Lecture 6 Flashcards
1
Q
Give some examples of types of diabetes caused by defects in glucose homeostasis
A
- Type 1 diabetes (T1DM) - Type 2 diabetes (T2DM) - Type 3c (pancreatic damage) - MODY (Maturity Onset Diabetes of the Young) - Gestational Diabetes - T2DMY (youth-onset) - Others
2
Q
What metabolic changes cause ketoacidosis?
A
- Person is insulin deficient so are in a fasting state - Increase in counter-regulatory hormones (e.g epinephrine, glucagon) - This causes lipolysis - These cause the production of ketone bodies which causes ketoacidosis
3
Q
What metabolic changes cause dehydration?
A
- Person is insulin deficient so are in a fasting state - Hyperglycaemia: - Have increased protein catabolism - Have increased gluconeogenesis - Have reduced glucose uptake - Have increased hepatic glucose output - Hyperglycaemia causes osmotic diuresis and solute/electrolyte loss - Causes dehydration
4
Q
What are the consequences of diabetes?
A
- Associated with serious complications, e.g stroke, amputation, angina etc - Shortens lifespan - Contributes to age-related morbidity - Accelerates ageing
5
Q
How is diabetes diagnosed?
A
- Fasting blood glucose (FBG) - Also called the oral glucose tolerance test (OGTT)
6
Q
How is the OGTT carried out?
A
- Need people to fast for 12 hours before test to reduce blood glucose levels - Given glucose bolus (75g sugary drink) - Blood samples are taken at timed intervals and can test what happens to the glucose
7
Q
Is the OGTT still used?
A
- Yes but being phased out as it is unpleasant
8
Q
What are the typical results of the OGTT in a diabetic person?
A
- For someone with diabetes, their fasting blood glucose is already quite high (at top end of normal range) - In normal, impaired and diabetic patients, blood glucose levels rise in the first 30 minutes - In normal, levels now start falling and after 2 hours, back to almost where they start - In impaired, levels fall gradually but not back to the starting level - In diabetes, levels keep rising and stay very high –> takes a long time to come back down to normal
9
Q
Which external factors can influence the oral glucose tolerance test (OGTT) result?
A
- High carbohydrate intake in the days prior to the test - Duration of fasting prior to the test (~12 hours) - Smoking (lowers blood glucose reading at 2 hours) - Consumption of caffeine (negatively affects insulin sensitivity) - Exercise
10
Q
How might you predict a normal OGTT result to look if the person didn’t fast beforehand?
A
- Starting blood glucose would be higher - Rise in level may not be as sharp - Would still expect the glucose readings to come back down to normal
11
Q
What is the HbA1c test?
A
- Based on premise that glucose in blood binds irreversibly to haemoglobin in erythrocytes - Forms glycated haemoglobin (HbA1c) - Higher levels of glucose in blood = higher amount of HbA1c - HbA1c reflects the prevailing blood glucose over the preceding 2-3 months as RBCs live ~3 months
12
Q
How is the HbA1c test used to diagnose diabetes? Compare the HbA1c blood concentrations of normal, impaired and diabetic patients
A
- Normal have a conc of <42mmol/mol - Impaired have a conc of 42-47mmol/mol - Diabetes have a conc of >48mmol/mol
13
Q
What is the prevalence of diabetes?
A
- See age-related increase in incidence in population - As population gets older, see more and more people diagnosed with this - More prevalent in men than women - Linked to obesity
14
Q
What are the symptoms of type 1 diabetes? What is its cause?
A
- Symptoms: - <10% of diabetes cases (diagnosed in children/adolescents) - Short illness - Polyuria - Fatigue - Weight loss - Excessive thirst - Type 1 diabetes leads to almost absolute insulin deficiency –> T cell mediated autoimmune destruction of pancreatic beta cells - Cause = unknown: - Genetic factors (HLA class II, DR -3/-4) - GWAS studies (INS promoter, PTPN2 IL2Ra)
15
Q
What are the key features of type 2 diabetes?
A
- Most common form of diabetes –> 300 million people worldwide (~3 million in the UK) - Heterogeneous –> interaction between genetic predisposition and environment - Combination of insulin resistance and pancreatic beta-cell dysfunction - Traditionally found in older adults but now as common as T1D in teenagers in US
16
Q
What are some of the genetic causes/features of type 2 diabetes?
A
- One of the major risk factors of T2DM = family history –> e.g genetic predisposition - T2DM actually has greater heritability than T1DM - Genetic risk factors = inherited from both parents - Several gene polymorphisms have been identified as increasing risk
17
Q
What are the key environmental risk factors of type 2 diabetes?
A
- Obesity (~80% of all new cases) - Physical inactivity - Foetal development - Ageing - These factors all drive insulin resistance
18
Q
What is insulin resistance? What is impaired in insulin resistance?
A
- Defined as the inability of insulin to produce its usual biological effects - No stimulation of glucose uptake - No inhibition of glucose production - No suppression of lipolysis - Associated with post receptor signalling
19
Q
Roughly what proportion of people that are insulin deficient develop type 2 diabetes? Which event actually causes type 2 diabetes?
A
- Only 20% of insulin resistant people develop T2DM - Key diagnostic event in switch from insulin resistance to diabetes = beta-cell dysfunction - Initially, cells = insulin resistant - Leads feedback back onto beta cells to produce more and more insulin as the target cells are not able to detect that insulin - Beta cells become exhausted –> leads to secretory dysfunction and beta cell loss/death - In early stages of insulin resistance, the problems are reversible but once beta cells start being lost, becomes much more complex
20
Q
What are the treatments for type 1 diabetes?
A
- Insulin replacement therapy - Requires monitoring for changes in blood glucose - Bolus infusions after consumption of food
21
Q
What are some of the key ways to ‘treat’ type 2 diabetes?
A
- Lifestyle - Oral antidiabetics - Insulin analogues - Novel drugs
22
Q
What dictates the treatment for type 2 diabetes?
A
- Depends where on the scale of disease you are
23
Q
How can you change your lifestyle in early stage T2DM?
A
- Diet - VLCD - Exercise - Need to control carbohydrate intake - Need to reduce weight and fat mass - Exercise induces insulin-independent glucose uptake
24
Q
What are oral antidiabetics? What do they do?
A
- Secretagogues - Sensitisers - Inhibitors of glucose absorption - Incretin therapies - What they do: - Increase insulin output (sulphonylureas) - Decrease glucose production in the liver (biguanides) - Increase insulin sensitivity (thiazolidinediones) - Decrease carbohydrates absorption (alpha glucosidase)
25
What are insulin analogues? When are they used?
- They are long/short acting insulins (insulin replacement therapy) - Used when beta cells have been lost - Used in T2DM
26
Give some examples of novel drugs for T2DM
- SGLT2 inhibitors - GLP-1 analogues - DPP4 inhibitors - GLP-1GIP combined therapies
27
What is intermittent fasting?
- New development for T2DM treatment - Also known as time-restricted feeding - Food intake is only permitted during set hours --> no restriction on calorie intake - Promotes weight loss in diabetic patients in short term - Also demonstrated reduced blood sugars
28
What is beta-cell transplantation? Who is it used on?
- Only used on patient with T1D that fulfil certain criteria - 'Hypo-unaware' --> unable to recognise when they are hypoglycaemic - Does not permanently stop requirement for insulin replacement therapy
29
What are human hiPSCs used for?
- Use of human cells to treat beta cell dysfunction - Used these instead of donors to try and prevent rejection etc - Unsure if they will work for everyone, very new at the moment
30
What are some of the complication of diabetes?
- Retinopathy --> blindness - Nephropathy --> leads to requirement of renal replacement therapy - Erectile dysfunction - Macrovascular disease --> ~65% of all heart attack deaths are in diabetes - Foot problems --> e.g foot ulcers, may lead to amputations
31
How is Alzheimer's disease linked to diabetes?
- People with diabetes are at an increased risk of developing dementia - Called type 3 diabetes - Diabetes is linked to dementia risk factors - E.g high blood pressure, high cholesterol, obesity - Similar molecular/cellular changes in Alzheimer's and diabetes - E.g neurones in Alzheimer's brain become resistant to effects of insulin - Issue as brain = obligate glucose user so without signal, cannot take up glucose - May contribute to accumulation of amyloid peptides and Tau protein
