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Diabetes (Definition / Prevalence (Group of metabolic diseases…

- - - - Increase in GLUT4 activity in fat and muscle/GLUT2 in liver -> more glucose absorbed -> more glycogen/protein/lipid synthesised
    - - Glucose is not absorbed and remains in bloodstream -> glycogen/protein/lipid not produced.
        .
        IR can be induced by high levels of fatty acids or centralised obesity and increased adipokine release.
        
        Increased central adiposity
        
        This occurs as a consequence of the imbalance between
        maintained (or increased) food intake and reduced physical
        activity
        
        Also, reduced oestrogen and testosterone levels that occur
        with ageing contribute to the increased visceral fat mass
        (oestrogen and testosterone increase lipolysis)
        
        Expanded adipocytes secrete adipokines, such as TNFα -
        obese people have chronically elevated TNFa levels
        
        IN ANIMALS TNFa is associated with:
        
        reduced GLUT4 expression.
        
        increased blood glucose
        
        increased fasting plasma insulin
        
        decreased insulin sensitivity
        
        Increased free fatty acids levels - saturated fat.
        
        FFAs activate inflammatory signalling, decrease mitochondrial
        function and stimulate accumulation of DAG and reactive oxygen species (ROS)
        
        Increased DAG, via de novo synthesis or through mitochondrial dysfunction, activates PKC isoforms
        
        FFAs stimulate Toll-like receptor 4 to activate JNK and IKKb, which are also activated by increased ROS
        
        PKC, JNK and IKKb phosphorylate IRS1/2 on serine residues to inhibit insulin receptor interaction
        
        Decreased IRS1/2 tyrosine phosphorylation results in
        reduced insulin signalling.
        
        These kinases increase serine phosphorylation of IRS proteins -> insulin resistance
        
        Decreased Skeletal Muscle Mass
        
        Mitochondria in aged skeletal muscle produce less ATP and
        more ROS, promoting oxidative stress and insulin resistance
        
        This reduces the rate of calories used by the body and
        exacerbates the problems associated with increased
        adiposity
    - - Impaired β-cell stimulus-secretion coupling
        
        Increased ROS generation, decreased ATP synthesis and
        decreased [Ca2+]
        
        In normal mitochondria oxidation of NADH and FADH2 drives ATP synthesis.
        
        β-cells have very low levels of SOD and catalase so are susceptible to damage when ROS levels are
        abnormally high.
        
        Increased glycolysis under hyperglycaemia overloads the mitochondria driving increased ROS generation
        
        Impaired b-cell mitochondria function results in decreased ATP generation
        
        Ageing leads to:
        
        Islet mitochondria malfunction
        
        Reduced Ca2+ entry and mobilisation from endoplasmic reticulum stores
        
        Impaired Ca2+ in response to glucose
      - Islet amyloid deposition and increased β-cell apoptosis
        
        Amyloid deposition is commonly seen in T2D.
        
        Amyloid is the trigger for a protein complex called the inflammasome that leads to the production of the proinflammatory agent IL-1b, which can induce β-cell apoptosis
        
        Protein misfolding and ER stress could also lead to cell apoptosis
      - Reduced beta-cell proliferation
        
        Healthy beta cells can respond to insulin resistance by increasing proliferation
        
        BUT THIS ABILITY DECREASES IN AGE.