Summary of all lecture notes for exam revision. With these notes, I achieved a 1st last year. ONLY 1/4 OF THE WHOLE DRUGS AND DISEASE MODULE. ALSO PURCHASE THE OTHER 3 LECTURE NOTES FOR COMPREHENSIVE NOTES OF THE DRUGS AND DISEASE MODULE.
(Trying to provide drugs that fit in with natural rhythms of body cycles – use agonists – replace failing
signals for example – exploitation of negative feedback processes)
Diabetes
• Diabetes insipidus – defective antidiuretic hormone signaling, causing the production of large
volumes of very dilute urine and a need to greatly increase fluid intake to compensate
• Diabetes mellitus - a group of metabolic diseases characterized by hyperglycaemia resulting
from defects in insulin secretion, insulin action or both.
(“mellitus” comes from Latin (honey-flavoured) - first used in 1675 by Charles Willis -
Increased volumes of sweet urine – tendency to attract insects)
Type 1 diabetes mellitus (T1DM)
~8% of cases
Associated with autoimmune damage to the pancreas and the loss of insulin-
producing cells, so reduced blood [insulin]
Body's immune system attacks the pancreatic beta cells that produce insulin
“Insulin-dependent diabetes mellitus”
Type 2 diabetes mellitus (T2DM)
~90% of cases
Associated with insulin resistance, with elevated blood [insulin] but reduced
tissue responses
Genetic predisposition (higher in certain ethnic groups) with interaction with
environmental factors (lifestyle, in utero conditions)
“Non-insulin-dependent diabetes mellitus”
A new patient is diagnosed with T2DM every 2 minutes
NHS spending on diabetes >£10 billion, ~10% of the entire budget
Risks and consequences of diabetes:
Not because of hyperglycaemia but due to its metabolic consequences…
- Stroke
- 2- to 4-fold increase in cardiovascular mortality and stroke
- Cardiovascular Disease
- 80% of diabetic patients die from CV events
- Diabetic Neuropathy
, - Leading cause of non-traumatic lower extremity amputations. “Diabetic foot” related to
sensory neuropathy (loss of sensation) so injuries not detected and poor wound healing due
to damaged vasculature
- Diabetic Nephropathy
- Leading cause of end-stage renal disease due to loss of protein (albumin) in urine linked to
peripheral oedema; eventual loss of filtration function of kidney
- Diabetic Retinopathy
- Leading cause of blindness in working-age adults linked to damage to small blood vessels in
the retina
- Diabetes risk factor for death/long hospitalisation for Covid-19 due to poor glycaemic control
- Many of the detrimental effects of diabetes are linked to vascular pathology, particularly
atherosclerosis formation leading to atherosclerotic diseases, particularly coronary heart
disease and stroke
- Chemical modification of proteins by glucose / increased oxidative stress leads to cellular
dysfunction
- Diabetes linked to elevated LDL cholesterol, elevated triglycerides and hypertension, all risk
factors for atheroma formation
- Diabetes predisposes atherosclerosis development as high levels of glucose in blood
damages surface proteins on endothelial cells, proteins are glycated, endothelial dysfunction
causes development of atherosclerosis
Diagnosis of diabetes:
- Symptoms include increased drinking (polydipsia) and increased frequency of urination
(polyuria)
- Type 1 DM associated with weight loss (despite increased eating) and fatigue
- Type 2 DM associated with weight gain and sensory abnormalities (e.g. numbness,
tingling pain)
- Test for glycated haemoglobin (HbA1c) above 48mmol / mol (glucose stuck to
haemoglobin)
- Red blood cells last for ~120 days, so avoids fluctuations of blood [glucose]
Physiology of insulin: mechanism of release:
- Uptake of glucose in the pancreatic beta cells by glucose transporter GLUT2 in response to an
increase in blood glucose.
- Glucokinase enzyme has a high affinity for glucose and is only active when glucose levels are
high converting glucose to glucose-6-phosphate
- When glucose enters the beta cells via GLUT2, it is metabolized through the process of
glycolysis generating ATP.
- The increase in ATP levels leads to the closure/inhibition of ATP-sensitive potassium (KATP)
channels, which allows depolarization of the beta cell membrane.
- Depolarization of the beta cell membrane leads to the opening of voltage-gated calcium
channels inducing calcium entry into the beta cell.
, - The increase in intracellular calcium levels triggers the fusion of insulin-containing vesicles
with the cell membrane, which releases insulin into the bloodstream.
- Goes onto lower the heightened blood-glucose levels.
Furthermore..
- When GIP binds to GIP-R receptor on the surface of beta cells, it activates Gαs, a G protein
that stimulates the production of cyclic AMP (cAMP)
- Increase cAMP acts to enhance the calcium current in the VDCC allowing for greater calcium
entry and thus exocytosis of insulin
- Oral glucose administration causes more insulin release than equivalent i.v. administration
suggesting G.I. factors also regulate (enhances) insulin release – incretins
- Glucagon-like peptide (GLP1), produced from intestinal L cells; acts on GLP1 receptor on
pancreatic cells stimulating release of insulin
- Gastric inhibitory peptide (GIP), from intestinal K cells; acts on GIP receptor on pancreatic
cells stimulating release of insulin
GLUT-2: Low affinity; high capacity; constitutively present at membrane
GLUT-4 (also some GLUT-1): High affinity; low capacity; requires insulin presence –
particularly in liver, skeletal muscle, adipose tissue (expressed in key tissues for insulin
effects)
Insulin:
- Insulin promotes glucose uptake and storage
- Stimulates the uptake of glucose by muscle and adipose tissue, and also stimulates the liver
to store glucose as glycogen
- To lower blood glucose levels and ensures that glucose is available for use as energy by the
body.
- Inhibits gluconeogenesis – making glucose from amino acids
- Increases lipogeneses – building triglycerides using glucose
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