T2 L8: Diabetes

• What is type 1 diabetes?

  lack of insulin

  due to autoimmune destruction of beta-cells of islets of Langerhans

  can follow viral infections

  treatment: insulin injections

  classic symptoms: thirst, tiredness, weight loss, polyuria (frequent urinating) containing glucose + ketone bodies, ketoacidosis, hyperglycaemic coma
• How is type 1 disease also a disease of glucagon excess?

  no feedback inhibition of insulin on alpha cells

  glucagon levels remain high
• What are the metabolic consequences of Type 1 diabetes?

  blood insulin levels low despite high glucose

  glucagon levels raised

  insulin:glucagon ratio cannot increase

  metabolism stuck in starved state

  induction of catabolic enzymes and repression of anabolic enzymes
• How is the liver like in the type 1 diabetic state?

  • high glucagon -> liver remains gluconeogenic -> lactate & amino acids used -> muscle wasting
  • liver uses energy from fatty acid oxidation -> Acetyl CoA formed -> converted to ketone bodies -> accumulation of ketone bodies & H+ -> ketoacidosis
  • glycogen synthesis inhibited -> glycolysis inhibited -> liver cannot buffer blood glucose
• What are ketone bodies?

  formed by condensation of 2 acetyl CoA molecules (catalysed by thiolase)

  occurs normally but increases dramatically during starvation
• What does prolonged low insulin:glucagon ratio result in?

  increased mobilisation of fatty acids from adipose tissue

  more ketone bodies formed

  more enzymes needed to synthesise and utilise ketone bodies
• Why does inceased lipid mobilization stimulate ketone body formation?

  increased demand for gluconeogenesis in liver results in depletion of oxaloacetate

  decreases capacity of TCA cycle and acetyl CoA accumulates

  which form ketone bodies via condensation
• How is muscle like in type 1 diabetic state?

  little glucose entry due to lack of insulin - contributes to hyperglycaemia

  fatty acid and ketone body oxidation as major fuel source

  proteolysis occurs to provide carbon skeletons -> muscle wasting
• How is adipose tissue like in type 1 diabetic state?

  little glucose entry due to lack of insulin

  low insulin:glucagon ratio enhances lipolysis

  release of fatty acids and glycerol into bloodstream
• How is plasma and urine like in type 1 diabetic state?

  hyperglycaemia

  • glucose concentration exceeds renal threshold & excreted in urine with loss of water - development of thirst
  • fatty acid synthesis greatly diminished: VLDLs (liver) and chylomicrons (from gut) cannot be metabolised as expression of lipoprotein lipase controlled by insulin

  result: hypertriglyceridaemia & hyperchylomicronaemia

  increases susceptibility to cardiovascular events
• What are the possible short-term life-threatening cosequences of diabetes?

  hyperglycaemia and ketoacidosis (type 1)

  hyperosmolar hyperglycaemic state / non-ketotic hyperosmolar coma: high plasma glucose with no acidosis (type 2)
• What are the possible long-term life-threatening consequences of diabetes?

  predisposition to CV disease and organ damage

  retinopathy - cataracts, glaucoma, blindness

  nephropathy

  neuropathy
• Why is glucose toxic in excess?

  high concentration of glucose results in:

  • generation of ROS
  • osmotic damage to cells
  • glycosylation leading to alterations in protein function (inflammatory)
  • formation of advanced glycation end products (AGE) which increase ROS and inflammatory proteins
• How is diabetes diagnosed (due to WHO guidelines)?

  two major tests:

  • fasting blood glucose levels (overnight fast)
  • glucose tolerance test (morning after overnight fast)
• What is HbA1c?

  glycated haemoglobin

  provides useful longer-term gauge of blood glucose control
• What is the HbA1c target (limit) for diabetics?

  48 mmol/mol (6.5%)
• How is type 1 diabetes treated?

  mimic normal daily insulin secretion via injections

  insulin secretion peak after 1 hour of meal

  plasma glucose levels return to normal after 2 hours

  different types: fast-acting, intermediate-acting, long-acting insulin

  usually patients have a combination

  
• What is type 2 diabetes?

  not enough insulin to keep blood glucose normal

  combination of:

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

  
• What are the causes of type 2 diabetes?

  failure of body to respond properly to insulin:

  1. Defects in receptors and cell signalling (insensitivity of target cells to insulin)
  2. Amyloid deposits reducing beta-cell mass (impaired insulin secretion)
• What are the mechanisms of insulin resistance?

  can be caused by a number of possible defects:

  • mutations in insulin receptor gene (very rare)
  • most important: defects in insulin signalling pathway
• What is peripheral insulin resistance induced by?

  excess fatty acids inhibit peripheral glucosa disposal & enhance hepatic glucose output

  dysregulated adipokines from adipose tissue

  defects in cellular translocation of GLUT4 & glucose uptake in adipocytes; NOT skeletal muscle (both obesity and diabetes)
• What are the features of type 2 DM?

  • develops over many years
  • approx 90% of diabetic population type 2
  • patients often older and obese
  • associated with macrovascular disease, stroke, atherosclerosis (increased VLDL and LDL)
  • may be asymptomatic or have classical hyperglycaemic symptoms
  • ketone bodies present in low concentrations
• How is metabolism like in type 2 diabetes?

  glucagon levels not as high as type 1, as some insulin present to suppress glucagon secretion

  so no uncontrolled lipolysis/ketone body secretion

  hyperglycaemia

  hypertriglycaemia & macrovascular disease due to increased VLDL synthesis in liver
• How is type 2 DM treated?

  diet and exercise (effect on GLUT 4)

  oral hypoglycaemic agents - various mechanisms of action:

  Metformin (biguanides) increase tissue insulin sensitivity