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MedSci 7 2/24/09 Slide 1 LECTURE 7 Liver — Blood Glucose (Sherwood 704-715) Diabetes mellitus • Inputs and Outputs • Fed • Fasting • Types 1 & 2 – Effects • Long-term • Short-term • Regulation – Insulin – Glucagon • Food intake Dr Alan Tuffery — Physiology • • • • Diabetic Coma Types Causes Symptoms Treatment. Medical Science 2008/09 1 Sole fuel for CNS function Slide 2 Blood Glucose Concentration Sherwood Fig. 19-14 Essence: to understand how all these inputs/outputs are affected in feed/fasting states. Dr Alan Tuffery — Physiology Medical Science 2008/09 2 1 MedSci 7 2/24/09 ‘Aim’: to maintain glucose[blood] Slide 3 Glucose [blood] (Biochemical reactions in Liver) Increases Glucose [blood] 1. Glycogenolysis – Breakdown of glycogen • Liver, muscle Contributory reactions ‘new’ glucose from amino acids Dr Alan Tuffery — Physiology • Glycogen synthesis • From circulating glucose AND Switch off production 2. Gluconeogenesis – Decreases Glucose [blood] FEEDING FASTING Proteins Amino Acids Triglycerides Fatty acids. Medical Science 2008/09 3 Slide 4 Feeding & Fasting — CHO Fasting Fed • Glucose freely available Maintaining blood glucose for CNS – major energy source • Form glucose (increased supply) – Glycogenolysis • Glycogen synthesis/storage • Excess to fat Dr Alan Tuffery — Physiology • glycogen to glucose – Gluconeogenesis • forms new glucose from Amino Acids (AA) • Glucose Sparing (reduced demand) – tissues switch from glucose to Free Fatty Acids and Amino Acids. Medical Science 2008/09 4 2 MedSci 7 2/24/09 Slide 5 Amino acid homeostasis Fasting Fed (high [AA]blood) • All cells (low [AA]blood) • Muscle – AA to Protein synthesis – Proteins to AA • Liver – AA to keto-acids for energy or triglyceride synthesis which in • Liver – Gluconeogenesis • Triglycerides to adipose tissue Dr Alan Tuffery — Physiology • i.e. forms glucose. Medical Science 2008/09 5 Slide 6 Lipid homeostasis Fed Fasting (low [fat]blood) (high [fat]blood) • Fat cells • Fat cells (adipocytes) – Triglycerides to FFA + glycerol – via blood to… – Fats, protein + glucose form triglycerides (TG) • …Most cells – Fats to energy • Liver • …Liver – FFA to ketones* – triglyceride synthesis • Alt. energy source for CNS. • to adipose tissue Dr Alan Tuffery — Physiology Medical Science 2008/09 6 3 MedSci 7 2/24/09 GIP release stim by glucose in duodenum — ‘anticipatory’ Slide 7 Insulin Secretion • Rise in [Glucose]blood is main stim of secretion and release (endocrine pancreas) Esp. GIP • Acts to damp rise in glucose following digestion/absorption • Main effect is to increase glucose uptake by all cells ‘Fight/flight’. – There are other insulin responses leading to a fall in [glucose]blood Sherwood Fig. 19-15 Dr Alan Tuffery — Physiology Slide 8 Medical Science 2008/09 7 Think: inputs and outputs of [glucose]blood Insulin — acts to reduce [glucose]blood Carbohydrate 1. Remove glucose from blood [primary and unique effect of insulin] • • Increases cellular uptake (via GLUT-4 transporter recruitment) Promotes hepatic phosphorylation of glucose – Increases glucose gradient into hepatocytes • Promotes glycogenesis – Stores glucose in liver as glycogen 2. Decreases supply of glucose • Inhibits gluconeogenesis (blocks enzymes, reduces protein breakdown) • Inhibits glycogenolysis. Dr Alan Tuffery — Physiology Medical Science 2008/09 8 4 MedSci 7 2/24/09 Slide 9 Insulin acts to reduce fat/protein in blood Insulin actions (contd) Fat Protein 1. Remove fat from blood • Promotes glucose entry to cells • Promotes formation of Fatty Acids from glucose Promotes entry of Fatty Acids to cells • 1. Remove protein from blood • Promotes (active) Amino Acid entry to cells • Promotes protein synthesis 2. Reduce Amino Acid addition • Inhibits protein breakdown – 2. Reduce fat formation • Inhibits lipolysis Dr Alan Tuffery — Physiology See gluconeogenesis. Medical Science 2008/09 9 Slide 10 Insulin and Glucagon • Opposite effects: – Insulin reduces [glucose]blood – Glucagon increases [glucose]blood • Combined effect: – Maintains [glucose]blood within 70-110 mg/dl [mg/100 ml] Dr Alan Tuffery — Physiology Medical Science 2008/09 Sherwood Fig. 19-17 – Hyperglycaemia >120 mg/dl – Hypoglycaemia <60 mg/dl. 10 5 MedSci 7 2/24/09 Slide 11 Diabetes mellitus Type 1 (IDDM) Type 2 (NIDDM) • Insulin-dependent – Impaired insulin production (beta cells) • Auto-immune • Non-insulin-dependent • Impaired target-cell responsiveness to insulin • adult onset • 85-90% cases • 80% are obese • juvenile onset • 10-15% cases • Insulin replacement – Weight control – Exercise. – (islet-cell implant etc) • Monitor [glucose]blood Dr Alan Tuffery — Physiology Medical Science 2008/09 11 Slide 12 Type 1 (IDDM) — possible effects • Lipolysis increased: – – – – Blood [FFA] up: ketosis metabolic acidosis CNS (coma, death) Stanfield & Germann p 617 • Protein synthesis inhibited – Impaired growth/repair/muscle weakness. Dr Alan Tuffery — Physiology Medical Science 2008/09 12 6 MedSci 7 2/24/09 Slide 13 Diabetes — other effects (Sherwood, Fig. 19-16) Glucosuria • Urine volume increased (osmotic) – Dehydration – Blood volume (BP) down (collapse, death) Damage to blood vessels – Atherosclerosis (reduced flow) – Stroke, heart disease, renal failure – Impaired repair (gangrene) – Diabetic retinopathy. Dr Alan Tuffery — Physiology http://www2.warwick.ac.uk/fac/med/research/csri/proteindamage/physi ology/diabetes/ Medical Science 2008/09 13 Slide 14 Paradoxical rise in glucagon (IDMM) One effect of insulin lack is impaired permeability of pancreatic alpha cells to glucose (Increased permeability to glucose is a principal effect of insulin.) Hence perceived fall in [glucose] and consequent glucagon production Exacerbates hyperglycaemia. Dr Alan Tuffery — Physiology Medical Science 2008/09 14 7 MedSci 7 2/24/09 http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Diabetes_and_coma?OpenDocument Slide 15 Diabetic Coma Hyperosmolar Ketoacidotic (Type I) (Type II) Symptoms • Xs fat breakdown • Thirst • Urination • Progressive drowsiness • ‘Fruity breath’ Treatment • Fluids (iv) • Insulin • Na+ , K+ Symptoms Hypoglycaemic Symptoms • Hypoglycaemia • Hyperglycaemia (hyperosmosis) (<3.5mmol/L; 63 mg/dL) • Sweating • Severe dehydration • Hunger • Slow onset (days) • Confusion Treatment Treatment • Fluids (iv) • Medical emergency • Insulin • Glucagon/glucose. • Na+ , K+ Dr Alan Tuffery — Physiology Medical Science 2008/09 15 Slide 16 Factors Affecting Food Intake • • • • • Short-term Long Term Gut distension Glucose utilisation Insulin ATP/ADP turnover CCK • Fat stores (‘lipostat’)… • Release leptin… • Signals size of store to CNS… • Inhibits feeding [?Effect of anti-leptin or leptin deficiency] Dr Alan Tuffery — Physiology Medical Science 2008/09 16 8