diabetes mellitus Flashcards
what is type 1 diabetes?
when patients lack insulin
how do you treat type 1 diabetes?
insulin injections
what are the classic symptoms of type 1 diabetes?
- thirst, tiredness, weight loss
- polyuria (containing glucose and ketone bodies)
- ketoacidosis
- hyperglycaemia coma
how does type 1 diabetes occur?
- results from autoimmune destruction of the beta cells of the islets of Langerhans
- sometimes follow viral infection such as mumps, rubella or measles
- there is no feedback inhibition by insulin on alpha cells so glucagon levels remain high therefore also a disease of glucagon excess
what are the metabolic consequences of type 1 diabetes?
- blood insulin levels low despite high glucose, whereas glucagon levels are raised
- insulin:glucagon ratio cannot increase even when dietary glucose enters from the gut so metabolism is stuck in the starved state
- low insulin:glucagon ratio leads to induction of catabolic enzymes and repression of anabolic enzymes
what is the type 1 diabetic state in the liver?
- despite high blood glucose, 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 are also inhibited; therefore liver cannot adequately buffer blood glucose
- fatty acids from lipolysis enter liver and provide energy to support gluconeogenesis while excess fatty acids are converted to TAGs and VLDL
- excess acetyl CoA from fatty acid oxidation converted to ketone bodies and if not used sufficiently rapidly can lead to ketoacidosis due to accumulation of ketone bodies and H+ ions in the blood
when do ketone bodies occur?
occurs normally under all conditions but increases dramatically during starvation
what does prolonged low insulin:glucagon ratio result in?
- increased mobilisation of fatty acids from adipose tissue
- increased amounts of the enzymes required to synthesise and utilise ketone bodies
why does increased lipid mobilisation stimulate ketone body formation?
- in the liver, the increased remain fro gluconeogenesis results in depletion of oxaloacetate
- this creases the capacity of the TCA cycle which increases the levels of acetyl CoA present
- acetyl CoA is the substrate for production of ketone bodies
what is converted back to acetyl CoA in peripheral tissues for use in the TCA cycle?
acetoacetate and D-beta-hydroxybutyrate
what forms ketone bodies?
condensation of 2 molecules of acetyl-CoA
what is the type 1 diabetic state in muscle?
- relatively little glucose entry into muscle and peripheral tissues because of insulin lack which contributes to hyperglycaemia
- fatty acid ad ketone body oxidation used as the major source of fuel
- proteolysis occurs to provide carbon skeletons for gluconeogenesis leading to muscle wasting
what is the type 1 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 ration 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
what is the type 1 diabetic state in plasma and urine?
- constant production of excess glucose while utilising less leads to hyperglycaemia
- glucose concentration exceeds renal threshold and is excreted in the urine with loss of water and development of thirst
- fatty acids synthesis greatly dismissed in the diabetic state; VLDL secreted by the liver and chylomicrons entering from the gut cannot be metabolised properly and expression of lipoprotein lipase is regulated by insulin which results in hypertriglyceridaemia and hyperchylomicronanaemia and susceptibility to CV events
what are the short term consequences of diabetes?
- hyperglycaemia and ketoacidosis: characteristic of type 1 diabetes
- hyperosmolar glyerglycaemic state: characteristic of type 2 diabetes
what are the long term consequences of diabetes?
- predisposition fo CV disease and organ damage
- retinopathy: cataracts, glaucoma, blindness
- nephropathy
- neuropathy
what does high concentrations of glucose result in?
- generation of ROS
- osmotic damage to cells
- glycosylation leading to alterations in protein function
- formation of advanced glycation end products which increases ROS and inflammatory process
what are the 2 major tests to diagnose diabetes?
- fast blood glucose levels
- glucose tolerance test
what happens with the fasting blood glucose levels test?
after an overnight fast a blood glucose values of 126mg/dl and above on at least 2 occasions indicates diabetes
what happens with the glucose tolerance test?
performed in the morning after an overnight fast. fasting blood sample is removed and subject drinks a glucose drink containing 75g of glucose. blood glucose is then sampled at 20mins, 1hr and 2hrs
what does HbA1c show?
HbA1c measurements can be used to reflect average blood glucose levels over that duration, providing a useful longer term gauge of blood glucose control
what causes type 2 diabetes?
a combination of:
- impaired insulin secretion
- increased peripheral insulin resistance
- increased hepatic glucose output
what is type 2 diabetes?
a disease where there is not enough insulin to keep the blood glucose normal
what are the causes of type 2 diabetes?
failure of the body to respond properly to insulin:
1) insensitivity of target cells to insulin (defects in receptors and cell signalling)
2) impaired insulin secretion (amyloid deposits reducing beta cell mass)
3) linked to obesity
what is the mechanism of insulin resistance?
can be caused by a number of possible defects:
- mutations in insulin receptor gene
- most important defects in insulin signalling pathway
what is peripheral resistance induced by?
- presence of excess fatty acids: inhibit peripheral glucose disposal and enhance hepatic glucose output
- deregulated adipokines from adipose tissue
- also induced by defects in cellular translocation of Glut-4 which has been observed in adipocytes in both obesity and diabetes
what are the features of type 2 diabetes?
- develops over many years, 2-6% of adults affected
- approximately 90% of diabetic population are type 2
- patients can survive long term without insulin and are often older and obese but increasingly observed in adolescents
- associated with macro vascular disease, stroke and atherosclerosis
- may be asymptomatic but may have classical hyperglycaemia symptoms
- ketone bodies present in low concentrations
what is metabolism like in type 2 diabetes?
- glucagon levels not raised to same extent as in type 1, as some insulin present to suppress glucose secretion
- therefore uncontrolled lipolysis and therefore ketone body formation are not a feature of type 2
- hyperglycaemia arises mainly from a lack of glucose uptake
- hypertriglyceridaemia and macro vascular disease isa characteristic due to increased VLDL synthesis in liver from glucose and fatty acids from diet and fatty acids from adipose tissue
what is the treatment for type 2 diabetes?
- diet and exercise
- oral hypoglycaemic agents: various mechanisms of action
what are some of the oral hypoglycaemic agents used to treat type 2 diabetes?
- sulphonylureas increase insulin secretion
- biguanides or thiazokidinediones increase tissue insulin sensitivity
- glucosidase inhibitors reduce the absorption and digestion of carbohydrates
