W6 Type 1 Diabetes Mellitus (SM) Flashcards
What is DM in a nutshell?
Chronic metabolic disorder characterised by hyperglycaemia,
* Insulin deficiency (Type 1)
* Impaired b-cell function and/ or loss of insulin sensitivity (insulin resistance) (Type 2)
Pathophysiology of T1DM:
What are the 2 factors that make up the Beta cell ER stress?
What are the steps of pathophysiology?
T1DM is an autoimmune (abrupt immune system or b-cell or both) and heterogeneous disease
A) 1. Genetic factors
individual with a predisposing
genetic risk (carried mainly by
specific types of major histocompatibility complex (MHC) or human leucocyte antigen (HLA) genes
2. Environmental factors
(Drugs/ toxins, viruses, genetic mutations)
B) Immune System
- Activation of adaptive immunity
(autoantibodies & cytotoxic T cells) - Activation of innate immunity
(inflammatory cytokines/chemokines)
.C) B cell (endoplasmic reticulum stress)
- Cellular damage
- Insulin defieciency
- T1DM
Thus Beta cells are destroyed (in an effort to protect the cell) and insulin cannot be produced
T1DM
What are the presenting symptoms?
- Asymptomatic
- Onset at any age (usually < 40 years)
- Rapid onset
- Lead to ketoacidosis
- Long-term secondary complications
Pathophysiology of T1DM:
In depth explanation
- In a genetically predisposed individual, undefined genetic/environmental factor(s) (depicted in pink) will trigger the
induction of beta cell endoplasmic reticulum (ER) stress which leads to the activation of compensatory immune responses
(autoantibodies and cytokines storm) toward the beta cells and ultimately destroys the beta cells. - Once pancreatic beta cells fail, a vicious process advances due to the release of (neo)antigens and cytokines/chemokines
reinforcing the ongoing autoimmune responses and contributing to (complete) destruction of functional pancreatic beta
cells. As this destruction process is highly immunogenic, it is by itself a trigger to reinitiate this cascade in adjoining (so far)
healthy islets. - The constant interaction between beta cells and the immune system may vary in at-risk individuals, leading to disease
heterogeneity
Acute complications of T1DM
(Diabetic ketoacidosis)
What is ketogenesis?
Ketone bodies are produced by the liver and used peripherally as an energy source when glucose is not readily available.
Insulin inhibits fatty acid breakdown, ketogenesis and maintains blood ketone levels
Liver: Fatty acids (aetyl coA)
— Ketone bodies
*Acetoacetate (AcAc)
* 3-beta-hydroxybutyrate (3Hβ)
* acetone (least abundant
- ask ai to explain this diagram
Diabetic Ketoacidosis
(a specific complication of type 1 diabetes mellitus, less common in type 2 DM)
What is it caused by?
In DM (predominately in T1DM), due to
insulin deficiency, the abrupt rise of fatty
acids breakdown and consequent increase in
ketone bodies makes the blood highly acidic,
ketoacidosis/metabolic ketoacidosis
Hyperglycaemia:
Dehydration
(polyuria, polydipsia,
glucosuria)
low cerebral blood flow
Low renal flow
Peripheral circulatory failure
Ketosis:
Nausea & vomiting
Abdominal pain
CNS depression
Diabetic coma
Both of these= Medical emergency (10-20% mortality rate)
Insulin (T1DM & T2DM)
What regimen is first line?
- Initially, insulin was obtained from either
animals or semi-synthetics. - Insulins in clinical use (nearly all types) are
manufactured using Genetic engineering and
recombinant DNA technology (E-coli and
yeast) - Basal-Bolus insulin regimen is the first line of
choice in T1DM - Cell replacement therapy (islet transplantation) are emerging treatment options for T1DM:
-Approved by NHS in 2008, ~ 5 centres in the UK.
What are the 4 types of insulin?
- Rapid-acting
- Short-acting (regular)
- Intermediate-acting
- Long-acting
- Pre-mixed or biphasic insulin (tailored to suit patient needs)
Rapid-acting insulin:
Onset of action?
Duration of action?
When to use?
(onset of action: 15 mins, duration of action: 2-3 hrs)
– Recombinant human insulin analogues (aspart, lispro, glulisine)
– Soluble (break apart into monomers -rapid absorption)
– Can be used just before food
– Short duration of action reduces the risk of hypoglycaemia
Short-Acting insulin (regular)
Onset of action?
Duration of action?
When to use?
– Insulin mixed with Zinc, soluble (Actrapid)
– 30-40 mins before food, subcutaneous (intravenous in DKA)
Intermediate-acting insulin:
Onset of action?
Duration of action?
(onset of action: 1-2 hrs, duration of action: 11-24 hrs)
– Insulin suspended with protamine (Isophane), cationic proteins or zinc ions (Lente)
– Mimic endogenous basal insulin
Long acting insulin:
Onset of action?
Duration of action?
(onset- up to a few hours , duration of action: up to 36 hrs)
– insulin zinc suspension (Ultralente)
– analogues (glargine, detemir, degludec)
– Mimic endogenous basal insulin secretion
What is Pre-mixed or biphasic insulin (tailored to suit patient needs)?
- A mix of short- and intermediate-acting insulin
- Mimic endogenous basal insulin secretion
Pharmacokinetics of Insulin:
What are the ADME properties?
Administration & Absorption
* No oral bioavailability
* SC, IM: Good
* Nasal: Good (Investigational)
Distribution:
* <5% bound in plasma
Metabolism:
* Liver, Muscle and Adipose
Excretion:
* None
Half-life:
* 5-10 min
Where to administer insulin?
Upper outer arms
Lower abdomen (semi-circle under belly button)
Upper outer thigh
Buttocks
