Insulin Resistance and Type 2 Diabetes Flashcards
What is the most important factor in type 2 diabetes development?
Age
Is the influence of genetics on type 2 diabetes usually monogenic or polygenic?
Polygenic
What is the response of a normal subject to the homeostatic model assessment of insulin resistance and B-cell resistance?
Early increase in blood glucose
Absorbed and metabolised by tissues
Decrease to fasting glucose concentration
What is the response of a diabetic subject to the homeostatic model assessment of insulin resistance and B-cell resistance?
Early increase in blood glucose
Remains elevated - decreased tissue efficiency in glucose uptake
What is the response of a prediabetic subject to the homeostatic model assessment of insulin resistance and B-cell resistance?
Normal fasting blood glucose levels
‘Diabetic’ curve - good indicator of insulin and B-cell resistance
What are the 3 types of cells in the islets of Langerhans and what are their roles?
Alpha - produce glucagon - stimulates glucose release from liver
Beta - produce insulin
Delta - produce somatostatin - suppresses insulin and glucagon secretion
What is the effect of the increased insulin resistance in prediabetes?
Causes increased B-cell function - to compensate - make more insulin
How does the blood insulin level change after diabetes onset and why?
Decreases
Decreased B-cell function - decreased capacity to compensate - B-cell failure - requires exogenous insulin injection
What is the evidence of B-cell adaptation in diabetes in mice?
Leptin receptor mutant mice - eat excessively
Insulin resistant at 12 weeks - B-cells enlarge to compensate
At 24 weeks B-cells decrease in number and size - fail due to glucolipotoxicity
Mice become diabetic
What are the effects of insulin resistance?
Hyperglycaemia - due to decreased skeletal muscle glucose uptake, increased liver glucose output
Hyperlipidaemia - due to increased lipolysis
What may be the mechanism behind B-cell failure?
Glucotoxicity, lipotoxicity, oxidative stress
Cause B-cell apoptosis
How might senescent cells be linked to diabetes?
Drive insulin resistance
Drive diabetes complications
How do senescent cells cause B-cell damage?
SASP - pro-inflammatory
What is the glucose-induced insulin secretion from a normally functioning islet?
1st phase release
Smaller 2nd phase
Return to fasting insulin level
What is the glucose-induced insulin secretion from an early T2D islet?
Loss of 1st phase release
Delayed 2nd phase release
Insulin levels remain elevated
What is the glucose-induced insulin secretion from a late T2D islet?
Loss of 1st and 2nd phase releases - no insulin release
Insulin levels remain at fasting level
What is an advanced glycosylation end-product (AGE)?
Adduct of proteins and carbohydrates
Why do AGEs form?
High carbohydrate level for long time
What is the process of AGE formation?
Carbohydrate reacts with amino group of protein - f0rms Schiff base
Schiff base rearranges - forms Amadori product
Amadori product reacts with amino group of another protein - forms cross-linked AGE - 2 protein molecules linked together
What are the effects of AGE formation?
Can occur multiple times - form protein aggregates
Activates pro-inflammatory signalling
Cause tissue stiffness and loss of elasticity
How does AGE accumulation change with age and in diabetes?
Increases with age
Accelerated in diabetes
Which proteins are prone to AGE formation?
Glycated haemoglobin (HbA1c) Proteins with slow/absent turnover - e.g. eye lens crystallins
Which environmental source do some AGEs come from?
Dietary intake
Which affects of AGEs contribute to old-age frailty?
Brain - AD Eyes - cataract formation Blood vessels - hypertension Bone - osteoporosis, fractures Muscle - sarcopenia
What is dietary restriction?
Decreasing caloric intake by >=30%
How does dietary restriction affect mice, flies, and worms?
Increases lifespan
Decreases circulating insulin and IGF-1 levels - shows increased insulin sensitivity
How could the benefits of dietary restriction be achieved in diabetics without undergoing the programme?
Deduce pathways behind effects
Develop small chemical mimetics of DR
How might senolytics be useful in treating diabetes?
Specifically eliminate senescent cells - suppress SASP
May improve functioning of cells in islets of Langerhans - positive metabolic effects
