13 - Diabetes Mellitus Flashcards
Prevalence of T1D
10%
What is t1d
chronic autoimmune disease,
T-cell mediated disruption of pancreatic B cells within islets of Langerhans –> causes insulin deficiency
Evidence of immune mediated disease in T2D
Infiltration of pancreas islets by mononuclear cells (insulitis)
• T lymphocytes, monocytes etc.
90 percent with autoantibodies against islets
Immunosuppression –> delayed B cell disruption
t2d prevalence
85-90%
T2D genetics
gkrp
pparg
Risk factors t2d
Obesity
family history
ethnicity
age
Causes of abnormal insulin action (resistance)
Obesity
Hyperinsulinaemia
Adipokines
Lipoglucotoxicity
How can obesity cause t2d
Lipids, metabolites + FFA
= Chronic inflammation affecting adipocytes –> altered adipokine levels –> resistance –> hyperinsulinaemia
How does hyperinsulinaemia cause t2d
Obesity - cells dont respond to insulin
pancreas increases insulin levels –> increases lipid synthesis –> exacerbates
How does Adipokine alter pathway of insulin
Normally, insulin causes the phosphorylation of tyrosine via IRS which activates PI3K and Akt. In resistance, Threonine and serine phosphorylated instead. No activation of Akt so no downstream activation.
Why do fat pregnant ppls not have t2diabetes
Compensation of b cells
- increase in size and no
- increase in function
Why do beta cells decrease in t2d
Genetic factors make some b cells more susceptible to dysfunction
What is lipoglucotoxicity
Excess lipids/glucose in blood –> damage Beta cells –> even less insulin
Treatment for T2D
Biguanides - Metformin Sulfonylureas TZD DDP-4 inhibitors SGLT2 inhibitors
MoA of metformin
• Increases AMPK activation
1) improve insulin receptor function
2) improved glucose transport (GLUT 4)
3) reduce F.A synthesis
4) reduce hepatic gluconeogenesis via inhibiting cAMP activation
5) Increases GLP-1
MoA of sulfonylureas
Closes the K+ channel –> depolarisation –>increased Ca2+ –> insulin secretion.
MoA of thiazolidinediones
• Affects PPARG which is a transcription factor, so it activates genes that increase glucose uptake, decrease gluconeogenesis
DDP-4 inhibitors
sitagliptin- DDP4 breaks down GLP-1 normally and GLP-1 reduces glucagon secretion
SGLT2 inhibitors
target kidney reabsorption of glucose
What is MODY
maturity onset diabetes of the young
What is LADA
latent autoimmune diabetes in adults)
In between the two different types of diabetes m.
Autoantibodies present
Type 3c diabetes
Malfunction in pancreas due to other disease
Diagnostic plasma glucose
Random >11.1
Fasting >7
- Two fasting venous plasma glucose samples needed in asymptomatic
Symptoms of diabetes t2
1) thirst, 2) increased urination 3) weight loss 4) drowsiness 5) coma 6) recurrent infections
What is oral glucose test
patients drinks sugary drink then after two hours, their BGL (blood glucose level) measured
o >11 = diabetes
What does HbA1c measure
glycation of haemoglobin
=48 mmol/mol or 6.5 percent cut off point
What causes ketoacidosis
o Lack of insulin –> prolonged fasting state–> B-oxidation increases –> accumulation of ketone bodies –> dissociate into anions and H+ –> ketoacidosis (acetoacetate + B hydroxybutarate)
o Bicarbonate tries to buffer, blood and urine acidity rises –> death
What is hypoglycaemia
<3.9 mmol/L/ <70mg/dl
Causes of hypoglycaemia
1) excess alcohol (gluconeogenesis inhibited at low levels of lactate dehydrogenase/depletion of NAD+
2) Insulinoma
3) Excessive exercise
4) Reactive hypoglycaemia
5) T1D- insulin injection but missed meal
Symptoms of hypoglycaemia
Palpitations, trembling, anxiety, confusion, drowsiness, coma
Prolonged effect of hypoglycaemia
• Growth hormone and cortisol decrease glucose utilisation in favour of fat –> shortage of glucose for brain –> coma, seizures, loss of cognitive function.
Macrovascular complication of hyperglycaemia
Dyslipidaemia
Atherosclerosis
Microvascular complications of hyperglycaemia
Nephropathy (kidney)
Neuropathy
Retinopathy
What is nephropathy
o Damage to glomerular vessels critical for blood filtration
Glomerular hypertrophy, proteinuria, renal fibrosis
1/3 of diabetics get it, leading cause of renal failure
Cause of neurophathy
o Damage to blood vessels supplying the nerves –> pain, weakness or autonomic control changes.
Difference between proliferative and non proliferative retinopathy
Non-proliferative- dilation of retina veins, microaneurysms which cause internal haemorrhages and oedema in central retina
Proliferative- Fragile, new blood vessels form near the optic disk and grow on the vitreous chamber and elsewhere in the retina –> can bleed
How are bv damaged in diabetes
Excess glucose diverted to other pathways e.g. PKC–> DAG pathway which damage blood vessels by
increased permeability, increased occlusion, increased ROS, Increased inflammation, mitochondrial dysfunction
