BIOC Lecture 11: Diabetes Flashcards
When is the age of type 1 onset?
Usually during childhood or puberty
What is the age of type 2 onset?
Frequently after age 35
What is the nutritional status at time of type 1 onset?
Frequently undernorished
What is the nutritional status at time of type 2 onset?
Obesity usually present
What is the prevalence of type 1 diabetes vs type 2?
Type 1 = 10%
Type 2 = 90%
What is the genetic predisposition of type 1 vs type 2?
Type 1 = moderate
Type 2 = very strong
What is the defect that causes Type 1?
Beta cells are destroyed, eliminating production of insulin
What is the defect that causes type 2?
Insulin resistance combined with inability of beta cells to produce appropriate quantities of insulin
What is the frequency of ketosis in type 1 vs type 2?
Type 1 = common
Type 2 = rare
What is plasma insulin in type 1 vs type 2?
Type 1 = low to absent
Type 2 = high early in disease, low in disease of long duration
What is the acute complications of type 1 vs type 2?
Type 1 = ketoacidosis
Type 2 = hyperosmolar state
What is the response to oral hypoglycemic drugs in type 1 vs type 2?
Type 1 = unresponsive
Type 2 = responsive
What is the treatment for type 1 diabetes?
Insulin is always necessary
What is the treatment for type 2 diabetes?
Diet, exercise, oral hypoglycemic drugs, reduction of risk factors (smoking, blood pressure)
What is glycosuria?
high glucose levels in urine
What is osmotic diuresis?
water will move into areas of high glucose concentration which leads to dehydration
What fasting glucose indicates diabetes?
> 7.0mmol/L (fasting)
11.1mmol/L (fed)
What is HbA1c?
Glycated hemoglobin - measure of longer-term glucose status
What HbA1c indicates diabetes?
> 50mmol/mol
What are other symptoms of diabetes?
- Glycosuria, osmotic diuresis, dehydration
- Ketoacidosis
- Thirst, frequent urination, fatigue
What underlies developing type 2 diabetes?
- Certain sensitive genotype
- Metabolic stress
- Inflammation
Why is being overweight such a strong risk factor for type 2 diabetes?
Being overweight causes inflammation and high metabolic/oxidative stress
How does obesity lead to T2D?
- Insulin resistance causes…
- Glucose intolerance causes…
- Metabolic syndrome causes…
- Type 2 diabetes
What is metabolic syndrome?
a cluster of biochemical and physiological abnormalities associated with the development of cardiovascular disease and type 2 diabetes
What does prediabetic insulin resistance look like in the blood after feeding?
A lot more insulin than normal people to get the same level of control - over time, the insulin resistance gets worse to a point where you lose the glucose control
What do fasting glucose levels look like in diabetics?
Their fasting glucose levels are higher - levels never really get back down before the next meal whereas in normal people it spikes and then comes back down
What is insulin resistance?
Reduced response to the same amount of insulin
What happens to glucose, glycolysis and fatty acids from IR?
Glucose uptake, glycolysis and fatty acid uptake are decreased
What happens to gluconeogenesis, lipolysis, fatty acid oxidation and ketogenesis from IR?
They are increased
How is glucogenesis increased by IR?
- The liver is putting out lots of glucose
- Normally would be inhibited by insulin
- There is no response to insulin, the normally low levels of glucagon during the fed state are much higher
- Glucagon drives glucogenesis
How is lipolysis increased by IR?
- Insulin inhibits fat mobilization from adipocytes
- IR means TAG’s and fatty acids are mobilized by HSL
- HSL is usually inhibited by insulin
- You get mobilization of fats and a lot of fatty acids coming back to the liver
What does the influx of fatty acids back to the liver promote?
more fat being made and that ends up promoting VLDL production, this is part of the reason type 2 diabetics have high TAG levels
What is the insulin receptor?
Tyrosine kinase receptor
What needs to happen to the tyrosine kinase receptor for it to be activated?
there is tyrosine residues in its structure that need to be phosphorylated before it can be activated - once insulin binds it can promote auto phosphorylation
What happens to tyrosine kinase once it is activated?
IRS proteins are recruited to the receptor once its been phosphorylated
What do IRS proteins do?
recruit a whole lot of kinases which trigger downstream activation or inhibition of various proteins - Ultimately you end up in a response
What is happening in the signalling pathway during IR?
- Proteins are not being phosphorylated
- Proteins are mis-phosphorylated
What are the two theories of obesity causing oxidative stress?
- increased flux of glucose and lipid metabolism
- overstimulated NADH oxidases
Both cause increased oxidative molecules
What are examples of oxidative molecules?
- Superoxide O2
- Hydrogen peroxide H2O2
How do increased oxidative molecules impact the insulin signalling pathway?
- activate a lot of serine kinases
- kinases can mis-phosphorylate proteins in pathway
- can inactivate them and stop pathway from working
How does an increased flux of glucose and lipid metabolism cause increased oxidative molecules?
- obese people have increased flux of this metabolism
- this ramps up ETC
- high levels of superoxide and hydrogen peroxide are produced
How do overstimulated NADH oxidases cause increase oxidative molecules?
- NADH oxidases aim is to produce superoxide
- in diabetes they are overstimulated
- produce a lot of superoxide
Are all tissues equally effected by insulin resistance?
No, i.e. TAG synthesis in liver is still very active during IR
Diabetes can develop fatty…
Livers
What does fatty livers lead to?
Cirrhosis
What does endurance training do for glucose tolerance?
Enhances glucose tolerance
What is metformin?
The most common drug used for type 2 diabetes
What is metformin transported into the liver by?
Oct1
What is the main goal of metformin?
Indirectly activates AMPK and downregulates mGPD which leads to a reduction in glucose production
What is the role of AMP kinase?
Regulates a lot of metabolic pathways, alters activity of TF which reduce/alter genes in the gluconeogenic pathway
What does AMP kinase ultimately reduce?
Gluconeogenesis by downregulating mGPD and regulating cellular energy homeostasis
What is AMP kinase activated by?
high levels of AMP
How does metformin increase AMP levels to activate AMP kinase?
- Inhibits first complex in ETC
- Slows ETC and reduces ATP
- ATP to AMP ratio goes down because there is more AMP
Once AMPK levels are increased, what enzyme is downregulated?
mGPD
How does mGPD reduce gluconeogenesis?
- downregulating mGPD causes increased NADH levels
- increased NADH means more lactate is formed in the liver
- therefore pyruvate that was being used for glucose production, is now being used to produce lactate
