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Diabetes (risk factors (Age, Nutrition (high fat/sugar diet), obesity,…

- - - - secrete insulin and amylin
      - glucose sensors
    - - secrete glucagon
    - - secrete somatostatin
    - - secrete pancreatic polypeptide
  - - - increase glucose uptake
      - increase utilisaation of glucose, AAs and fats
      - increased uptake of K+ and Ca2+
    - - increase glycogen synthesis (glycogenesis)
      - reduced glycogen breakdown (glycogenolysis)
      - increase glucose utilisation (glycolysis)
      - reduced glucose synthesis (glucogenesis)
    - - increase glucose uptake, glycolysis and glycogenogenesis
      - increse AA uptake ant protein synthesis
    - - reduce lipolysis
      - increase lipogenesis
  - - - increases glycogenolysis and gluconeogenesis
    - - increase glycogenolysis and decrease glucose uptake
    - - Increase gluconeogenesis and decrease
        glucose uptake & utilisation
  - - - Insulin is the main regulatory hormone
      - [Insulin] increases by 5-10 fold on glucose ingestion
      - decreases blood [glucose]
    - - counter regulatory hormones maintain blood [glucose]
      - glucagon, catecholamines, glucocorticoids and growth hormone
      - all increase blood [glucose]
      - essential regulators in tissues such as brain and kidney, which cannot use free fatty acids as source of energy
  - - - inside the cell glucose is metabolised in a few steps to ATP
      - ATP closes the K+ channels
        (Katp channels are open at resting state)
      - cell depolarises to about -40 mV
      - the voltage change opens vg Ca2+ channels
      - Ca2+ comes into the cell and helps to pack insulin
        in to the vesicles, which are later exocytosed
      - glucose is transported into the cell by GLUT2
    - - intracellular Ca2+ release
      - only stimulated by glucose
      - de novo synthesis of granules
- - - - used to treat hyperglycaemic ketoacidosis
      - used in sever type 2 diabetes, where diet
        and other anti-diabetic drugs fail
      - used to maintain type 1 diabetes
    - - Preproinsulin: removal of 24aa hydrophobic signal --> Proinsulin
      - Further processing in Golgi and granules with endopeptidases PC2 and PC3
      - 10% of circulating "insulin" is proinsulin (2% of insulin activity)
      - release into the portal circulation with conc (2-4ng/ml) in portal blood and conc (0.5ng/ml) in peripheral circulation
    - - soluble insulin
      - lente insulin
        
        slow release preparations of insulin,
        combined with zinc or the protein protamine
      - route of administration
        
        intravenous injections (soluble only)
        with NaCl and K+ for ketoacidosis
        
        subcutaneous injections for maintenance
    - - Conventional insulin therapy
        
        injection before breakfast and dinner
        
        combination of mixed long and short lasting preparations
      - Itensified insulin therapy
        
        once every 24h injection of long-acting insulin preparation
        
        short acting insulin injection before every meal
      - aim to mimic physiological background and
        post-prandial peaks of insulin without hypoglacaemia
    - - hypoglycaemia
        
        G<3.5 - adrenergic symptoms
        
        G<2.5 neuroglycopaenic symptoms
        
        Management
        
        Mild episodes
        
        drining a sugary drink
        
        More sever episodes
        
        administration of Glucogel to buccal mucosa
  - - - Sulphonyluraes
        
        block Katp channel - K+ cammot move out - depolarisation - increased Insulin release - hypoglycemia
        
        require functional B-cells
        
        1st generation
        
        Chloropropamide
        
        Tolbutamide
        
        Gliclazide
        
        2nd generation
        
        Glibenclamide
        
        Glipizide
        
        Glimepiride
        
        100 times more potent
        
        Katp channels
        
        found in
        
        Pancreatic B-cells
        
        smooth muscle cells
        
        Central and peripheral neurons
        
        skeletal muscle cells
        
        heart muscle cells
        
        play role in
        
        glucose dependent insulin release
        
        vascular smooth muscle tone
        
        glucose sensors in the brain
        
        muscle fatigue
        
        protective during ischemia
        
        Ischemic preconditioning
        
        these channels express different molecular make-ups in different tissues allowing for some specificity of drugs for certain tissues
        
        Gliclazide shows greater B-cell specificity than glibenclamide
    - - Biguanides
        
        Metformin
        
        also reduces hepatic glucose production
        
        also inhibits glucose absorption in the GI
        
        enhances peripheral glucose uptake
      - Thiazolidinediones
        
        Rosiglitazone
        
        Pioglitazone
        
        Toglitazone
        
        act primarily on skeletal muscle and adipose tissue to increase insulin-stimulated glucose uptake
    - - alpha-glucoside Inhibitors
        
        Acarbose
        
        delay carbohydrate absrption in the gut to reduce post-prandial blood glucose elevation
        
        useful in obese type 2 diabetic patients
        who are irresponsive to other agents
  - - - Exenatide
        
        stimultes Insulin release
        
        inhibits glucagon release
    - - Gliptins
        
        DPP-4 inactivates GLP-1
    - - Incretin and GLP-1 use the same pathway
  - - - obese
        
        Metformin
        
        Metformin + Sulphonylurea
        
        Insulin, Glitazones, Exenatide/Gliptins
      - non-obese
        
        Sulphonylurea
        
        Metformin + Sulphonylurea
        
        Insulin, Glitazones, Exenatide/Gliptins
- - - - Insulin deficiency leads to ketogenesis
      - excess lipid breakdown and appearance
        of ketone bodies in the blood
      - metabolic acidosis
      - hypeglycaemia
      - osmotic diuresis and volume loss - ketonurea
    - - Hypovolaemic shock
      - Hypokalaemia
      - Gastroparesis
      - Coma