Liver and metabolism L10 Flashcards
Type 1 insulin dependent diabetes
Cannot survive without insulin
Mainly young, but increasingly observed later in life
Ketosis may lead to death
Autoimmune destruction of B cells of islets of Langerhans
Sometimes follows viral infections (mumps, rubella, measles)
Treatment: insulin injections
Classical symptoms of type 1 diabetes
Thirst, tiredness, weight loss
Polyuria
Hyperglycaemic coma
Metabolic consequences of type 1 diabetes
Blood insulin levels low despite high blood glucose, whereas glucagon levels are raised
Insulin: glucagon ration cannot increase even when dietary glucose enters from the gut
Low insulin: glucagon ration leads to induction of catabolic enzymes and repression of anabolic enzymes
Type 1 diabetes- the liver
Liver remains gluconeogenic because of high glucagon
Lactate and amino acids such as alanine from protein breakdown are main substrates for glucose production hence muscle wasting
Glycogen synthesis and glycolysis inhibited
Fatty acids from lipolysis enter liver and provide energy for gluconeogenesis
Excess acetyl CoA from fatty acid oxidation converted to ketone bodes and if not used sufficiently can rapidly lead to ketoacidosis due to accumulation of ketone bodies and H+ in blood
Type 1 diabetes- the muscles
Relatively little glucose entry into muscle and peripheral tissues because of insulin lack- hyperglycaemia
Fatty acid and ketone body oxidation used as major source of fuel
Proteolysis occurs to provide carbon skeletons for gluconeogenesis leading to muscle wasting
Type 1 diabetes- adipose tissue
High glucose concentrations in plasma but uptake of glucose diminished by loss of insulin
Low insulin: glucagon ration enhances lipolysis leading to continuous breakdown of triacylglycerol and release of fatty acids and glycerol into blood stream to support energy production in peripheral tissues and gluconeogenesis in the liver
Type 1 diabetes- plasma and urine
Constant production excess glucose while utilising less leads to hyperglycaemia
Glucose concentration exceeds renal threshold, excreted in urine with loss of water and development of thirst
Fatty acid synthesis greatly diminished; VLDL secreted by liver and chylomicrons entering from gut cannot be metabolised properly as expression of lipoprotein lipase is regulated by insulin
Results in hypertriglyceridaemia and hyperchylomicronaemia and susceptibility to cv event
Short term consequences
Hyperglycaemia and ketoacidosis characteristics of type 1 diabetes
Hyperosmolar hyperglycaemic state (non ketotic hyperosmolar coma) characteristc of type 2 diabetes
Long term life threatening consequences of diabetes
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 which increase ROS and inflammatory protein
Two major tests for diagnosing diabetes
Fasting blood glucose levels
Glucose tolerance test
Fasting blood glucose levels test
After overnight fast a blood glucose value of 126mg/dl and above on at least two occasions indicates diabetes
Glucose tolerance test
Performed in morning after and overnight fast
Fasting blood sample is removed and subject drinks ‘glucola’ drink containing 75g glucose
Blood glucose then sampled at 20 min, 1 hour and 2 hour
Treating type 1 diabetes
Aim: 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
Insulin treatment regimes
Premixed insulin
- requires less injecting
- timing of meals may be critical
Insulin and food taken at the same time
- greater flexibility for those doing shift work
- potential nocturnal hypoglycaemia
Rapid acting with short half life
- reduces potential for nocturnal hypoglycaemia
- more expensive
Type 2 non insulin dependent diabetes
Not enough insulin to keep the blood glucose normal
Combination of
- impaired insulin secretion
- increased peripheral insulin resistance
- increased hepatic glucose output
Insensitivity of target cells to insulin
Link to obesity
Glucagon secretion not increased
Mechanisms of insulin resistance
Mutations in insulin receptor gene (very rare)
Defects in insulin signalling pathway
Include defects in cellular translocation of Glut-4 (observed in obesity and diabetes)
Peripheral insulin resistance induced by presence of excess fatty acids- inhibit peripheral glucose disposal and enhance hepatic glucose output
Features of type 2 diabetes
Develops over man years
May be up to 90% diabetic population
Survive long term without insulin and often older and obese
Associated with macrovascular disease, stroke and atherosclerosis
Incidence in Japan increasing with western diet
May be asymptomatic, but may have classic hyperglycaemic symptoms
Ketone bodies present n low concentrations
Metabolism in type 2 diabetes
Glucagon levels not raised to same extent as type 1, some insulin present and suppresses glucagon secretion
Hyperglycaemia arises from lack of glucose uptake
Uncontrolled lipolysis and therefore ketone body formation not features of type 2 as insulin release suppresses glucagon secretion
Hypertriglyceridaemia and macrovascular disease due to increased VLDL synthesis in liver
Treatment of type 2
Diet and exercise
Oral hypoglycaemic agents- various therapeutic targets
Insulin secretion e.g. sulphonylureas
Tissue insulin sensitvity e.g. biguanides
Absorption and digestion of carbohydrates e.g. glucosidase inhibitors
Sulphonylureas
Glucose depolarises the membrane by ATP dependent closing of K+ channels
Depolarisation of the membrane opens voltage-dependent Ca2+ channels with influx of Ca2+ causing secretion
Sulphonylureas interact with receptor closing K+ channel
Metformin
1St choice hypoglycaemic agent
Does not produce hypoglycaemia
Suppresses appetite- useful if overweight
Only effective in the presence of insulin
Increases insulin sensitivity
Reduces LDL and VLDL and CV risk
Thiazolidinediones
Slow onset, effect achieved after 1-2 months of treatment
Reduces hepatic glucose output and increase glucose uptake into muscle, enhances effectiveness of endogenous insulin and reduces amount of exogenous insulin needed
Reduction in glucose may be accompanied by reductions in circulating insulin, free fatty aids, triglycerides and small dense LDL particles
Bind to nuclear receptor, the peroxisome proliferator activator receptor -y regulating gene expression, particularly in adipose tissue
GLP-1 and GIP targeting
Produced by endocrine cells of intestine following ingestion of food and stimulate insulin secretion
Have very short half life in vivo so ineffective as therapeutic
Exendin-4
39 amino acid peptide hormone found in the saliva of the poisonous gila monster
Powerful stimulator of GLP 1 receptor
Exenatide
Synthetic version of exendin 4 with longer half life in vivo
Stimulates insulin secretion
Inhibits glucagon secretion
Glucose production by the liver
Vildagliptin
Inhibits the inactivation GLP-1 and GIP allowing increased activity of GLP-1
Can be used in combination with oral hypoglycaemics
Danger of hypoglycaemia
