diabetes mellitus

Question 1

what is type 1 diabetes?

Answer 1

when patients lack insulin

Question 2

how do you treat type 1 diabetes?

Answer 2

insulin injections

Question 3

what are the classic symptoms of type 1 diabetes?

Answer 3

• thirst, tiredness, weight loss
• polyuria (containing glucose and ketone bodies)
• ketoacidosis
• hyperglycaemia coma

Question 4

how does type 1 diabetes occur?

Answer 4

• 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

Question 5

what are the metabolic consequences of type 1 diabetes?

Answer 5

• 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

Question 6

what is the type 1 diabetic state in the liver?

Answer 6

• 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

Question 7

when do ketone bodies occur?

Answer 7

occurs normally under all conditions but increases dramatically during starvation

Question 8

what does prolonged low insulin:glucagon ratio result in?

Answer 8

• increased mobilisation of fatty acids from adipose tissue

- increased amounts of the enzymes required to synthesise and utilise ketone bodies

Question 9

why does increased lipid mobilisation stimulate ketone body formation?

Answer 9

• 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

Question 10

what is converted back to acetyl CoA in peripheral tissues for use in the TCA cycle?

Answer 10

acetoacetate and D-beta-hydroxybutyrate

Question 11

what forms ketone bodies?

Answer 11

condensation of 2 molecules of acetyl-CoA

Question 12

what is the type 1 diabetic state in muscle?

Answer 12

• 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

Question 13

what is the type 1 diabetic state in adipose tissue?

Answer 13

• 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

Question 14

what is the type 1 diabetic state in plasma and urine?

Answer 14

• 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

Question 15

what are the short term consequences of diabetes?

Answer 15

• hyperglycaemia and ketoacidosis: characteristic of type 1 diabetes
• hyperosmolar glyerglycaemic state: characteristic of type 2 diabetes

Question 16

what are the long term consequences of diabetes?

Answer 16

• predisposition fo CV disease and organ damage
• retinopathy: cataracts, glaucoma, blindness
• nephropathy
• neuropathy

Question 17

what does high concentrations of glucose result in?

Answer 17

• 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

Question 18

what are the 2 major tests to diagnose diabetes?

Answer 18

• fast blood glucose levels

- glucose tolerance test

Question 19

what happens with the fasting blood glucose levels test?

Answer 19

after an overnight fast a blood glucose values of 126mg/dl and above on at least 2 occasions indicates diabetes

Question 20

what happens with the glucose tolerance test?

Answer 20

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

Question 21

what does HbA1c show?

Answer 21

HbA1c measurements can be used to reflect average blood glucose levels over that duration, providing a useful longer term gauge of blood glucose control

Question 22

what causes type 2 diabetes?

Answer 22

a combination of:

• impaired insulin secretion
• increased peripheral insulin resistance
• increased hepatic glucose output

Question 23

what is type 2 diabetes?

Answer 23

a disease where there is not enough insulin to keep the blood glucose normal

Question 24

what are the causes of type 2 diabetes?

Answer 24

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

Question 25

what is the mechanism of insulin resistance?

Answer 25

can be caused by a number of possible defects:

• mutations in insulin receptor gene
• most important defects in insulin signalling pathway

Question 26

what is peripheral resistance induced by?

Answer 26

• 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

Question 27

what are the features of type 2 diabetes?

Answer 27

• 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

Question 28

what is metabolism like in type 2 diabetes?

Answer 28

• 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

Question 29

what is the treatment for type 2 diabetes?

Answer 29

• diet and exercise

- oral hypoglycaemic agents: various mechanisms of action

Question 30

what are some of the oral hypoglycaemic agents used to treat type 2 diabetes?

Answer 30

• sulphonylureas increase insulin secretion
• biguanides or thiazokidinediones increase tissue insulin sensitivity
• glucosidase inhibitors reduce the absorption and digestion of carbohydrates