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Met integrated PBL (Type 2 Diabetes Mellitus (Risk factors (Environment…

- - - - Common alterations
        
        :arrow_down: GLUT4
        
        Level
        
        Function
        
        Adipose tiss. & Liver
        
        Fatty acid transporter CD36
        Excess FA from blood in cell
        
        ATP produced
        
        Sat. FA metabolised
        
        Ceramide made
        TOXIC :biohazard_sign:
        
        1 more item...
        
        :arrow_up: activity Tyrosine phosphatases
        
        Tyrosine an AA in insulin receptor
        
        No Tyrosine = No activation
        
        :arrow_down: number of insulin receptors
        
        IGF-I
        
        IGF-II
        
        :arrow_down: catalytic activity of the receptor
        
        :arrow_down: PI3K/Akt activity
        
        cell signal activation
        
        :arrow_up: Ser/Thr Phosphorylation of the IRS receptor
        
        Serine/ Theonine Kinases
        activated by Pro-inflam.
        cytokines, Sat. FFA & AA
        
        Obesity = :arrow_up: Pro-inflam. cytokines & Sat. FFA
        
        IRS phosphorylated
        
        :arrow_down: Tyrosine phosphorylation :arrow_up: degredation
        
        1 more item...
      - Obesity
      - Different pathways
        
        Hyperinsulinaemia
        
        Blood insulin :arrow_up:
        
        Because Glucose :arrow_up:
        
        :arrow_up: lipid synthesis
        (Gain weight)
        
        Exacerbates insulin resistance
        
        Intrinsic
        
        Endoplasmic Reticulum Stress
        
        Mitochondrial dysfunction
        
        Oxidative stress
        
        Extrinsic
        
        Major mech. for insulin resistance
        
        Lipid accumilation
        
        :arrow_up: conc. FFA circulating
        
        Altered adipokine levels
        
        Adipose factors
        
        1 more item...
        
        Visceral adipose
        
        more likely
    - - Insulin resistance physiological
        
        Pregnancy
        
        Weight gain
        
        New Beta cells generated
        
        Increase :arrow_up:
        
        Number
        
        Size
        
        Function
        
        Glucose tolerance
        
        maintained
      - T2DM
        
        :arrow_down: Beta cells
        
        Susceptible Beta cells
        
        Overworked
        
        Cease to work
        
        ?genetics +/- environment
        
        Beta cells dysfunction
        
        apoptosis
        
        glucose tolerance
        
        1 more item...
      - Precursors
        
        Inherited
        
        Abnormal beta cell function
        
        Abnormal beta cell mass
    - - Hyperglucagonaemia
        
        T2DM
        
        ? insulin secretion defect
        
        ? resistance of alpha cells
        
        Insulin
        
        Hyperglycemia
  - - - Urbanisation
      - Lifestyle changes
    - - Inflammation
      - Mitochondria dysfunction :arrow_up:
    - - Genetics
    - - BMI >31
        
        :arrow_up: risk X 40
  - - - Drowsiness
        
        Lack of glucose to the brain
      - Recurrent infections
        
        Poor blood flow
        
        :arrow_up: glucose
      - Thirst
        
        Hyperglycemia
      - :arrow_up: urination
        
        Hyperglycemia
        
        11mmol.L in blood
        
        Excreted in urine
        
        Glucose osmotically active
        
        :arrow_up: water excreted
      - Weight Loss
        
        No lipogenesis
      - Coma
        
        Lack of glucose to the brain
    - - Abnormal glucose
        
        Fasting
        
        >/= 7mmol/L
        
        Random
        
        >/=11.1 mmol/L
      - 1 abnormal blood glucose :heavy_plus_sign: Symptoms
    - - 2 Abnormal fasting blood glucose
    - - DM Dx
        
        48 mmol/L (6.5%)
      - Advantages
        
        Reliable
        
        Stable levels
        
        No fasting
      - Limitations
        
        Cost
        
        Influence of Hb traits
        
        conditions affecting RBC turnover
      - Measures
        
        Glycosilated Hb
  - - - :arrow_up: GLP-1
        
        Insulintropic hormone
        
        :arrow_down: blood glucose
        
        Synthesised
        
        GIT
        
        L cells
        
        Colon particularly
        
        Inhibits
        
        Food intake
        
        CNS
        
        feel satiated
        
        Gastric emptying
      - GLUT4 :arrow_up:
        
        :arrow_up: Increase
        
        Glucose uptake
      - Biguanide
      - Mechanism
        
        Not understood
      - Inhibits
        
        Gluconeogenesis
        
        via Mitochondrial resp. chain complex 1
        
        :arrow_down: glucose production
    - - Thiazolidinedione
      - Weight gain
      - Binds to PPARG
        
        Found on
        
        Adipocytes
        
        Liver
        
        Skeletal :muscle:
        
        Transcription factor
        
        Glucose metabolism
        
        FFA Metabolism
        
        Adipocytes
        
        :arrow_up: increase
        
        Glucose uptake
        
        FA uptake
      - :arrow_up: increase effects
        
        Endogenous insulin
        
        :arrow_down: exogenous insulin
        
        :arrow_down: glucose production
        
        Liver
        
        :arrow_up: Glucose intake
        
        Skeletal :muscle:
        
        :arrow_up: Lipogenesis
    - - DDP-4 Inhibitor
        
        :arrow_up: like of GLP-1
        
        DDP breaks down GLP-1
        
        :arrow_up: GLP-1
        
        Insulintropic hormone
        
        :arrow_down: blood glucose
        
        Inhibits
        
        Food intake
        
        CNS
        
        feel satiated
        
        Gastric emptying
    - - e.g. Gliclazide
      - Simulate
        
        Beta cells
        
        :arrow_up: insulin
        
        Appetite
        
        Weight :arrow_up:
      - MOA
        
        binds
        
        Sulfonylurea receptor
        
        K+ ion channel closes
        
        Cell depolarises
        
        Opens Ca2+ ion channel
        
        1 more item...
      - Early T2DM
        
        Need
        
        Functioning Beta cells
    - - T2DM
        
        impaired islet compensation
      - Weight :arrow_up:
      - Monitor blood glucose lvls
      - Prolonged T2DM
        
        :arrow_down: Beta cell function
        
        :arrow_down: insulin produced
        
        Needs replacing
      - !st line
        
        Long acting Insulin
        
        +/- short acting
- - - - Low
    - - Inhibited :forbidden:
    - - Not synthesised :forbidden:
    - - Not synthesised :forbidden:
    - - Main hormone
        
        29aa peptide
      - Activates
        
        Glycogenolysis
        
        Gluconeogenesis
      - Production
        
        Islet of Langerhans
        
        Alpha cells
      - Synthesis
        
        Preproglucagon
        
        Proglucagon
        
        Glucagon
      - Secretion
        
        Regulation
        
        Low :arrow_down: glucose
        
        stimulates opening (via Katp channels)
        
        T & N type Ca2+ channel
        
        Voltage dependant Na+ channel
        
        Ca2+ influx
        
        triggers action potential
        
        1 more item...
        
        High :arrow_up: glucose
        
        :arrow_up: intracellular ADP/ATP ratio
        
        Blocks Katp channels
        
        Depolarising the membrane
        
        Inhibited
        
        Insulin
        
        Somatostatin
        
        Delta cells
        
        Phosphodiesterase
        
        Insulin activates
        
        Inhibits
        
        Glucagon - dependent signalling
        
        Alters Camp
        
        1 more item...
        
        Stimulation
        
        Low :arrow_down: blood glucose
        
        Increased :arrow_up: blood amino acid
        
        Alanine
        
        Arginine
        
        Exercise
      - :arrow_up: increases
        
        Glycogenolysis
      - Gluconeogenesis
        
        Inhibited by Insulin
        
        Low Insulin
        High Glucagon
        
        Not inhibited
        
        :arrow_up: increases
      - Lipolysis
        
        Inhibited by Insulin
        
        :arrow_up: increased in fasting
        
        Triglyceride stores
        
        Hormone sensitive lipase
        (Activated by Glucagon)
        
        FFA + Glycerol
      - Inhibits
        
        Glycolysis
        
        :arrow_up: uptake of amino acid
        (in liver)
        
        Inhibition of PFK-1
        (cAMP/PKA mediate)
        
        Inhibition of pryuvate kinase
        (cAMP/PKA mediated)
      - Beta Oxidation
        
        Glucagon stimulates CPT-1
        
        FFA enter mitochindria
        
        Carnitine Shuffle
    - - Accumilation
        
        Converted
        
        Ketone Bodies
    - - Released
        
        Stress
        
        Hypoglycemia
      - Epinephrine
        
        Inhibits
        
        Insulin
        
        Stimulates
        
        Glycogenolysis
        
        Liver
        
        Muscles :muscle:
        
        Glucagon secretion
        
        :arrow_up: increases
        
        Lipolysis
        
        Adipose tissue
      - Noradrenaline
      - Glucocorticoids
        
        Made
        
        Cortex cells
        
        Secreted
        
        Adrenocorticotropic Hormone (ACTH)
        
        From the Pituitary
        
        :heavy_minus_sign:ve feedback :recycle:
        
        Cortisol
        
        Enhances
        
        Gluconeogenesis
        
        Inhibits
        
        Glucose uptake
        
        Stimulates
        
        Muscle :muscle: Proteolysis
        
        Adipose tissue lipolysis
    - - Adipose tissue
        
        :arrow_up: Lipolysis
        
        :arrow_down: Glucose uptake
        
        :arrow_down: lipogenesis
        
        :arrow_down: re-easterfication of FFA
        
        :arrow_down: Body fat mass
      - Skeletal muscle :muscle:
        
        :arrow_down: glucose uptake
        
        :arrow_up: LPL activity
        
        :arrow_up: beta oxidation
      - Liver
        
        :arrow_up: VLDL secretion
        
        :arrow_up: HL activity
        
        :arrow_down: PPARa expresion
        
        :arrow_up: production & uptake
        
        LDL
        
        HDL
        
        IDL
        
        :arrow_up: Gluconeogenesis
  - - - :arrow_up: basal metabolic rate
    - - Number
      - Activity
      - :arrow_up: ATP synthesis
    - - Carbohydrate metabolism
        
        Rapid glucose uptake
        
        Enhance
        
        Glycolysis
        
        Gluconeogenesis
        
        :arrow_up: Insulin secretion
      - Fat metabolism
        
        Lipid mobilised rapidly
        
        :arrow_up:: Farry acids conc. in plasma
  - - - Inhibits
        
        Glucagon secretion
        
        Hepatic glucose production
      - Augments
        
        Glucose -induced
        
        insulin secretion
      - Slows
        
        Gastric emptying
      - Promotes
        
        satiety
      - Restores
        
        Beta cell function
      - :arrow_up: Insulin biosynthesis
      - Promotes
        
        Beta cell differentiation
  - - - Glucose storage
      - Synthesis
        
        Pancreas
        
        Islet of Langerhans
        
        Beta cells
        
        Two chains
        
        3 dishuphide linkages
        
        Preproinsulin
        
        Proinsulin
        (endoplasmic reticulum)
        
        Endopeptidases
        (Golgi apparatus)
        
        C peptide cleaved off
        
        Insulin
        
        Regulation
        
        Transcription
        
        mRNA stability
        
        mRNA translation
        
        Post-translation modification
      - Secretion
        
        Glucose enters Beta cells
        (GLUT2)
        
        Glucokinase acts a sensor
        
        Km High
        
        Lvl > ~5 mM
        
        :arrow_up: ATP:ADP ratio in cell
        
        Katp channels close
        
        Membrane depolarises
        
        1 more item...
        
        Km High
        
        2 Phase release
        
        First
        
        Rapid
        
        Glucose levels trigger
        
        Second
        
        Sustained
        
        Slow release
        
        Newly formed vesicles
        
        Other signals
        
        Catabolism of amino acids
        
        Intracellular
        
        :arrow_up: ATP/ADP ratio
        
        Leucine
        
        allosteric activation of GDH
        
        transaminated to KIC
        
        converted into acetyl-CoA
        
        Arginine
        
        directly depolarise the plasma membrane
        
        GLP-1
        
        Glucose dependant insulintropic peptide (GIP)
        
        Fatty acids
        
        Acetylcholine
        
        Parasympathetic release
        
        via phospholipase C
        
        Cholecystokinin (CCK)
        
        via phospholipase C
      - Physiological role
        
        Insulin responsive cells
        
        Insulin receptor
        
        Transmembrane
        
        Activated by
        
        Insulin
        
        Binds to extracellular portion
        Alpha subunits
        
        1 more item...
        
        IGF-I
        
        IGF-II
        
        Tyrosine kinase receptor
        
        Insulin
        
        Activate
        
        IRS
        
        PI3K
        
        Akt
        
        GLUT4 translocation
        
        1 more item...
        
        Glucose can enter cell
        
        Can be converted to glycogen
        
        Stimulates
        
        :muscle:
        
        Glycogen synthesis
        
        Glycogen synthase kinase (GSK) in activated by Akt
        
        Activation of glycogen synthase (GS)
        
        Adipocytes
        
        Lipogenesis
        
        Triglycerides
        
        Liver
        
        Glucose uptake
        
        Glucokinase activity :arrow_up:
        
        Glycogen synthesis
        
        Lipogenesis :arrow_up:
        
        exported as lipoproteins
        
        Inhibits
        
        Lipolysis
        
        via hormone sensitive lipase
        
        Malonyl-CoA
        
        Inhibits
        
        FFA entering mitochondria
        
        Gluconeogenesis
        
        Other functions
        
        Promotes
        
        Protein synthesis
        
        Protein storage
        
        Potassium Intracellular uptake
        
        Stimulates
        
        Amino acid transport
        
        into the cell
        
        Increases
        
        translation of mRNA's
        
        Inhibits
        
        catabolism of proteins
    - - Energy
        
        ATP
      - Stored in specific organs
        
        Liver
        
        Adipose tissue
        
        Skeletal :muscle:
      - Converted into stored molecules
        
        Glycogen
        
        Triglcerides
- - - - <18.5
    - - 18.5-24.9
    - - 25-29.9
    - - >30
    - - >40
  - - - Muscular people
    - - Better correlation
  - - - Insulin resistance
    - - altered
      - Leptin
        
        High
    - - Breakdown
        
        :arrow_up: lipids in tiss.
    - - Breakdown
        
        Regulation
  - - - Lifestyle changes
        
        Diet
        
        Exercise
    - - Lipase inhibitor
        
        :arrow_down: dietary Fat absorption
    - - Criteria
        
        Weight management
        
        BMI
        
        >40
        
        >35 + Obesity-related complications
      - Restrictive
        
        Gastric Band
        
        Sleeve gastroplasty
      - Malabsorptive
        
        Roux-en-Y gastric bypass
        
        Biliopancreatic diversion
        
        Nutrient deficiencies