T2 L10 Diabetes Flashcards
What is type 1 insulin-dependent diabetes?
Patients can’t survive without insulin
Mainly starts when young but can be observed in later life
Ketosis may lead to death
No feedback inhibition by insulin on alpha cells so glucagon levels remain high
Treatment is insulin injections
What is IDDM caused by?
Autoimmune destruction of beta cells of the islets of Langerhans
Sometimes follows a viral infection such as measles, mumps or rubella.
What are the symptoms of IDDM?
Thirst Tiredness Weight loss Polyuria Hyperglycaemic coma
Why does insulin deficiency cause weight loss, weakness & fatigue?
A low insulin:glucagon ratio Increased protein breakdown Increased plasma amino acid levels Loss of muscle mass Weight loss, weakness & fatigue
What happens to the liver in IDDM?
Liver remains gluconeogenic because of the high glucagon regardless of high blood glucose
Lactate & amino acids such as alanine from protein breakdown are the main substrates for glucose production which leads to muscle wasting.
Glycogen synthesis & glycolysis are inhibited so the liver can’t adequately buffer blood glucose.
Fatty acids from lipolysis enter the liver & provide energy to support gluconeogenesis. Excess fatty acids are converted to TAG & VLDL
Excess acetyl CoA from fatty acid oxidation is converted to ketone bodies
What happens if the ketone bodies from the liver aren’t used rapidly?
Accumulation of ketone bodies & H+ in the blood can lead to ketoacidosis
What happens to the muscle in IDDM?
Relatively little glucose entry into the muscle & peripheral tissue due to the lack of insulin - contributes to hyperglycaemia
Fatty acid & ketone body oxidation are the major source of fuel
Proteolysis occurs to provide carbon skeletons for gluconeogenesis which leads to muscle wasting.
What happens to the adipose tissue in IDDM?
Despite high glucose concentration in the plasma the uptake of glucose is diminished by the loss of insulin.
A low insulin : glucagon ratio enhances lipolysis & leads to continuous breakdown of TAG & release of fatty acids & glycerol into the bloodstream.
What happens to the plasma & urine in IDDM?
Constant production of excess glucose leads to hyperglycaemia
Glucose concentration exceeds renal threshold & is excreted into the urine - causes loss of water & thirst
Fatty acid synthesis is decreased - VLDL secreted by the liver & chylomicrons entering the gut can’t be properly metabolised due to the expression of lipoprotein lipase being regulated by insulin.
Results in hypertriglyceridaemia & hyperchylomicronaemia & susceptibility to CVD.
What are the short term consequences of diabetes?
Hyperglycaemia & ketoacidosis (type I diabetes)
Hyperosmolar hyperglycaemic state (type II diabetes)
What are the long term consequences of diabetes?
Predisposition to CVD & organ damage
Retinopathy - cataracts, glaucome & blindness
Nephropathy
Neuropathy
What does excess glucose result it?
Generation of ROS
Osmotic damage to cells
Glycosylation leading to alterations in protein function
Formation of advanced glycation end products which increase ROS & inflammatory proteins
What are the 2 major tests to diagnose diabetes?
Fasting blood glucose levels
Glucose tolerance test
Describing the fasting blood glucose levels test
Overnight fast
Blood glucose value of 126mg/dL & above on 2 separate occasions.
Normal ranges are 70-110mg/dL
Describe the glucose tolerance test
Performed in the morning after an overnight fast
Fasting blood sample is removed. Individual drinks glycols drink containing 75g of glucose.
Blood glucose is sampled at 20min, 1 hour & 2 hour
What are the insulin treatment regimes for type I diabetes mellitus?
Premixed insulin
Insulin & food taken at same time
Rapid acting with short half life
What are the pros & cons of premixed insulin?
Requires less injecting
Timing of meals may be critical
What are the pros & cons of insulin & food taken at the same time?
Provides greater flexibility for those doing shift work
Potential nocturnal hypoglycaemia
What are the pros & cons of rapid acting with a short half life?
Reduces potential for nocturnal hypoglycaemia
More expensive
What is type 2 non-insulin dependent diabetes?
Disease where there is not enough insulin to keep blood glucose normal
Combination of impaired insulin secretion, increased peripheral insulin resistance, increased hepatic glucose output
Failure of body to respond properly to insulin
Insensitivity of target cells to insulin - defects in receptor & cell signalling
Impaired insulin secretion
Glucagon secretion is not increased.
What are the mechanisms of insulin resistance?
Mutation in insulin receptor gene - very rare
Defects in insulin signalling pathway - includes defects in cellular translocation of glut-4
Peripheral insulin resistance is induced by presence of excess fatty acids.
What are the features of NIDDM?
Develops over many years - 2-6% of adults
May be up to 90% of diabetic population
Patients can survive without insulin
Associated with microvascular disease, stroke & atherosclerosis
Ketone bodies present in low concentrations
What are the symptoms of NIDDM?
Thirst
Polyuria
Weight loss
What is the treatment of NIDDM?
Diet & exercise - increases expression & translocation of glut 4 to the cell membrane
Oral hypoglycaemic agents
Absorption & digestion of carbohydrates - glucosidase inhibitor
What are oral hypoglycaemic agents?
Insulin secretion - sulphonylureas. Hypoglycaemia is a side effect.
Tissue insulin sensitivity - Biguanides or thiazolidinediones
What is sulphonylureas?
Gliclazide
Glucose depolarises the membrane by ATP dependent closing of K+ channels
Depolarisation of the membrane opens voltage-dependent calcium channels with influx of calcium ions stimulating secretion of insulin.
Sulphonylureas interacts with the receptor closing K channel
What is metformin?
Biguanides 1st choice hypoglycaemic agent Doesn't produce hypoglycaemia Suppresses appetite Only effective in the presence of insulin Increases insulin sensitivity Increases AMP kinase Decreases plasma glucose Reduces LDL, VLDL & CV risk
What is the effect of metformin on the liver?
Decreases gluconeogenesis, glycogenolysis, glucose output & lactate uptake
What is the effect of metformin on adipocytes & muscle?
Increases glucose uptake & utilisation
What is the effect of metformin on the brain?
It decreases appetite
What is the effect of metformin on the intestines?
Decreases glucose absorption
What are thiazolidinediones?
Slow onset - 1-2months of treatment
Reduce hepatic glucose output & increase glucose uptake into the muscle, this enhances the effectiveness of endogenous insulin & reduces the amount of exogenous insulin needed
Reduction in glucose may be associated with reductions in circulating insulin, free fatty acids, triglycerides & small, dense LDL particles
Binds to nuclear receptor the peroxisome proliferator-activated receptor gamma to regulate gene expression
What genes are regulated when thiazolidinediones bind to PPAR gamma?
Those coding for lipoprotein lipase, fatty acid transporter protein, fatty acyl CoA synthetase
When and where are GLP-1 & GIP produced?
By the endocrine cells of the intestine following ingestion of food which stimulates insulin secretion
What is Exendin-4?
39 amino acid peptide hormone found in saliva of Gila monster
Stimulates GLP-1 receptor
What is Exenatide?
A synthetic version of exendin-4 with a longer half life in vivo.
Stimulates insulin secretion
Inhibits glucagon secretion & glucose production by the liver
Suppresses appetite & induces weight loss.
What does Vildagliptin do?
Inhibits the inactivation of GLP-1 & GIP to increase the activity of GLP-1
Can be used with oral hypoglycaemic but there is a risk of hypoglycaemia
