Intro to diabetes Flashcards
What happens in the fasting state?
- Glycolysis
- Gluconeogenesis
- Glucose delivered to insulin
independent tissues, brain and
RBCs
- Glucose delivered to insulin
- Insulin ↓
- Muscles use FFA
What happens after feeding?
- Rising glucose (5-10 min after eating) stimulates insulin secretion and suppresses glucagon
- 40% of ingested glucose goes to liver and 60% to periphery, mostly muscle
- Ingested glucose helps to replenish glycogen stores both in liver and muscle
- High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall
What occurs in between alpha and beta cells in islets of langerhan?
Paracrine ‘cross talk’
Local insulin release inhibits glucagon, effect lost in diabetes
Describe the steps of insulin secretion by beta cells
- Glucose enters cell by GLUT-2 transporter
- Glucose either aerobically respired to produce ATP or converted into glycogen by glucokinase
- ATP binds to K+ channels, K+ channel closes (some K+ leave passively)
- Depolarisation of cell membrane
- VG Ca2+ channel open, Ca2+ influx
- Insulin vesicles fuse with membrane and are released
Describe the steps of insulin action in muscle and fat cells
- Insulin binds to receptor
- Intracellular signalling cascades causing intracellular GLUT4 vesicles to move to membrane
- Glucose can enter cells through GLUT4
What are the roles of insulin?
- Supresses hepatic glucose output:
- Glycogenolysis
- Gluconeogenesis
- Increases glucose uptake into insulin sensitive tissues (muscle, fat)
- Suppresses
- Lipolysis
- Breakdown of muscle
What are the roles of glucagon?
- Increases hepatic glucose output
- Glycogenolysis
- Gluconeogenesis
- Reduce peripheral glucose uptake
- Stimulate peripheral release of gluconeogenic precursors (glycerol, AAs)
- Lipolysis
- Muscle glycogenolysis and breakdown
What are other counterregulatory hormones to insulin?
adrenaline, cortisol, growth hormone
What is diabetes mellitus?
A disorder of carbohydrate metabolism characterised by hyperglycaemia
How can diabetes mellitus cause morbidity and mortality?
- Acute hyperglycaemia which if untreated leads to acute metabolic emergencies diabetic ketoacidosis (DKA) and hyperosmolar coma (Hyperosmolar Hyperglycaemic State)
- Chronic hyperglycaemia leading to tissue complications (macrovascular and microvascular)
What are macrovascular tissue complications that chronic hyperglycaemia can cause?
heart, brain, nerves affected→ can lead to stroke, CVD, amputations
What are microvascular tissue complications that chronic hyperglycaemia can cause?
Blindness, end stage renal disease
Which type of diabetes is gestational and medication induced diabetes a part of?
Type 2
What is diabetes defined as?
- Symptoms and random plasma glucose > 11 mmol/l
- Fasting plasma glucose > 7 mmol/l
- No symptoms - GTT (75g glucose test) fasting > 7 or 2h value > 11 mmol/l (repeated on 2 occasions)
- HbA1c of > 48mmol/mol (6.5%)
Describe the pathogenesis of type 1 diabetes
An insulin deficiency disease characterised by loss of beta cells due to autoimmune destruction
What happens due to the failure of insulin secretion?
- Continued breakdown of liver glycogen
- Unrestrained lipolysis and skeletal muscle breakdown providing gluconeogenic precursors
- Inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake
What is the renal threshold of glucose concentration before there is urinary glucose losses?
10mM
What does failure to treat no insulin lead to?
- Increase in circulating glucagon (loss of local increases in insulin within the islets leads to removal of inhibition of glucagon release), further increasing glucose
- perceived ‘stress’ leads to increased cortisol and adrenaline
- progressive catabolic state and increasing levels of ketones
Describe the pathogenesis of type 2 diabetes
Insulin resistance and impaired insulin secretion due to a combination of genetic predisposition and environmental factors (obesity and lack of physical activity)
What does impaired insulin action lead to?
- Reduced muscle and fat uptake after eating
- Failure to suppress lipolysis and high circulating FFAs
- Abnormally high glucose output after a meal
What are the principles of treatment in diabetes?
- Control of symptoms
- Prevention of acute emergencies, ketoacidosis, hyperglycaemic hyperosmolar states
- Identification and prevention of long-term microvascular complications
- Limited evidence yet that glucose control reduces cardiovascular events in the short-term
- But long-term follow-up indicates a modest reduction in IHD from tight glucose control if started at diagnosis
- HbA1c 50mmol/mol (6.5%) (as low as possible in those not on insulin or sulphonylureas)
What do sulphonylureas do?
- Binds to potassium receptors that cause depolarisation to allow Ca to enter
- Stimulate insulin release by binding to b-cell receptors
- Improve glycaemic control (1-2% in HbA1c)
What are the disadvantages of sulphonylureas?
- significant weight gain
- Do not prevent the gradual failure of insulin secretion
- Can cause hypoglycaemia (occasionally prolonged and fatal, particularly in the elderly and when renal function is impaired)
What is an example of sulphonylureas?
gliclazide
What would an ideal type 2 diabetes drug do?
- Reduce appetite and induce weight loss
- Preserve b-cells and insulin secretion
- Increase insulin secretion at meal time
- Inhibit counterregulatory hormones which increase blood glucose such as glucagon
- Not increase the risk of hypoglycaemia during treatment
What is the first line drug for diabetes type 2?
Metformin
