Diabetes

Diabetes

1. Type 2

   • Characteristics
     • Hyperglycaemia
       • Causes
         • Increased gluconeogenesis in the liver
         • Decreased Insulin secretion
         • Reduced Insulin Sensitivity
           • Post receptor
       • Elevated Glucose
         • Random glycosylation reactions with amines on proteins
           • Protein oxidation
         • Test (HbA1c)
         • AGEs and RAGEs
           • Inflammation
     • Insulin Resistance
       • Hyperinsulanaemia
         • Normal Beta cells
           • Increased size and function
           • NGT
       • IGT & NIDDM
         • Beta cell dysfunction
           • Apoptosis
       • Hypertension
       • Dislipidaemia
         • Elevated lipids
           • Toxic to B cells
           • Inhibits insulin signalling
       • Hyperuricaemia and gout
       • Acanthosis Nigrans
       • Premature Atherosclerosis
     • Reduced Insulin secretion
     • Obesity
       • Decreased oxidative capacity
       • Reduced mitochodrial density
   • Genetic Predisposition
     • Familial ethnic predisposition
       • Many related genes
         • ABCC8 gene A1369 allele
           • K+ ATP channel
             • Reduced ATP sensitivity
   • NIDDM

2. Insulin action

   • Promotes anabolism
   • Increased carb and lipid storage
   • Increased protein synthesis
   • Suppress catabolism
   • Target tissues
     • Adipose
       • FA and glycerol-3 phosphate
         • Make triglycerides
       • Upreguate GLUT4
         • Increased glucose transport
     • Liver
       • Glycolysis and glycogen synthesis
       • Suppress lipolysis and glucogenesis
       • Fatty acid, triglyceride synthesis
         • VLDL - lipid to periphery
       • Upregulate GLUT4
     • Muscle
       • Upregulate GLUT4
         • Increase glucose transport
       • Increase glucose metabolism and glycogen synthesis
       • Increased amino acid uptake and protein synthesis

3. Insulin signalling

   • Insulin Receptor
     • Heterotetramer
       • 2 EC alpha subunits
         • 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 TM Beta subunits
         • Signal transduction
         • Cytoplasmic Tyrosine Kinase domain
       • Linked by disulphide bond

4. DTC

   • Diagnosis
     • OGTT
     • FPG
     • RPG
     • Insulin clamp
       • Hyperglycaemic CT
         • Index for insulin secretion
           • Serum levels maintained
       • Hyperinsulinaemia CT
         • Index for glucose metabolism
   • Treatment
     • IR
       • Diet & excersize
       • Drug therapy
         • Metformin
           • Activates aMPK
             • suppresses gluconeogenesis
             • Increase GLUT4
         • Glitazones
           • Target PPARgamma
             • adipocyte differentiation
         • Sulphonylureas
           • Block ATP K+ channel
             • Increased insulin secretion
         • Gliptins
           • Inhibit DPP4
             • Stimulates insulin release
             • Inhibits glucogon release
   • Complications
     • Macrovascular
       • Hear attack
     • Microvascular
       • Nephropothy
         • Long time
       • Neuropathy
         • Loss of myelination
         • Diabetic foot
           • Grade 5 = gangrene
         • Of the autonomic systme
       • Retinopathy

5. Types

   • Diabetes Mellitus
     • Markers
       • Islet cell antibodies
       • Insulin antibodies
       • GAD
     • IDDM
   • MODY
     • Autosomal dominant
     • 11 mutations
       • Genes for pancreas development
       • Genes for insulin secretion