Biochemistry of Type 2 Diabetes Flashcards
What is the single highest risk factor for type 2 diabetes?
BMI >25
Can diet make a difference to the risk of developing type 2 diabetes?
Yes, independent of BMI
Below what blood glucose concentration is it critical hypoglycaemia?
2.2 mM
Why does type 2 diabetes develop?
Can’t compensate for loss of insulin sensitivity
What is the initial hyperinsulinaemic phase of type 2 diabetes?
Increased insulin production by pancreas compensates for insulin resistance of peripheral tissues
- Beta cell mass can expand
What leads to hyperglycaemia in type 2 diabetes?
Loss in beta cell function/mass
What is the onset of type 2 diabetes?
Gradual
What are the three phases of type 2 diabetes progression?
1) Hyperinsulinaemia
2) Impaired glucose tolerance
3) Hyperglycaemia in fasting state
What happens during the hyperinsulinaemia phase in type 2 diabetes?
Peripheral tissues have insulin resistance
To compensate pancreatic insulin secretion increases
Normal glucose
Elevated insulin
What happens during the impaired glucose tolerance phase in type 2 diabetes?
Hyperglycaemia despite elevated insulin > pre-diabetic
Elevated glucose
Elevated insulin
What happens during the hyperglycaemia in the fasting state phase in type 2 diabetes?
Insulin secretion declines > overt diabetes
Elevated glucose
Decreased insulin
What is the earliest detected abnormality in people who are likely to develop type 2 diabetes?
Insulin resistance
What is insulin resistance?
When biological effects of insulin subnormal for glucose disposal in skeletal muscle and suppression of endogenous glucose production by liver
When is the action of insulin impaired?
After it binds to insulin receptor - signalling affected
How can insulin resistance be observed?
Hyperinsulinaemia in response to glucose load
What are the key precipitating factors of insulin resistance?
High circulating levels of free fatty acids - Activation of TLRs - Intracellular signalling Enhanced pro-inflammatory cytokines in obesity - TNF-alpha - IL-6 Extra altered intracellular activities - Mitochondrial ROS - ER stress
What is the end signalling result of the key precipitating factors of insulin resistance?
Phosphorylation of serine residues on IRS1 > inhibition of signalling cascade activated by insulin binding
Increased SOCS levels > degrade IRS1 > prevent signalling
Why might bariatric surgery decrease the severity of type 2 diabetes?
Weight control
Altered timing and amount of secretion of gut hormones > influence insulin production
Increased production of certain bile acids > make more cells sensitive to insulin
Surgery-induced changes to gut microbiome
What is the response of beta pancreatic cells in type 2 diabetes?
Responses blunted
What do higher blood glucose levels in type 2 diabetes trigger in beta pancreatic cells?
Lower insulin secretion rates
What is the pattern of beta pancreatic cell loss in type 2 diabetes?
Delayed but progressive
What does a smaller beta cell population in type 2 diabetes mean for the remaining cells?
Remaining cells must individually produce higher insulin levels to maintain total insulin production > extra strain on remaining cells
How might obesity impact beta cell dysfunction?
Exposure to free fatty acids > loss of co-localisation of voltage-gated Ca channels and insulin secretory granules > Ca channels open but influx occurs in “wrong” place > no secretion
What are the factors contributing to beta cell decline?
Direct glucotoxicity Dietary fatty acid Obesity Inflammation-induced cytokines ER stress
What is ER stress?
Imbalance between protein folding capacity of ER and protein load
Accumulation of misfolded proteins > trigger downstream signalling events = unfolded protein response
What are the long term complications of diabetes closely related to?
Severity and duration of hyperglycaemia
What is the most common cause of diabetic ketoacidosis in Australia?
Poor adherence to treatment
What factors, other than poor adherence, can cause diabetic ketoacidosis?
Infection/other illness - Higher levels of hormones countering effect of insulin Drugs affecting carbohydrate metabolism - Corticosteroids - Sympathomimetics - Atypical antipsychotics - SGLT1 inhibitors
What is SGLT1?
Glucose transporter in kidney’s proximal tubule
What are the clinical features of diabetic ketoacidosis?
Hyperglycaemia
Hyperketonaemia
Metabolic acidosis
What is the key diagnostic criterion for diabetic ketoacidosis?
Direct measurement of beta-hydroxybutyrate
What are the clinical features of hyperglycaemic hyperosmolar state?
Slower onset than diabetic ketoacidosis - several days More severe manifestations of - Hyperglycaemia - Dehydration - Plasma hyperosmolality
What are common causes of hyperglycaemic hyperosmolar state?
Infection
Poor adherence to therapy
What is the key diagnostic criterion for hyperglycaemic hyperosmolar state?
Plasma glucose >33.3 mM
Absence of acidosis and ketonaemia
What is the most frequent and serious adverse effect of antidiabetic therapy?
Hypoglycaemia
