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Insulin & Oral Hypoglycaemic (Summary (Treatment for T2D -…
Insulin
& Oral Hypoglycaemic
Control of Blood Glucose
Glucose is the obligatory energy source for
brain
.
Yet we have an intermittent food supply and a variable metabolic demand
Need for a storage / release mechanism to:
Store digested energy after eating
Mobilise those stores during periods of fasting
Glucose levels are tightly regulated to keep blood glucose levels within normal range
Glucose Regulating Hormones
Pancreas - Islets of Langherans
Insulin - B Cells
Glucagon - A cells
Other Hormones & Their Sources
Adrenalin - Adrenal Medulla
Glucocorticoids - Adrenal Cortex
Growth hormone - Pituitary
Insulin - A Fuel Storage Hormone
Sotred in B cell granules as pro-insulin
Proteolytically cleaved - Mature insulin (a+b chain) and C-peptide
Insulin Release Stimulation
Increased glucose
Amino acids and fatty acids
Peptide gut hormones - Incretins (GLP1, CCK)
Activation of Insulin Receptor
Insulin receptor (Ins-R) is a receptor tyrosine kinase (RTK)
Ins-R binds insulin, dimerises and first phosphorylates itself
Then phosphorylates major substrate → IRS-1
pIRS-1 → Activates several pathways
PI3K / Akt Pathway phosphorylates & activates many substrates
GLUT 4 transporter → Glucose enters cells
Glycogen synthase (glucose → glycogen) & other "storage" enzymes
Cell growth & gene expression pathways
Diabetes Mellitus (Chronic Metabolic Disorder)
Relative or absolute insulin deficiency
Symptoms
Polyuria → Due to glycosuria
Polydipsia → Thirst
Polyphagia → Hunger
Weight Loss → Catabolism +++
Tiredness / Confusion / Irritability
Poor healing & infections (candidiasis)
Blurred vision
Diagnosis → Hyperglycaemia
Diabetes
Fasting → >7.0 mmol/L
2hr after meal (OGTT) → >11.0
Casual → > 11.0 + Symptoms
Pre-Diabetes
Fasting Glucose → 5.6-7.0
Impaired OGTT → 7.8 - 11.0
Glycated Hb (HBA(1c)) > 6.5
Types
Type 1 Diabetes
Absolute
insulin deficiency
Auto-immune destruction of B cells
Usually juvenile onset
Not the only form of IDDM
Not associated with obesity
Treatment
Recapitulate the physiological
pattern of pancreatic insulin secretion
Insulin → Obligatory & lifelong
Diet/exercise i.e lifestyle (T1D is not associated with obesity)
Regular monitoring of glycaemic control → Glucometers
Insulin as Therapy
Administration
Insulin is a peptide (destroyed in gut)
Administered subcutaneously
Injection sites must be rotated
Other methods of administration
Aerosol inhalation → Didn't sell
Nanotechnology → Microneedles
Pharmacokinetics
Absorption affected by formulation, blood flow, scars
Short-lived Effects → t(1/2) ~20 minutes (~5 minutes if IV)
Enzymatically inactivated in cells after uptake
Insulin Pharmacokinetics
GRAPH
Types of Therapeutic Insulin
*→ Analogue
a→ Cannot be mixed with other insulins
Mimicking Normal Insulin Levels
Ideal (Close to normal)
Constant basal insulin production
Post-prandial insulin surges
Basal-Bolus Regimen
Long-acting basal insulin (bedtime)
Rapid-acting insulin at mealtimes
4 or more injections/day
Superior control, especially analogues
Insulin Pumps (CSII)
Basal infusion + patient-activated boluses
Side Effects
Hypoglycaemia
<3.5 mmol/L
Very common with intensive insulin ℞
Occasionally very sever - Life-threatning
Sweet snack
Weight Gain
Injection Site Issues
Scarring
Lipohypertrophy
Lipoatrophy
Type 2 Diabetes
90-95% of adult cases
Relative
insulin deficiency
Peripheral insulin resistance
Subsequent progressive ↓ in B cell function/mass
∴ May become insulin dependent
Strongly associated with obesity (∴ rates are ↑↑↑)
Treatment
Lifestyle Changes→ Aiming for weight loss as T2D is strongly associated with obesity
Healthy Diet
CHO counting
Low GI diet
Exercise
Weight Loss → 5% is often all that's needed
Stop smoking!
Regular monitoring of glycaemic control
GARPH
Works for <10% & remainder need drugs
Oral Hypoglycaemic Agents → Wide range of mechanisms of action so more than one drug can be used in combination
DIAGRAM
Metformin
Mechanism of Action (uncertain but)
Mainly ↓ gluconeogenesis
May also ↑ GLP1 release → Incretin effect
Additional Benefits
No hypoglycaemia
No ↑ in appetite → No weight ↑
Improved lipid profile
Pharmacokinetics
Excreted unchanged in urine (avoid in renal failure)
Drug interactions - ↓ clearance with other renal excreted drugs
Side Effects & Cautions
Gastrointestinal (30%) but transient (help with weight control)
Lactic Acidosis → Extremely rare
Sulphonylureas
Mechanism of Action → Insulin Secretagogue
Binds SU receptor (SUR1) on β cells to
block K+ channel → insulin release
Patients need functioning β cells
Pharmacokinetics
Bind albumin in blood, metabolised in liver & excreted in urine
Drug interactions - very common & ↑ hypoglycaemic effect
Albumin binding competitors - Aspirin, sulphonamides
CYP2C9 metabolism - NSAIDs, warfarin, alcohol, sulphonamides
Side Effects & Cautions
Hypoglycaemia - Avoid long t(1/2) SUs in elderly, renal failure, alcoholism
Hepatic Metabolism - Avoid with liver failure
Weight gain (2-5kg) - Appetite stimulants
Incretin-Based Therapies
Incretin Effect - Oral glucose induces a 50-70% greater insulin response than an equivalent IV glucose dose
Incretins - Gut peptides that ↑ insulin release after food (not IV)
Incretin response is ↓ in T2D
GLP1 Mimetics (>>t(1/2)
Peptide → Subcutaneous administration
E.g.
Exenatide
:star:
DPP-4 Inhibitors
Orally administered
E.g.
Sitagliptin
:star:
↑ insulin in a glucose dependent manner
May ↑ β cell function/mass
Side Effects
GI
Pancreatitis
SGLT2 Inhibitors
E.g.
Dapagliflozin
:star:
Sodium glucose co-transporter 2 inhibitors
Block glucose reabsorption in proximal tubule → lost in urine
Intestinal α-Glucosidase Inhibitors
E.g.
Acarbose
:star:
Competitive inhibition of maltose → glucose
S/E - bloating, flatulence & diarrhoea
Thiazolidinediones (TZDs/Glitazones)
E.g.
Pioglitazone
:star:
PPARγ agonists - activate gene transcription
↑ insulin sensitivity (30%) - Effects take weeks to develop
Insulin → Added on top of oral hypoglycaemic agents if/when needed (majority eventually will)
Reduction of Cardiovascular Risk
Treat hypertension
Treat dyslipidaemia
Treat albuminuria
Complications
Acute
Diabetic ketoacidosis (DKA)
Insufficient/absent insulin in IDDM
Fats used for energy → Acetyl-CoA
Ketosis
Acidosis
Dehydration
Chronic - Mostly due to Vascular Diseases
Macrovascular (AS)
Hypertension (80%)
Heart attacks (2-4x↑)
Strokes (2-4x↑)
Microvascular
Retina
Kidney
Diabetic Foot
Summary
Diabetes mellitus is characterised by sustained hyperglycaemia
It is due to either an ABSOLUTE (T1D) or RELATIVE (T2D) insulin deficiency
Complications of DM are life threatening (DKA, CVD, RF)
Treatment for T1D - lifelong insulin ℞ + lifestyle
Treatment for T2D - progressive disease, ∴ step-wise ↑ in ℞s
Lifestyle modifications aiming at weight loss
Hypoglycaemic mono therapy
Hypoglycaemic multi therapy e.g. Metformin + SUs + acarbose
Many new therapies coming online - incretin-based, SGLT2
If HbA1c levels still indicate poor control - bariatric surgery?
