Week 3 type 2 diabetes Flashcards
What is diabetes?
A variable disorder of carbohydrate metabolism caused by a combination of hereditary and environmental factors
What are the key characteristics of diabetes?
Poorly controlled blood glucose
Defective insulin production and/or utilisation
Defective lipid metabolism
What is the difference between T1 and T11 diabetes?
1 usually occurs in earlier in life and pancreas doesn’t produce enough insulin
2 tends to happen later in life and is related to obesity / inflammation. Over time, poorly controlled glucose destroy beta cells in the pancreas so cant produce insulin anyways, this can lead to developing double diabetes.
What does diabetes look like?
Fasting plasma glucose higher in a diabetic because liver producing too much glucose because insulin resistance has developed.
More exaggerated response after meals because of impaired glucose tolerance
What is skeletal muscle responsible for after a meal?
clearing approx. 90% of circulatory glucose .
What is the aim of diabetic therapies?
to bring glucose levels down into a healthy range
What do microvascular diseased affect?
nerves / small vessels
What do macrovascular diseases affect?
affects whole systems
What is HbA1c?
Glycated haemoglobin - a clinical biomarker used to look at glucose control over a period of bout 3 months.
How does high levels of HbA1C indicate high glucose levels?
Very high levels of glucose lead to the glycation of haemoglobin
Carbohydrates then attach to Hb producing HbA1C
HbA1C not affected by nutritional intake so doctor can monitor over about a 12 week period.
What is an oral glucose tolerance test?
Used as part of diagnosis of diabetes
Drink sugary drink with 75mg glucose in, measurements then taken after two hours.
What did a study by Tancredi et al (2015) find about T11 diabetes and excess mortality?
15% higher risk of death in T11 patients than control
Each 1% increase in A1C leads to a 12% increase in mortality
What are some major complications of diabetes?
Diabetic retinopathy (leading cause of blindness)
Stroke (2-4x increased risk)
8/10pts with diabetes die of cardiovascular events
Diabetic neuropathy (affects 50% of T11 pts)
Diabetic nephropathy (leading cause of end-stage kidney disease).
According to the triumvirate what three factors lead to hyperglycaemia?
Beta cell dysfunction (impaired insulin secretion)
Insulin resistance - skeletal muscle (Decreased glucose uptake)
Insulin resistance - liver (increased HGP)
Obesity leads to chronic low grade inflammation, how does this lead to increased glucose levels?
Inflammatory proteins go through muscle tissues and block insulin signalling
This stops the muscle responding to insulin so cant take glucose out of the circulation.
What is the liver responsible for and how can insulin resistance in the liver contribute to hyperglycaemia?
Responsible for releasing glucose when fasted but when we eat glucose levels rise and should shut off this process.
If the liver is insulin resistant it doesn’t pick up this signal so constantly producing too much glucose.
What does lipotoxicity result from?
adipose tissues expand when obese which leads to having lots of free circulating fatty acids which leads to uncontrollable lipolisis.
What can lioptoxicity lead to?
ectopic fat deposited in the pancreas which is toxic to beta cells so beta cells ultimately stop producing insulin and die.
How can diabetes also be affected by genes?
Some individuals have genetic susceptibility, e.g. South Asian 4-5x more likely to develop diabetes than white Europeans.
The ominous octet - how can increased glucagon secretion contribute to hyperglycaemia?
Causes liver to throw out too much glucose
The ominous octet - how can neurotransmitter dysfunction contribute to hyperglycaemia?
Brain can become insulin resistant promoting increased food uptake leading to obesity
The ominous octet - how can the kidneys contribute to hyperglycaemia?
As glucose levels increase initially the kidney compensates by changing the threshold that glucose is excreted in the urine - holds onto more glucose.
The ominous octet - how can lipolosis contribute to hyperglycaemia?
Glycerol can go to the liver and undergo gluconeogenesis which produces glucose.
What are incretin effects?
Hormones that are secreted after we eat to help the pancreas produce insulin?
What do studies suggest about diabetes reversal?
Suggest T11 diabetes can be reversed within 4 years
Predominantly through a low calorie diet, can now be prescribed on NHS (milkshake drinks)
Although once its past 4 years, evidence suggests the beta cells of the pancreas are dead so then it cannot be reversed.
What does observational evidence suggest about PA and T11 diabetes?
Dose response - as weekly PA energy expenditure increases, risk of T11D decreases.
Cohort studies show a 20-30% reduction in risk for people who are regularly active.
What does lifestyle intervention evidence suggest about PA and T11D? Study by Knowler et al (2002) - USA
Intervention group - goals were at least 7% weight loss and at least 150 min/wk PA
Compared to control, people in intervention had 58% decrease in risk of getting T11D. This was superior to improvement induced by metformin medication.
What does exercise intervention evidence suggest about PA and T11D? Sigal et al (2007)
251 adults with T11D
6month training programme - 3x per week
Aerobic group - half a % decrease in HbA1C
Resistance group - still a reduction but not as much as in aerobic group
Combined group - biggest % reduction (almost out of high risk criteria)
Describe the process that happens when we eat (healthy person)
Insulin levels increase in blood
Bind to insulin receptors on muscle and stimulate phosphorylation events
This leads to the activation of proteins which cause GLUT4 to move from intracellular vesicles in the muscle to muscle membrane to allow facilitated diffusion down a concentration gradient into the muscle.
Diabetics are insulin resistant - this process does not happen / is less effective.
How can exercise stimulate the mechanisms by which glucose diffuses down a concentration gradient into the muscle, completely separate to insulin?
Increase in AMP which gets phosphorylated to ATP
When ratio of AMPK goes up (which is an energy crisis within the cell) this stimulates phosphorylation of AS160 which leads to GLUT4 translocation
When a muscle contracts there is an influx of calcium within the cell, that can also stimulate this
Stretch and mechanical response can also stimulate
What do guidelines for exercise and T11D say?
Not to have more than two days off between bouts of exercise because regardless of diabetic/non-diabetic, insulin sensitivity can be improved for two days after a single bout of exercise.
In an untrained individual during bout of exercise there is an increase in muscle glucose uptake, what is this due to?
Increased microvascular recruitment and blood flow
Increased Glut4 translocation
Increased glycolysis
Increased oxidative phosphorylation
What increases in an untrained individual post exercise, compared to at rest?
Microvascular recruitment in insulin resistance
GLUT4 translocation by insulin
Glycogen synthesis
What did Little et al (2011) state about mitochondrial capacity and T11D?
Low volume high intensity interval training reduces hyperglycaemia and increased muscle mitochondrial capacity in T11D patients
Outline some of the mechanisms by which exercise impacts T11D - chronic
Myokines
Fat partitioning
Hepatokines
Incretin response
Outline some of the mechanisms by which exercise impacts T11D - acute
Ectopic fat
Body composition
Low grade inflammation (adipokines)
B-cell function
Adipose tissue browning
Muscle capillarisation
role of glucagon?
break down glycogen in liver to provide fuel
what is the aim of diabetic therapies?
to reduce plasma glucose levels to normal range
what is lipolysis?
(the breakdown of triglyceride and adipose tissue into glycerol and FFA)
what can now be prescribed by NHS?
low calorie diet (800kcal)
what is the reduced risk of T2DM if we are regularly active?
20-30%
how does exercise enhance insulin sensitivity during exercise?
delivery of glucose and substrate improved because exercise creates dilation around muscle, aiding delivery of glucose, so less glucose in blood
increase in glut4 translocation to cell membrane to allow glucose in
when exercising, increase in glycolysis and phosphorylation stimulating glucose uptake
HITT training, what improvements can be seen?
improvement in glucose control after 6 weeks
25% reduction of glucose
after just 2 weeks, 3 fold increase in levels of glut4
improved mitochondrial function
What is diabetes usually characterised by?
an inadequate secretion or utilisation of insulin, excessive urine production, thirst, hunger, weight loss.
