Diabetes Mellitus Flashcards
Type 1 diabetes overview
Patients who lack insulin, mainly in young
Treatment is insulin injections
Classic symptoms: thirst, tiredness, weight loss, polyuria, ketoacidosis, hyperglycaemic coma
Results from autoimmune destruction of the beta cells of the islets of Langerhans - Sometimes follows viral infection such as mumps, rubella, or measles
No feedback inhibition by insulin on alpha cells - glucagon levels remain high, so is also a disease of glucagon excess
Metabolic consequences & explanation
Weight loss Hyperglycaemia Dehydration Ketoacidosis Hypertriglyceridaemia Insulin:glucagon ratio cannot increase even when dietary glucose enters from gut Metabolism stuck in starved phase Low ratio leads to induction of catabolic enzymes and repression of anabolic enzymes
T1 Diabetic state in liver
Despite high glucose, liver remains gluconeogenic because of high glucagon.
Lactate and amino acids (alanine) are main substrates for glucose production - muscle wasting
Glycogen synthesis and glycolysis also inhibited (liver cannot buffer blood glucose)
Fatty acids from lipolysis enter liver and provide energy for gluconeogenesis (excess fas converted to TAGs and VLDL)
Excess acetyl CoA from fatty acid oxidation converted to ketone bodies –> ketoacidosis = more ketone bodies and H+ in blood
Ketone bodies
Increases during starvation
Prolonged low insulin: glucagon ratio result in: Increasing mobilisation of fatty acids from adipose tissue; Increased amounts of the enzymes required to synthesize and utilise ketone bodies
This is because: the increased demand for gluconeogenesis in liver results in depletion of oxaloacetate; This decreases the capacity of the TCA cycle which increases the levels of acetyl-CoA present; Acetyl-CoA is the substrate for production of ketone bodies
Formation of ketone bodies
Condensation of 2 molecules of acetyl CoA - catalysed by thiolase.
Acetoacetate and D-beta-hydroxybutyrate can be converted back to acetyl-CoA in peripheral tissues for use in the TCA cycle
T1 Diabetic state in muscle
Relatively little glucose entry into muscle and peripheral tissues because of insulin lack. This contributes to hyperglycaemia
Fatty acid and ketone body oxidation used as the major source of fuel
Proteolysis occurs to provide carbon skeletons for gluconeogenesis leading to muscle wasting
T1 Diabetic state in adipose tissue
Despite the high glucose concentrations in the plasma, uptake of glucose is diminished by loss of insulin
Low insulin: glucagon ratio enhances lipolysis leading to continuous breakdown of triacylglycerol and release of fatty acids and glycerol into the blood stream to support energy production in peripheral tissues and gluconeogenesis in the liver
T1 Diabetic state - plasma and urine
Constant production of excess glucose while utilising less leads to hyperglycaemia
Glucose concentration exceeds renal threshold and in excreted in the urine (glycosuria) with loss of water and development of thirst
Fatty acid synthesis greatly diminished in the diabetic state; VLDL secreted by the liver and chylomicrons entering from the gut cannot be metabolised properly as expression of lipoprotein lipase is regulated by insulin. Results in hypertriglyceridemia and hyperchylomicronaemia and susceptibility to cardiovascular events
Short term and long term life-threatening consequences
Short term: Hyperglycaemia and ketoacidosis – type 1
Hyperosmolar hyperglycaemic state (non-ketotic hyperosmalr coma) – type 2
Long term: Predisposition to CV disease and organ damage; Retinopathy – cataracts, glaucoma and blindness; Nephropathy; Neuropathy
High concentration of glucose
Results in:
Generation of ROS
Osmotic damage to cells
Glycosylation leading to alterations in protein function
Formation of advanced glycation end products (AGE) which increase ROS and inflammatory proteins
Diagnosing Diabetes
Fasting blood glucose levels (WHO criteria): After an overnight fast a blood glucose value of 126mg/dl (7.0mM) and above on at least 2 occasions indicates diabetes (normal ranges 70-110mg/dL or less than 6.1mM)
Glucose tolerance test
o Performed in morning after an overnight fast
o Fasting blood sample is removed and subject drinks glucola drink containing 75g of glucose. Blood glycose is then samples at 20 minutes, 1 hour and 2 hours
HbA1c: lifespan of RBCs is 8-12 weeks, so measurements of HbA1c can be used to reflect average blood glucose levels - useful longer term gauge of blood glucose control (target 6.5%)
Treating T1 Diabetes
Mimic normal daily insulin secretion
Endogenous insulin secretion normally peaks within one hour after a meal with insulin secretion and plasma glucose levels returning to basal levels within two hours of the end of the meal induced hyperglycaemia
Type 2 diabetes mellitus overview
Disease where there is not enough insulin to keep the blood glucose normal
It is a combination
- Impaired insulin secretion
- Increased peripheral insulin resistance
- Increased hepatic glucose output
Causes of T2 Diabetes
Failure of the body to respond properly to insulin:
- Insensitivity of target cells to insulin (defects in receptors and cell signalling)
- Impaired insulin secretion (amyloid deposits reducing beta-cell mass)
Overall: inability of beta cells to compensate for insulin resistance
Linked to obesity
Mechanisms of insulin resistance
Can be caused by a number of possible defects: Mutations in insulin receptor gene (rare);
Most important are defects in insulin signalling pathway.
Peripheral insulin resistance is induced by: Presence of excess fatty acids – inhibit peripheral glucose disposal and enhance hepatic glucose output; Dysregulated adipokines from adipose tissue; Also induced by defects in cellular translocation of Glut-4 (and glucose uptake).
This has been observed in adipocytes (but not skeletal muscle) in both obesity and diabetes
