Fuel Mobilisation - I Flashcards
Type I diabetes vs. Type II diabetes key features of that table
Type I:
- age of onset: usually during childhood or puberty, symptoms develop rapidly
- defect: beta cells are destroyed, eliminating production of insulin
- frequency of ketosis: common because they produce a lot of ketones, which are acidic so it you don’t. use them up your blood pH will drop (ketoacidosis)
- plasma insulin: low to absent
- treatment: insulin is always necessary
Type II:
- age of onset: frequently after 35; symptoms develop gradually
- defect: insuoin resistance combined with inability of beta cells to produce appropriate quantities of insulin
- frequency of ketosis: rare
- plasma insulin: high early in disease; low in disease of ling duration
- treatment: diet, excersise, oral hypoglycaemic drugs, insulin may or may not be necessary. reduction of risk factors (smoking cessation, BP control, treatment of dyslipidemia) is essential to therapy.
what are the biochemical features and symptoms of diabetes
- fasting glucose >7 mmol/L or random >11.1 mmol/L
- HbA1>50mmol/mol (6.7%) is the main diagnostic criteria (looking at glycated haemoglobin)
- glycosuria, osmotic diuresis and dehydration
- ketoacidosis (ketonemia and ketonuria). more common in type I
- symptoms include thirst, frequent urination, fatigue, hyperventilation (lots of CO2 to try and remove acid), blurred vision and coma
- associated with a number of complications ie. vascular disease
- associated with elevated blood ATG levels
describe glycated haemoglobin (HbA1c) ad how that can be used as an indicator for diabetes
When glucose builds up in your blood, it binds to the haemoglobin in RBCs. The HbA1c test measures how much glucose is bound.
As RBCs live fore about three months, the test shows the average level of blood glucose for the past three months
- so if you have poorly controlled diabetes, it shows this
HbA1c >50mmol/mol (6.7%) is indicative of diabetes.
describe the other proteins that can be glycated due to high blood glucose due to diabetes
Vascular pathologies can result from glycation of structural proteins in arteries, making them less compliant, and from he formation of advanced glycation end (AGE) products, which promote inflammation and atherosclerosis (which ultimately leads to heart disease).
- Macrovascular complications: arteries - CVD, cerebrovascular diseases, peripheral artery diseases
- Microvascular complications: arterioles and capillaries - retinopathy, nephropathy, neuropathy
describe the different levels seen in a glucose tolerant test
A glucose tolerance test sees how well the body handle glucose. An oral glucose load is given after an overnight fast and blood glucose levels are then monitored for 2 hours.
- Diabetic: diabetics have an elevated fating blood glucose >7mmol/L and a very impaired lowering ie. not returning to pre-load value
- Pre-diabetic: a pre diabetic will show slightly elevated fasting level (5.6 to 7) and an impaired lowering
- Athlete: much more sensitive to insulin so can control blood glucose very well with little insulin
- Control: fasting level at around 3.5 mmol/L, glucose spikes and then returns to pre-load level after the two hours
describe insulin resistance and how it is used to see that someone will become diabetic even before they are pre-diabetic
- early warning sign that an individual is heading towards diabetes
- over time the hyperinsulinaemia diminishes the ability of beta cells to respond to further increases in blood glucose and the individual becomes glucose intolerant (pre diabetic) and eventually diabetic
- can be picked up by looking at the insulin levels because they will be much higher than normal to return the blood glucose to normal levels (they become insulin resistant because they need much more insulin to get the same response)
describe the factors underlying type 2 diabetes development
- proven then there is a genetic basis to type II diabetes, which predisposes you to developing diabetes in the first place
- obesity also plays a role, as it increases inflammation and metabolic stress which lead to insulin resistance, glucose intolerance, metabolic syndrome and then type 2 diabetes mellitus
describe the metabolic disregulation that occurs in type two diabetes
- it appears that insulin isn’t working and glucagon effects are prominent ie. gluconeogenesis, lipolysis and ketone production
- leads to high blood glucose levels because can’t take in glucose but also making lots of new glucose
- get a breakdown and mobilisation of TAGs, so FFAs are released to the liver to make more glucose and VLDLs and glycerol is also released to the liver to make more glucose
- get a buildup of VLDL and chylomicrons because there are lots of FFAs coming from the adipose and some will be excreted as VLDLs
see this same response during starvation
why do we get a buildup of VLDL, chylomicrons and therefore an increase in blood TAGs during diabetes II?
- insulin activates LPL which hydrolyses TAGs to release FFAs into tissues where they are resynthesises into TAGs
- IR reduces the hydrolysis of TAGs in chylomicrons and VLDL by LPL. This leads to their accumulation and increase in blood TAGs.
describe insulin resistance
- reduced response to the same amount of insulin
- processes normally stimulated by insulin aren’t. ie. glucose uptake, glycolysis, glycogenesis, lipogenesis (Note: lipogenesis still occurs in the liver)
- processes normalising inhibited by insulin aren’t ie. gloconeogeneiss, lipolysis, fatty acid oxidation, ketogenesis (ketosis can occur is diabetes is poorly controlled)
- decreased glucose uptake and increased gluconeogeneiss are prominent features as is elevated blood FFAs
- the hyperglycaemia induced by IR causes the pancreas to produce more insulin but eventually the beta cells response diminishes, and insulin levels drop (some type 2 diabetic can require insulin)
NOT ALL TISSUES ARE EQUAL IN THEIR INSULIN RESISTANCE.
- adipose and muscle are quite affected
- liver not so much
diabetic can develop fatty liver, which can lead to…??
cirrhosis: a chronic disease of the liver marked by degeneration of cells, inflammation, and fibrous thickening of tissue
what is happening in the cells that causes insulin resistance?
There is evidence of reduced levels of phosphorylation and mis-phosphorylations (ie. pSerine instead of pTyrosine) in insulin signalling proteins which reduced GLUT4 translocation likely promoted by FFAs, inflammatory cytokines and oxidative stress.
- so basically signal transduction not happening properly when insulin binds to its RTK
describe the treatments available for type 2 diabetes
- treatments are mainly aimed at promoting insulin secretion and improving insulin sensitivity
- lifestyle changes ie. dietary intervention (low carb diets) and physical excerise, which increases insulin sensitivity, can be very effective:
- first call
- changes in diet: keto or mediterranean (complex carbs rather than simple sugars) - drugs ie. metformin, sulfonylureas, GLP-1 agonists, SGLT2 inhibitors, insulin (later stage)
how does excerise enhance insulin sensitivity?
- athletes (endurance) need much less insulin to be secreted for a good response
- mechanism is the same as what metformin does
Both metformin and excersise increase AMP levels, which activates AMPK (AMP kinase), which reduces gluconeogenesis. This reduces blood glucose levels.
- metformin increases AMP levels by inhibiting ETC complex I so ATP can’t be made
- excersise increases AMP levels because using lots of ATP
how does GLP-1 (and sulfonureas) potentiate insulin secretion in beta cells?
- peptide hormone synthesised in intestine
- synthesised in response to nutrients ie. amino acids
- made from glucagon via converterse enzyme
- acts through its receptor to stimulate insulin secretion
- GLP-1 agonists developed to treat type 2 diabetes
Note: sulfonureas block the K+ channel to also promote insulin secretion
