Diabetes

Diabetes

Type 2
1. Characteristics
  1. Hyperglycaemia
    1. Causes
      1. Increased gluconeogenesis in the liver
      2. Decreased Insulin secretion
      3. Reduced Insulin Sensitivity
        Post receptor
    2. Elevated Glucose
      1. Random glycosylation reactions with amines on proteins
        Protein oxidation
      2. Test (HbA1c)
      3. AGEs and RAGEs
        Inflammation
  2. Insulin Resistance
    1. Hyperinsulanaemia
      1. Normal Beta cells
        Increased size and function
        NGT
    2. IGT & NIDDM
      1. Beta cell dysfunction
        Apoptosis
    3. Hypertension
    4. Dislipidaemia
      1. Elevated lipids
        Toxic to B cells
        Inhibits insulin signalling
    5. Hyperuricaemia and gout
    6. Acanthosis Nigrans
    7. Premature Atherosclerosis
  3. Reduced Insulin secretion
  4. Obesity
    1. Decreased oxidative capacity
    2. Reduced mitochodrial density
2. Genetic Predisposition
  1. Familial ethnic predisposition
    1. Many related genes
      1. ABCC8 gene A1369 allele
        K+ ATP channel
        Reduced ATP sensitivity
3. NIDDM
Insulin action
1. Promotes anabolism
2. Increased carb and lipid storage
3. Increased protein synthesis
4. Suppress catabolism
5. Target tissues
  1. Adipose
    1. FA and glycerol-3 phosphate
      1. Make triglycerides
    2. Upreguate GLUT4
      1. Increased glucose transport
  2. Liver
    1. Glycolysis and glycogen synthesis
    2. Suppress lipolysis and glucogenesis
    3. Fatty acid, triglyceride synthesis
      1. VLDL - lipid to periphery
    4. Upregulate GLUT4
  3. Muscle
    1. Upregulate GLUT4
      1. Increase glucose transport
    2. Increase glucose metabolism and glycogen synthesis
    3. Increased amino acid uptake and protein synthesis
Insulin signalling
1. Insulin Receptor
  1. Heterotetramer
    1. 2 EC alpha subunits
      1. Binds insulin
        Activates
        Insulin Receptor phosphorylation
        IRS 1-4 recruitment and phosphorylation
        IRS1 bound p85
        recruits p110
        PIP2-PIP3
        PIP3 binds PH domains
        PDK1&2
        Akt
        Targets
        GSK3
        Increased glycogen synth
        AS160
        Translocation of GLUT4 to membrane
        Defects in aPKCs
        FOXO
        Regulatory TF
        Reduce gluconeogenic genes
        TSC1/2
        Increased protein synth
        Impaired binding
        Phosphorylation @ ser312
        Increased FFA exacerbates
    2. 2 TM Beta subunits
      1. Signal transduction
      2. Cytoplasmic Tyrosine Kinase domain
    3. Linked by disulphide bond
DTC
1. Diagnosis
  1. OGTT
  2. FPG
  3. RPG
  4. Insulin clamp
    1. Hyperglycaemic CT
      1. Index for insulin secretion
        Serum levels maintained
    2. Hyperinsulinaemia CT
      1. Index for glucose metabolism
2. Treatment
  1. IR
    1. Diet & excersize
    2. Drug therapy
      1. Metformin
        Activates aMPK
        suppresses gluconeogenesis
        Increase GLUT4
      2. Glitazones
        Target PPARgamma
        adipocyte differentiation
      3. Sulphonylureas
        Block ATP K+ channel
        Increased insulin secretion
      4. Gliptins
        Inhibit DPP4
        Stimulates insulin release
        Inhibits glucogon release
3. Complications
  1. Macrovascular
    1. Hear attack
  2. Microvascular
    1. Nephropothy
      1. Long time
    2. Neuropathy
      1. Loss of myelination
      2. Diabetic foot
        Grade 5 = gangrene
      3. Of the autonomic systme
    3. Retinopathy
Types
1. Diabetes Mellitus
  1. Markers
    1. Islet cell antibodies
    2. Insulin antibodies
    3. GAD
  2. IDDM
2. MODY
  1. Autosomal dominant
  2. 11 mutations
    1. Genes for pancreas development
    2. Genes for insulin secretion

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