Endocrine pancreas and the development of diabetes Flashcards
How is Blood Glucose controlled?
Control of Blood Glucose;
- Normally blood glucose is maintained between 4-6mM
- If low blood glucose, glucagon is released from A cells t stimulate glycogenolysis and gluconeogenesis in liver
- If high blood glucose, insulin is released from B cells to stimulate muscle and adipose cells to increase glucose uptake, by increasing GLUT4 in the cell membrane
- The liver helps control blood glucose levels through gluconeogenesis and glycogen synthesis
- Diabetes occurs when regulation of blood glucose is disrupted
What are the features of Diabetes Mellitus?
Diabetes Mellitus;
- 4.9 million in UK have Diabetes Mellitus (7% population)
- Results from insulin deficiency (5-10%) and/or reduced insulin insensitivity (approx 90%)
- 10% type 1 (insulin dependent)
- 85% -90% type 2 (insulin independent)
- 5% of pregnant women have gestational diabetes (Higher other areas world)
- Disrupted glucose metabolism leads to hyperglycaemia (blood glucose >11mM)
Type 1 - deficiency in insulin
Type 2 - insulin independent, tissues become insensitive to it and pancreas cannot overcome this resistance
How does Diabetes Mellitus cause a Sweet Siphon ?
As produces sweet urine
Once enter bowman’s capsule, have a bunch of transporters in proximal tubules which puts 90% glucose back into blood by SGLT2, distal tubule does 10%?
Glucose brings water with it so if isn’t getting reabsorbed is being taken out in urine drawing water with them making them susceptible to dehydration
What are the features of Type 1 Diabetes ?
- T1DM - genetic predisposition and exposure to enviro trigger needed - e.g Viral infection (coxsackie, etc)
- Pancreatic beta-cell destruction (Autoimmune reaction), leading to absolute insulin deficiency
- 2/3 0f patients present with life threatening Diabetic Ketoacidosis at diagnosis (DKA)
Characterised by rapid onset of osmotic symptoms including;
- Polyuria
- Polydipsia
- Polyphagia (3P’s)
- Weight loss
- Fatigue
- Hyperglycaemia
- Blurred vision and lens of eye swells
Note: - thirst due to angiotensin 2 which is a potent dipsogen (makes thirsty) and targets thirst centres to increase thirst, good as important in diabetic as they loose a lot of water in urine so are topping it up
What are the steps causing Diabetic Ketoacidosis ?
Uncontrolled Diabetes Mellitus gives off low insulin signalling, which increases Lipolysis and decreases Re-esterification of fatty acids in the liver.
Triglycerides are converted to excess Acetyl-CoA (via hydrolysis) which increases plasma frequency fatty acids in mitochondria which produces extreme amounts of acetyl co-a but not all can be used in the TCA cycle or cellular respiration, so excess will form acetic acid / ketone body which can be used by peipheral cells for energy in absence glucose but if not used they are converted into the last 3 ketones in diagram (Acetone, Acetoacetic acid and B-hydroxybutaric acid) and lowers blood pH causing metabolic acidosis which is life threatening
Get sweet breath in these patients
What changes does type 1 diabetes have on the pancreas?
Pancreas not producing insulin, muscle and fat not effectively stimulated to make glucose
GLUT 4 bring glucose into cell / adipose + skeletal muscle
In type 1 cannot activate insulin receptor cant get transporter to embed in in transporter
What are the features of Type 2 diabetes ?
- T2DM - genetic predisposition and progressive loss of insulin sensitivity and defective insulin receptor signalling
- Often due to impaired insulin receptor signalling leading to insufficient transport of glucose into tissues (Is environmental factor triggering?)
- Often associated with metabolic syndrome which starts with energy imbalance, high food consumption along with low energy expenditure
- Fatty deposits in visceral organs leads to altered insulin signalling, insulin resistance and beta cell damage (tissue insensitivity)
- T2DM progresses when approx 80-90% of beta cels fail
- Less insulin receptors so transporter cannot take up glucose from extracellular space
What happens in the run up to developing Type 2 Diabetes?
- There is a natural progression from prediabetes to T2DM
- Individuals with predicates have a lower insulin sensitivity that results in hyperinsulinemia
- Diabetes progresses when the beta-cells are exhausted and failing, resulting in low insulin secretion with low insulin sensitivity
- > 7 mM Fasting plasma glucose = Diabetes
What are the features and uses of the Oral Glucose Tolerance Test (OGTT) ?
Oral Glucose Tolerance Test (OGTT)
- Used to measure diabetes and prediabetes
- Give someone 75g oral glucose sugary drink and take blood glucose over 2 hours to see if can get back down to baseline, if not have insulin insensitivity or diabetes
- > 7.8 mM OGTT after 2 hours = Pre-Diabetes
(Impaired glucose tolerance) - > 11.1 mM OGTT after 2 hours = Diabetes
(Combined glucose intolerance - both impaired glucose tolerance and impaired fasting tolerance) - > 6mM at Start = Impaired fasting glucose - Individual glucose levels are higher than normal before starting test but drops back down at end of test
What happens in Gestational Diabetes Mellitus (GDM)?
Gestational Diabetes Mellitus (GDM) - Dysregulated glucose regulation during pregnancy;
- In healthy pregnancy, over the course of gestation, insulin sensitivity shifts depending on the requirements of pregnancy
- Beginning near the 2nd trimester (Week 13 - 26), local, foetal and placental hormones including E2, P4, Cortisol, placental lactose and placental GH together promote a state of insulin resistance
(Eat 2 Party 4 Christian Loser GrowtH) - This raises blood glucose ensuring glucose is readily transported across placenta to fuel the growth of the foetus
- Normally women compensate for these changes though hypertrophy and hyperplasia of pancreatic Beta cells and glucose stimulation insulin secretion
- Normally, maternal insulin sensitivity returns to pre-pregnancy levels within a few days of delivery
- GDM results when these normal pregnancy adaptations do not take place on a background of chronic insulin resistance
What are the features of Gestational Diabetes Mellitus (GDM)?
- GDM is a serious pregnancy complication, in which women not previously diagnosed with diabetes develop hyperglycaemia
- GDM affects 16.5% of pregnancies worldwide/5% in UK and is increasing due to the obesity epidemic
- Risks of GDM to foetus include increased risk of miscarriage, maternal CVD (cardio vascular disease), pre-eclampsia (pregnancy issue with high BP) and T2D
- Risks of GDM to foetus include increased risk of macrosomia, perinatal mortality and birth complications as child is usually heavier than normal (+4.5kg)
What are the GDM risk factors ?
GDM risk factors include;
- Chinese, Black African or African Caribbean origins
- A prior pregnancy in which the baby weighted more than 4.5kg or having a BMI over 30
What are the features of Glucose Monitoring ?
Glucose Monitoring;
- Effective diabetes management is usually measured by self monitoring of blood glucose (SMBG) - sampling capillary blood after a finger prick
- NICE recommends for adults with T1DM to SMBG at least four times a day (before each meal and at bed time) - fasting glucose levels above 7mM indicative of diabetes, or random glucose measurement above 11.1mM
- New continuous glucose monitoring systems have reached the market, that measure intestinal glucose every few minutes (recommends for T1 diabetes who experience frequent severe hypoglycaemia (high price tho - e.g Freestyle Libre)
- We can use HbA1c as a measurement to diagnose diabetes and evaluate glucose levels over a longer-time frame (120 days)
What does the HbA1c test show?
HbA1c test;
- Each RBC circulates for approx 120 days (Tells how someone’s levels have been past 120 days)
- Glucose naturally binds to haemoglobin, which creates glycated haemoglobin called HbA1c
- HbA1c provides an integrated measure of control over the lifespan of RBC’s over longer time
- HbA1c 6.0-6.4% = Prediabetes
- HbA1c >6.5% = Diabetes
What are the WHO guidelines for Diagnosing Diabetes ?
Diagnosing Diabetes;
1). Diabetes symptoms (e.g polyuria, polydipsia, etc) plus:
- A random venous plasma glucose concentration > 11.1mmol/l
OR
- A fasting plasma glucose concentration > 7mmol/l
OR
- 2 hour plasma glucose concentration > 11.1mmol/l 2 hours after 75g glucose in an oral glucose tolerance test (OGTT)
2). With no symptoms diagnosis should not be based on a single glucose determination but requires confirmation. If fasting random values are not diagnostic the the 2 hour value should be used
3). HbA1c > 6.5% (48mmol/mol) indicated diabetes
What are the acute effects of uncontrolled Diabetes Type 1 ?
Overall issue is having an insulin-signalling deficiency!
Insulin-signalling deficiency;
- A decrease in Glucose uptake by cells results in an intracellular glucose deficiency sensed by appetite centres in brain promoting Polyphagia
- The decrease in Glucose uptake by cells results in Hyperglycaemia which increases Hepatic glucose output
- Hyperglycaemia results in Glucosuria (as above renal threshold), which leads to osmotic diuresis which causes Polydipsia (thirst) and also Polyuria which leads to dehydration and cell shrinkage
Fats;
- Get a decrease in Triglyceride synthesis and an increase in Lipolysis (due to lack insulin) which both increases the bloods free fatty acids which can be used as an Alternative energy source. Acetyl CoA that isn’t used as energy then becomes ketone body which can be used by peripheral cells for energy in absence glucose but if not used they are converted into the last 3 ketones (Acetone, Acetoacetic acid and B-hydroxybutaric acid) which causes Ketosis and some are acidic, lowering blood pH causing metabolic acidosis which is life threatening, leading to increased ventilation
Proteins;
- Decreases uptake of amino acids by cells which leads to increased protein degradation, liberating and increasing amino acids in blood, which will be used and increase Gluneogenesis (to generate glucose) which can increase hepatic glucose output and cause Hyperglycaemia
- Increased protein degradation will also cause muscle wasting and weight loss
Close to Death;
- Dehydration and cell shrinkage lowers blood volume (body will try to release ADH and angiotensin 2 to retain water but can only do so much), so extreme blood volume loss will cause Peripheral circulatory failure and then renal failure. Low blood volume also causes low cerebral blood flow causing nervous system malfunction. Peripheral circulatory failure, Renal failure and Nervous system malfunction can all cause death.
- Increased ventilation, trying to remove excess acid by expiring CO2, eventually deplete bicarbonate buffer reserves and can put a patient into a diabetic coma and potentially cause death
What are the Long Term pathologies of Diabetes ?
- Increased Fat mobilisation causes increased plasma FFA/TG/Cholesterol
- Hyperglycaemia causes an Increase in glycation and glycoxidaiton of proteins, lipo-proteins (especially LDL)
- These both cause a modification of extracellular structural proteins in arteries and arterioles (deposition of fats in arterial walls) which will lead to Damage/loss of vascular endothelium (loss of nitric oxide release)
- Macrophages will come along and engulf abnormal fats and proteins but embed between endothelium and smooth muscles, become foam cells, in arterial walls, damages endothelium, loose nitric oxide (normally causes walls to relax), recruits fibroblasts loose elasticity, makes atherosclerosis
- This causes a loss of arterial compliance which will lead to Diabetic atherosclerosis and Hypertension ventilation which both cause Cardiovascular disease
- Cardiovascular disease can lead to longterm conditions like Angina, Cardiac arrhythmias and Renal disease
