Type __ =
Requires insulin injections from diagnosis.
Autoimmune destruction of pancreatic B-cells.
Type __ =
Non-insulin dependent (retain some insulin secretion).
Both decreased insulin secretion and insulin resistance.
Diagnosed > 35yrs (now in teenagers).
Define a complex trait.
A combination of genetic and environmental factors are involved in the aetiology.
Insulin is secreted from beta-cells of the ____1____. A beta-cell is a sophisticated cell because it can sense changes in glucose levels in the blood and secrete insulin in suitable accordance.
The enzyme that allows it to do this is ____2____.
As the glucose enters the cell it is phosphorylated by ____2____ before being metabolised by the mitochondria to raise the ATP levels. The rise in ATP levels closes the kATP (potassium) channel causing the depolarisation of the beta cell wall. This leads to a ____3____ influx into the cell that causes insulin secretion.
The brain cannot metabolise ____1____. It only usually metabolises glucose.
Therefore in preparation for sleep our bodies must ensure there is sufficient glucose for the brain to use. Overnight, the main source of this glucose is the ____2____.
As we awake and consume food (and therefore glucose), we want the glucose supplementation from the ____2____ to cease. Insulin causes this.
Insulin has 2 actions:
1. Switches off the release of glucose from the ____2____
2. Promotes the glucose uptake in ____3____ and ____1____ cells.
However, in insulin resistance:
The insulin doesn’t work so well at the ____2____ (therefore the glucose keeps being released) and there are problems with the ability to store the glucose in the ____3____ and ____1____. The net result of this is the rise of the blood glucose levels.
Define insulin resistance.
The decreased action of insulin at its target tissues.
Insulin resistance does not cause diabetes.
In non-diabetic subjects, as insulin resistance rises so too does insulin ____1____.
This ensures our blood glucose levels remain stable.
Type 2 diabetics can still secrete insulin but cannot secrete enough to restore the ____2____.
How obesity leads to increased insulin resistance
Adults cannot grow more fat cells. Instead as we become obese our fat cells ____1____.
The problem with this is that the adipocytes (fat cells) can only take so much before ____2____ occurs and they become stressed. This triggers ____3____ (adipocytes release inflammatory mediators etc.) causing inflammatory cells to move in and cause further ____3____ and so on (CYCLE).
The adipocytes then start to release less of the hormone adiponectin and the levels of circulating fatty acids ____4____.
The combination of these 3 contribute to the insulin resistance state.
Insulin signalling pathway
In a non-insulin resistant person - Insulin attaches to its receptor → signals to IRS-1 → signals to PI-3K → signals to PKB → ____1____ glucose uptake and glycogen synthesis (GOOD)
In insulin resistance however this pathway is impaired. ____2____ occurs and causes TNF-alpha levels to rise. TNF-alpha then blocks IRS-1 signalling.
This causes a reduction in the ability to uptake glucose etc.
5' AMP-activated protein kinase (AMPK) is the cells energy sensor.
If the energy levels in the muscles fall, then AMPK becomes activated and promotes ____1____ of glucose and oxidation of lipids (burn more fat).
One of the reasons exercise is good for you is because contraction of the muscles stimulates AMPK to do this.
Metformin has beneficial effects due to it stimulating AMPK.
Adiponectin has the same effect on muscle cells and the ____2____ caused by obesity reduces the amount released by adipocytes, therefore obese people have less of these good effects.
Fat is a very good energy source.
Obese subjects have ____1____ fatty acid levels.
Fatty acids are usually oxidised but if they cannot be oxidised the fat can either be ____2____ or broken down into intermediates (ceramide and DAG).
These can contribute to insulin resistance.
DAG does this by stimulating ____3____ within the tissues.
Ceramide blocks part of the insulin signalling pathway, ____4____.
So it isn’t that fats are bad for you, it is just bad when you cannot metabolise them or store them efficiently.
Ectopic Fat distribution
Limited capacity to store fatty acids in subcutaneous ____1____ leads to storage in ectopic sites. These include:
- Visceral fat stores
- Skeletal Muscle
- Around the heart
Failure to fully metabolize these ectopic fats leads to the build up of lipid intermediates (DAG, ceramides) which contribute to insulin ____2____ and toxicity.
Type 2 diabetes treatment
Initial management focuses on improving insulin resistance by ____1____ change (diet and exercise) and metformin.
As diseases progresses through beta-cell failure, add other agents to increase insulin ____2____ (sulphonylureas, GLP-1 analogues).
Add insulin once beta-cells fail.
How does sulphonylurea work?
By closing the K channels (by binding channel protein).
Type 2 diabetes complications
Small vessel complications
Retinopathy (____1____ disease)
Neuropathy (____2____ damage)
Nephropathy (____3____ damage)
Large vessel complications
2-3 fold increased risk of ischaemic ____4____ disease
2 fold increased risk of ____5____
3-4 fold increased risk of peripheral vascular disease
What percentage of the NHS budget goes towards treating Diabetes Type 2?
Type 2 diabetes is common and is increasing in prevalence (_1_% UK population; _2_% in those over 70yrs)
Through which receptor does glucose enter a beta-cell?
Biological candidate gene for Type 2 Diabetes
- Encodes a protein that is part of the __1__ channel
- Studies have shown that the E23K variant ___2___ the risk of Type 2 diabetes (Odds Ratio = 1.2)
- But, this E23K variant is present in 40% of the general population
The ______ of genotyping made GWAS studies possible.
Carrying the FTO SNP risk variant predisposes to the storage of ______, it alters metabolism.
In an abnormal place or position.
The higher your insulin ______, the lower the insulin resistance.
And vice versa.
Describe the ectopic fat paradox.
Type 2 diabetics have the most fat in their muscles.
This occurs because other subjects (athletic subjects in particular) possess mitochondria that are primed to oxidise fat and do so, whilst the diabetics may take longer to store fat because they are unable to utilize it efficiently. Therefore the fat builds up within the muscles.
State the 2 principles of treatment of Type 2 diabetes.
- Increase insulin secretion
- Improve insulin resistance
How does Metformin function?
It works by decreasing glucose production by the liver and increasing glucose use by body tissues.
Thiazolidinediones act by activating PPARs (peroxisome proliferator-activated receptors), a group of ____1____ receptors. The endogenous ligands for these receptors are free fatty acids and eicosanoids. When activated, the receptor binds to DNA in complex with the retinoid X receptor (another nuclear receptor), increasing transcription of a number of specific genes and decreasing transcription of others.
The main effect of expression and repression of specific genes is an increase in the ____2____ of fatty acids in adipocytes, thereby decreasing the amount of fatty acids present in circulation. As a result, cells become more dependent on the oxidation of ____3____, more specifically glucose, in order to yield energy for other cellular processes.
Why does the release of calcium ions with the beta-cell cause insulin secretion.
The insulin is stored in secretory vesicles which are sensitive to calcium. The vesicles secrete their contents in response to significant calcium influx.
How do GLP-1 analogues work?
They work by copying, or mimicking, the functions of the natural incretin hormones in your body that help lower post-meal blood sugar levels.
What are incretins?
How do they function?
Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels.
Incretins do so by causing an increase in the amount of insulin released from pancreatic beta cells of the islets of Langerhans after eating, before blood glucose levels become elevated.
Diabetic eyes can develop white material called exudates (where the fat has leaked out of the ____1____). This causes ____2____ and damage to the tissues around it. This leads to haemorrhages where the ____1____ have bled out into the eye.
These problems come and go but if they occur in a seeing part of the eye or you have a massive haemorrhage then it affects your vision.
Define an odoema.
A condition characterized by an excess of watery fluid collecting in the cavities or tissues of the body.
Compared with the non-diabetic population, type 2 diabetes leads to:
- 2-3 fold increased risk of ____1____ heart disease
- 2 fold increased risk of stroke
- 3-4 fold increased risk of peripheral ____2____ disease
Ischemia is a restriction in blood supply to tissues, causing a shortage of oxygen and glucose needed for cellular metabolism (to keep tissue alive).