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MSc Clinical Biochemistry.

MSc Clinical Biochemistry.

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MSc Clinical Biochemistry.

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  1. MSc Clinical Biochemistry. Carbohydrate Metabolism.

  2. Plan For The Evening. • History of Diabetes and some things you did n’t know.. • Carbohydrate Physiology. • Diabetes Mechanisms. • Treatment. • Complications. • Some Worked Examples.

  3. It’s all Greek to Me!!! • Diabetes Mellitus • Dia through • Betes to go. • Mellitus honey “Anyone got a sweet tooth?”

  4. Not a New Disease…. • www.diabetes.ca/about-diabetes/what/history/

  5. Famous Folks. • Below are just a handful of the celebrities, sportsmen, politicians and socialites who have diabetes yet have not let the condition hold them back from attaining their goals and dreams. • Showbusiness  • Andrew Lloyd Webber,ElizabethTaylor,HalleBerry,SharonStone,Victor Garber, Vanessa Williams. • Athletes  • Ayden Byle, Chris Southwell, Steve Redgrave, Gary Mabbutt. • Musicians • Damon Dash, Aretha Franklin,Randy Jackson, Nick Jonas. • Artists, Authors & Comedians  • Jimmy Tarbuck [Comedian]HG Wells [Author]

  6. There are currently over 2.6 million people with diabetes in the UK and there are up to half a million people with diabetes who have the condition and don't know it. Including both adults and children, we estimate that: 15 per cent of people with diabetes have Type 1 diabetes. 85 per cent of people with diabetes have Type 2 diabetes. From Diabetes.org.uk

  7. Physiology. • Glucose is the principle energy source for our body. • Most organs have alternatives. • Glucose and to lesser extent ketones are the only options for brain function because. • Can’t store significant glucose. • Can’t synthesise glucose. • Can’t metabolise other substrates.

  8. Insulin. • Peptide Hormone • Produced by b cells in the Islets of Langerhans in the pancreas • Starts as pro- insulin and is cleaved to produce C-Peptide and Insulin.

  9. Glucagon. • Peptide Hormone • Produced by the a cells in the Islets of Langerhans in the pancreas. • Generally opposes action of insulin.

  10. Normal Glucose Metabolism. • The gut as a result of hydrolysis or hepatic conversion of a variety of ingested carbohydrates. • Hepatic and some other glycogen stores (glycogenolysis) • New synthesis from precursors. Gluconeogenesis occurs in the liver 70-90%ish and kidneys 10-25% from glucogenic amino acids and from glycerol, lactate and pyruvate.

  11. Mechanisms Preventing /Reversing Hypoglycaemia. • Adrenergic/ Sympathetic Response. • Promotes glycogenolysis, gluconeogenesis and increased glucose output by the liver, reduces gluocse clearance by adipose and skeletal muscle. Promotes lipolysis to provide alternative fuel sources. Inhibits insulin secretion. • Counter-regulatory Hormones. • Glucagon promotes glycogenolysis, glucosneogenis and thus increased glucose output from the liver. May increase hepatic ketone production. • Cortisol promotes glycogenolysis, glucosneogenis and thus increased glucose output from the liver. reduces gluocse clearance by adipose and skeletal muscle • Growth Hormone promotes hepatic glycogenolysis and increased hepatic glucose output, promotes lipolysis. • Other mechanisms. • Insulin secretion inhibited • Feelings of hunger promote eating. • Hypoglycaemia per se stimulates hepatic glucose output

  12. Energy Use. • Glucose provides 40-60% of bodies fuel expenditure on standard Western Diet. • During high intensity exercise and 4-6 hours post prandial glucose is the most prominent energy source. • Glucose is also the most efficient source of energy • 6 moles ATP per mole of Oxygen consumed.

  13. Glucose Transport.

  14. Glucose Cellular Uptake. • Glucose is hydrophilic and requires a transporter to help it through the cell membrane. • GLUTS potentially bidirectional. Glucose trapped in cells by phosphorylation mediated by hexokinase/glucokinase. • Glucose then used for • Aerobic use, anaerobic use, synthesis of other molecules i.e. ( glycerol and carbon skeletons of non-essential amino acids), or stored as glycogen.

  15. The input of Insulin. • Insulin interacts with insulin receptors. The signal cascade that results from this leads to GLUT molecules migrating to the cell membrane. • The insulin and their receptor molecules are subsequently internalised. Receptors are later recycled to the surface. • It is thought that internalisation of insulin is important to convey growth and protein synthesis signals to the cell nucleus. • Also important to remove insulin from the circuation.

  16. Insulin and Growth Factors. • Insulin also has a measure of growth promoting activity. • Insulin-like Growth Factors IGF-1 and IGF-2 are closely homologous to insulin and are weak agonists to insulin receptors. Their impact on glucose metabolism is possibly less significant. The role is more relevent as a cellular growth factorr. • Tumour related hypoglycaemia can be a result of IGF excess.

  17. Diabetes Diagnosis.

  18. Type 1 • 5-10% of Diabetics. • Severe insulin deficiency resulting from autoimmune B cell destruction. • Absolute requirement for exogenous insulin to avoid rapid decline into cachexia, dehydration, ketoacidosis and death. • Pre Banting and Best very poor almost universially fatal prognosis.

  19. Type 2 • Probably heterogeneous diagnosis of exclusion. • Usually a measure of insulin resistance with often an ultimate insulin deficiency. • Some patients initially misdiagnosed may have LADA. • Usually present with obesity and increased BMI. • Some argue that insulin is often required to support oral and dietary control at a median 7 years post diagnosis.

  20. Type 2 continued… • Leaner Type 2’s tend to be more insulin deficient, plumper Type 2’s tend to be more insulin resistant. • Controversial as to which mechanism predominates in Europe. • Secondary idiopathic causes may also “muddy the waters” • Inheritability a strong factor.

  21. Progress From Resistance to Deficiency

  22. Secondary Causes to Consider. • Alcohol related • Haemochromatosis • Coeliac Disease • Endocrine • PCOS • Steroid • Acromegaly • Insulin Antibodies (Historical.)

  23. Diabetic Complications. • Microvascular. • ? Principally due to hyper glycaemia per se • Increased activation of the polyol pathway ultimately rendering cells vulnerable to oxidative stress. • Sorbitol found in cateracts, peripheral nerve damage and renal glomeruli. • Advanced glycation end products have also been implicated in structural changes leading to microvascular permeability.

  24. Retinopathy.

  25. Macrovascular. • Hypertension • Lipid abnormalities. • More often a combination of low HDL, small dense LDL and hypertriglyceridaemia.

  26. Treatment. • Diet • Exercise • Smoking Cessation • Aspirin • Lipid lowering agents • ACE inhibitors et al.

  27. DCCT and UKPDS • Microvascular and to some extent maybe macrovascular complications can be delayed or even prevented by tight glycaemic control. • Oral Hypoglycaemic “of choice” metformin reduces hepatic glucose output • Other options include sulphoylureas.

  28. Diabetic Emergencies.

  29. “Routine Diabetic Testing” • Glucose to diagnose and monitor • Microalbumin to assess early stage Diabetic Nephropathy. • Renal Function • Lipids. • HbA1c

  30. HbA1c

  31. HbA1c • Important Considerations • Glycation Rates. • Assay variability • Standardisation • Assay Frequency • Anaemia.

  32. HbA1c Many people are advocating using HbA1c for diagnosis! Discuss.

  33. A Little Bit on Hypoglycaemia…..

  34. Investigation.

  35. Hypos