L16 Flashcards
what is the glucose concentration in diabetic people
> 7 mM
what is the safe range of glucose concentration
2.5 mM to 7 mM
what are the features of type 1 diabetes
Caused by a failure of insulin
secretion
Characterised by very low/absent [insulin] and high [glucose]
Has sudden onset
Usually develops early in life
Sometimes referred to as juvenile
Relatively rare (~5% of diabetes)
what are the features of type 2 diabetes
Caused by insulin resistance in tissues
Insulin present in circulation but [glucose] remains elevated
Has gradual onset
Usually develops later in life
It is the most common form of diabetes – and is becoming much more common
Associated very strongly with obesity
describe Type 1 diabetes pathogenesis
Type 1 diabetes is caused by
destruction of β cells
Involves an autoimmune mechanism (CD8 cytotoxic T cells mediated)
Total failure of insulin secretion
Evidence of hereditary tendency although environmental factors crucial (viral infections, autoimmune disorders)
However can develop spontaneously in absence of family history or environmental trig
what does CD8 T react to
against peptides of insulin and of other specific proteins which are complexed with MHC II
what allotypes are associated with type 1 diabetes
HLA-DR3 and DR4
what haplotype is associated with type 1 diabetes for caucasians
DR4-DQ8
what mutation is common in Caucasians
substitution of Asp57 to Val/Ala/Ser in the HLA-DQ β1 chain
what are the symptoms of type 1 diabetes
Tissues cannot accumulate and store glucose
Tissues cannot use glucose as metabolic fuel
Body cannot store excess energy as fat
Reduced synthesis of protein
how does hyperglycemia lead to dehydration
High [Glucose] enters glomerular filtrate and overwhelms glucose absorbing capacity of proximal convoluted tubule
Increased fluid osmolarity in tubules
More water is secreted from cells into the proximal convoluted tubule
causes increased urine flow – diuresis
Water reabsorption is reduced
Dehydratation, excessive urine production and thirst
what are the effects of insulin on ketoacidosis
fatty acids and proteins are metabolised in the absence of insulin leading to rapid weight loss
degradation of fatty acids produces Ketone bodies
ketone bodies are acidic so blood pH is lowered leading to metabolic acidosis
this leads to acidotic coma
how can you predict glucose values of the past 6-8 weeks and to monitor the long term control
Glycosylated haemoglobin
how does lipohypertrophy happen
A major effects of insulin is to promote
the deposition of fat
Cells close to site of insulin injection exposed to high [insulin]
If same site used again and again will promote deposition of fat around injection site (lipohypertrophy)
Also clinically important as leads to unpredictable rate of insulin absorption
This could lead to poor glycaemic control and patients could experience hyper/hypoglycaemic events
what are the forms of insulin used for therapy
Animal insulin (porcine/bovine)
Human insulin
Human insulin analogue
what are the types of human insulin
soluble insulin
isophane insulin
insulin zinc suspension
what are the features of soluble insulin
Rapid and short lived
Used intravenously in emergency treatment of hyperglycemic emergencies only (e.g. chetoacidosis)
give features of Isophane insulin
Tends to form precipitates.
Intermediate acting
give features for Insulin zinc suspension
Tends to form precipitates
Long acting
what are the types of insulin analogues
Insulin Lispro
Insulin glargine & detemir
what are the features of Insulin Lispro
A modified insulin (analogue) obtained by switching a Lys28 and Pro29
Very rapid and very short lived. Normally taken from patients before a meal
what is Glargine
A modified insulin (analogue) obtained by mutating Asn21 in Gly and by adding 2 Arg at the end of the B chain.
Long-acting.
what is Detemir
A modified insulin (analogue) obtained by mutating Thr 30 (deletion)
Long-acting
what are the features of Insulin glargine & detemir
Normally taken from patients before a meal in combination with a short-acting form
Forms a micro-precipitate at the physiological pH of subcutaneous tissue
Slowly absorbed
what is Teplizumab
a monoclonal antibody that targets CD3 changing the interaction between APC and T cell
this leads to less of CD8 T cells and promoting more production of T reg cells
T reg cells inhibit the immune response
what are the steps of getting type 2 diabetes
- Genetic and environmental predisposition
- Life style
- Bad dietary habits
- Obesity
- Insulin resistance
- Glucose uptake
- Insulin pathway defects
- Hyperinsulinemia
- β cells try to compensate for peripheral - - - - - resistance
- Normal glucose levels can be maintained for years
- β cells failure and hypoinsulinemia
- β cells become “exhausted” and cannot keep up with the peripheral demand of insulin
- Insulin secretion decrease
- Diabetes
- Hyperglicemia develops
- Total failure of insulin secretion
- Exhausted Beta cells may convert to Alpha cells
what are the factors that lead to type 2 diabetes in FAT people
Free fatty acids (FFAs)
Adipokines
PPARγ
Inflammation
how do FFAs contribute to type 2 diabetes
Lead to insulin resistance in muscle and liver.
When in excess they are transformed in second messenger DAG
DAG activate PKC which phosphorylate IRS-1
This attenuates Insulin Receptor signal
how do Adipokines contribute to type 2 diabetes
Released by adipocytes
Adiponectin is anti-hyperglicemic, because improves insulin sensitivity by activating AMPK, enzyme promoting lipolysis in liver and muscle
Adiponectin expression is reduced in obesity
Also activates IRS1/2 improving insulin signalling and GLUT4 improving glucose uptake. (all of this is reduced in obese people)
AMPK activators can be used in therapy (metformin)
what are the types of adipokines
Pro-hyperglicemic
anti-hyperglicemic
how does PPARγ lead to type 2 diabetes
Nuclear receptor involved in adipocyte differentiation
Promotes secretion of anti-hyperglicemic adipokines
Mutations/Post-translational modifications (Ser273 phosphorylation) can cause diabetes
Agonists used in therapy
how inflammation contribute to type 2 diabetes
Adipocytes overexpress certain cytokines (IL-1/IL-6)
Cytokines activate JAK-STAT signalling
Promoting SOCS expression
SOCS3 compete for binding to phosphotyrosine residues attenuating insulin signalling
what does type 2 diabetes therapy include
Diet/Excercise
Thiazolidinediones
Metformin
Sulphonylureas
Insulin (Once disease fully developed)
what are the features of Thiazolidinediones – e.g. (Pioglitazone)
Agonist of nuclear receptor PPAR-γ
Promotes expression and secretion of anti-hyperglycaemic adipokines (so increase lipolysis)
Increase hypoglycaemic action of insulin by sensitizing cells to its action
Collectively reduce insulin-resistance in liver and other peripheral tissues
what are the features of Metformin
Suppress glucose release from liver
Activate AMPK
increase lipolysis in liver and muscles and therefore improving insulin receptor signalling
Suppress glucose release from liver
Useful in obese type 2 patients
how does Sulphonylureas (e.g. Gliclazide)
work
Bind to sulphonylurea receptors expressed on membranes of β cells
Block ATP-sensitive K + channels in β cells
K + accumulates inside cells
β cells depolarize
Ca++ channels open and allow insulin secretion by exocitosis
what Type 2 diabetes drugs are under research
Selective β3 agonists
α2 adrenoreceptor antagonists
GLP-1 (Glucagon like peptides) receptor agonists
SGLT-2 inhibitors (Sodium-glucose co-transporter
how would Selective β3 agonists work
β3 adrenoreceptors control lipolysis in fat cells
Under development
Potentially important for treating obese patients with type 2 diabetes
how would α2 adrenoreceptor antagonists
work
Increase insulin secretion
how would GLP-1 (Glucagon like peptides) receptor agonists work
Increase insulin secretion from Beta cells
Pro-survival effect on Beta cells
Promote weight loss (loss of appetite)
Renoprotective
how would SGLT-2 inhibitors (Sodium-glucose co-transporter work
Increase excretion of glucose in urine
Lower blood glucose and blood pressure
Induce ketogenesis
name a strategy under research for treating type 2 diabetes
Alpha-cells reprogramming
what is Alpha-cells reprogramming and how is it achieved
Reprogramming alpha-cells in insulin producing cells
In mice MafA and Pdx1 overexpression experimentally showed to convert Alpha to Beta cells
how are the long term consequences of diabetes caused
extra glucose is oxidised into reactive oxygen species ROS
ROS damage blood vessels leading to Microvascular complications which lead to retinopathy, leading to macrovascular complications
nephropathy (increased levels of LDL cholesterol, blood pressure, and insulin resistance) also lead to macrovascular complications
how are AGEs linked to the long term consequences of diabetes
glucose binds to protein producing AGEs
AGEs bind to receptors on endothelial cells of blood vessels promoting ROS production
which increases inflammation and metabolic an structural defects
describe AGEs and collagen effects on blood vessels
AGE’s crosslink with collagen
The basal membrane of the endothelium thickens
The thickened endothelium traps LDL and IgGs
leads to Oxidation, complement activation and inflammation
resulting in Blood vessel damage
give 2 examples of molecules that can lead to insulin resistance
DAG
IL-1
