Carbohydrate Metabolism

• insulin stimulates hepatic glycolysis and glycogenesis, muscle glucose uptake and glycogenesis, protein metabolism, lipid synthesis and inhibits hepatic gluconeogenesis, protein breakdown and lipolysis - it is released in the fed state
• glucagon stimulates hepatic glycogenolysis (glucose formation) and gluconeogenesis (glucose generation) and is released in the fasted state
• adrenaline stimulates hepatic and muscle glycogenolysis, lipolysis
• growth hormone (GH) stimulates protein synthesis and lipolysis and inhibits muscle glucose uptake
• cortisol stimulates hepatic gluconeogenesis, protein breakdowns and lipolysis. and inhibits muscle glucose uptake
• plasma glucose should be between 4.5 and 8.5mmol/l (normal value of 5.0mmol/l)
• plasma glucose after a meal is between 7.5 and 8.5 mmol/l
• plasma glucose after prolonged exercise is 3.0mmol/l
• raised plasma glucose causes insulin to be released from beta cells of islets of Lagerhan in pancreas
• blood glucose level is a measure of balance between uptake from the GI track and removal/utilisation by peripheral tissue with insulin favouring the latter
• polypeptide hormone is released as pro-insulin, from beta cells it is an anabolic hormone and its release is stimulated mainly by raised plasma glucose but also by raised plasma amino acids, ketones, and fatty acids
• muscle and adipose tissue have insulin receptors which bind insulin, where it is then internalized and used
• insulin is inactivated in the liver mainly by insulinase enzyme and has a half-life of 6 minutes to allow the rapid alteration in glucose uptake and utilisation.
• Should an individual become hypoglycaemic insulin secretion will decrease and glucagon secretion will increase from alpha cells causing a change in metabolism to correct the low glucose level. Thus blood glucose levels result from a balance between the actions of mainly insulin and glucagon.
• after binding insulin and receptor the complex is internalised by the surrounding membrane in a clathrin coated pit and forms an endosome - insulin is degraded in a lysome and receptors are recycled and held within cells
• prolonged increased insulin levels (obesity, type 2 diabetes, etc) lead to down-regulation of receptor numbers and contribute to insulin resistance.
• Glucose enters beta cells by the GLUT 2 transporter, which has a high Km of 15-20mmol/l
• GLUT 2 allows continual glucose entry into beta cells proportional to blood glucose levels, similar to the liver
• GLUT 2 is closely associated with glucokinase, which phosphorylates glucose and acts like a glucose sensor in the beta cell
• Glucose is metabolised via the glycolytic pathway in beta cells, leading to the production of ATP
• ATP production closes ATP-sensitive potassium channels in beta cells, causing depolarisation and the opening of calcium channels
• This opening of calcium channels results in an influx of calcium ions, triggering insulin-containing granules to translocate to the beta cell surface
• The translocation of insulin-containing granules leads to the release of insulin into the portal bloodstream from beta cells
• Sulphonylurea drugs are oral hypoglycaemic drugs which trigger insulin release and are used in treatment of type 2 diabetes: their action is to close the K channel without depending on glucose metabolism.
• actions of insulin:

  • recruit GLUT4 transporters in insulin sensitive tissue for rapid glucose uptake (muscle and adipose tissue)
  • increase synthesis of glycogen, fatty acids, lipid and protein synthesis
  • increase glycolysis
  • decrease degradation of lipids and muscle protein
  • decrease gluconeogenesis
  • increase lipoprotein lipase activity (within muscle and liver tissue)
• Insulin is secreted at a low basal level between meals and at an increased stimulated level at mealtimes
• insulin inactivity is the inability to use dietary glucose, TAG, and amino acids efficiently in the body
• insulin inactivity promotes catabolism - a starvation-like state and eventually death if untreated
• lack of insulin effects hyperglycaemia (increase glucose in blood), glycosuria and symptoms of uncontrolled diabetes
• diabetes mellitus (DM) is the most common endocrine disease world wide with all populations and age groups affected and can be caused by defects in insulin secretion, insulin action, or both. it causes chronic hyperglycaemia causing disturbances of carbohydrate fat and protein metabolism
• poor control of blood glucose leads to long-term damage, dysfunction and failure of various organs such as the eye kidney and nerves
• the number of individuals diagnosed with diabetes is rising with 3 new cases a second - making 10 million per year world wide with a projected 552 million by 2030 (1:10 of population)
• many type 2 patients remain undiagnosed
• DM type 1 (8-10%) is an absolute insulin deficiency due to beta cell destruction - an autoimmune system attack. onset usually in childhood (4-5, 10-12) and up to 40 y/o - very few are diagnosed older. it has a rapid onset of 6-8 weeks for symptoms and external insulin is required for survival
• DM type 2 (around 90%) is caused by impaired insulin activity (tissue unresponsive) due to tissue resistance and or secretory defect. usually, onset occurs over 40 y/o and it is insidious and slow
• gestational diabetes occurs due to changing hormones as your body is in a stressed state during pregnancy, but many develop diabetes within 10 years
• DM is classified using WHO (Alberti and Zimmet) criteria.

  type 1 - beta cell destruction usually leading to absolute insulin deficiency is an autoimmune idiopathic disease

  type 2 - range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with or without insulin resistance
• other specific types of DM include :

  • genetic defects of beta cell function (MODY - maturity onset of diabetes) or insulin action
  • diseases of the exocrine pancreas
  • endocrinpoathies
  • drug or chemical-induced
  • infections - often once the infection has cleared so will diabetes
  • uncommon forms of immune-mediated diabetes
  • other genetic syndromes sometimes associated with diabetes - cystic fibrosis
• DM symptoms include:

  lethargy, recurrent infections, blurred vision
• When hyperglycaemia exceeds 10mmol/l - the renal threshold is exceeded and glucose will be lost in the urine (glycosurea) which then leads to many of the presenting symptoms of diabetes