disrupting modified release
- Improve adherence vis ease of dose modifications
- Not great when we need to tweak doses
