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Insulin

Valentina Ardila Mora Medicina English

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Insulin

Insulin resistance
- measured as how much glucose is cleared from the blood in response to insulin
  - inability of peripheral target tissues to respond well to insulin
    - variability of insulin sensitivity
      - cells
      - tissues
      - individuals
    - affected by factors
      - age
      - body weight
      - physical activity levels
      - illness
      - medications
    - Effects on insulin responsive tissues
      - muscle
        decrease glucose transport
        greater impairment in nonoxidative glucose usage
        Impaired fatty acid oxidation and lipid accumulation
        lipid peroxides
      - adipose tissue
        increased lipolysis
        increased free fatty acid flux
        impair glucose utilization in muscle
        promote liver glucose production
        impair β cell function
        more visceral adiposity -> more insulin resistance
        Adipokines
        influence
        body weight
        appetite
        energy expenditure
        insulin sensitivity
        reduced adiponectin in obesity
        hepatic insulin resistance
        TNF-α, IL-6, resistin, and retinol-binding protein 4
        systemic insulin resistance
        inflammatory states
        high IL-6
        high C-reactive protein
      - liver
        fasting hyperglycemia
        decreased glycogen storage in postprandial state
        increased FPG levels
        increased VLDL triglyceride
        hepatic steatosis
        nonalcoholic fatty liver disease
        abnormal liver function tests
    - metabolic syndrome
      - include
    - insulin resistance syndrome
      - include
    - syndrome X
      - include
        insulin resistance
        hypertension
        dyslipidemia
        low HDL
        high triglycerides
        high LDL
        obesity
        central
        visceral
        impaired glucose tolerance IGT
        impaired fasting glucose IFG
        Type 2 diabetes mellitus
        Glucose metabolism in insulin-independent tissues is not altered
        peripheral, hepatic insulin resistance
        Compensating insulin release
        failure & exhaustion of pancreatic β-cell
        impaired β-cell function
        obesity accompanying type 2 DM
        part of the pathogenic process
        accelerated cardiovascular disease
        atherosclerosis
    - Mutations in the insulin receptor
      - 75 different mutations discovered
        receptor number
        ligand binding
        receptor phosphorylation
        receptor trafficking
    - Type A
      - young women
        undefined defect in the insulin-signaling pathway
        symptoms
        severe hyperinsulinemia
        obesity
        hyperandrogenism
    - Type B
      - middle-aged women
        symptoms
        severe hyperinsulinemia
        hyperandrogenism
        autoimmune disorders
        autoantibodies directed at the insulin receptor
        block insulin binding
        stimulate the insulin receptor
        intermittent hypoglycemia
    - Polycystic ovary syndrome (PCOS)
      - increases risk for type 2 DM
      - chronic anovulation
      - hyperandrogenism
    - Lipodystrophies
      - selective loss of adipose tissue
        severe insulin resistance
        hypertriglyceridemia
    - decreased peripheral glucose utilization
      - post & preprandial hyperglycemia
    - increases hepatic glucose output
      - post & preprandial hyperglycemia
    - Exercise
      - improve glycemic control
        energy availability falls
        insulin independent AMPK pathway
        fatty acid oxidation
        inhibits protein synthesis
        inhibits gluconeogenesis
        increased GLUT4 activity
        regulates energy expenditure
Insulin action
- Signaling pathway
  - plasma membrane heterotetrameric insulin receptor IR
    - linked α/β subunit dimers products of 1 gene
      - intrinsic tyrosine kinase activity is activated
        increased tyrosine phosphorylation
        One or more IRS molecules bind to the tyrosine-phosphorylated receptor
        IRS molecules are tyrosine phosphorylated
        GRB2 & PI-3K bind to IRS P-Y residues via their SH domains
        activation of intracellular signaling molecules
        mitogenic pathway
        growth effects of insulin
        cell growth and proliferation
        MAP kinase pathway
        activation p70S6K kinases
        phosphorylation of IRS
        docking of GRB2/mSOS
        small GTPase p21Ras activation
        activates Raf-1
        MEK
        ERK to nucleus
        transcriptoin factor MYC activation
        metabolic pathway
        regulates nutrient metabolism
        activation of PI-3 kinase
        PIP2 -> PIP3
        activate PDK1
        PKB/AKT
        GLUT 4–containing vesicles to cell membrane
        GLUT4
        glucose entrance
        skeletal muscle
        adipose tissue
        transcription factor Foxo1 inactivated
        gluconeogenesis inhibition
        inhibits GSK3
        GS activation
        glycogen synthesis
        PDE3B
        increases ATP
        HSL inhibitiion
        Lipogenesis
        increases ACC
        Lipogenesis
        increases ACL
        Lipogenesis
        inhibits TSC2
        Rheb
        mTOR1 activation
        protein synthesis
        caspase cascade inhibitoin
        pro survival gene expression
        SGK
        aPKC
- Function
  - promote storage of ingested nutrients
    - lowers blood glucose concentration after a meal
      - Reduction
        Glucose
        amino acids
        fatty acids
        ketoacids
- insulin secreted by pancreatic β Cells
  - 50% degraded by liver
    - insulin enters systemic circulation
      - binds to receptors in target sites
        intrinsic tyrosine kinase activity
        receptor autophosphorylation
        recruitment of intracellular signaling molecules
        metabolic effects
        mitogenic effects
- actions of insulin are mostly anabolic
  - Endocrine effects
    - Liver
      - Anabolic pathways
        glycogen synthesis and storage
        induces glucokinase and glycogen synthase
        storage capacity of 100 to 110 g of glycogen
        triglyceride synthesis
        protein synthesis
        VLDL formation
      - Catabolic pathways
        inhibits hepatic glycogenolysis
        inhibits gluconeogenesis
        Inhibits ketogenesis
    - Central nervous system
      - not considered an insulin-sensitive tissue
        key regions of the brain
        Insulin via PI3 kinase with leptin signaling
        hypothalamus
        Decreased appetite
        Increased energy expenditure
    - Skeletal muscle
      - Protein Synthesis
        Increases amino acid transport
        Increases ribosomal protein synthesis
      - Glycogen Synthesis
        500 to 600 g of glycogen are stored
        Increases glucose transport via GLUT4
        Induces glycogen synthase
        Inhibits glycogen phosphorylase
        inhibitis glycogen phosphorylase
        NOT a source of blood glucose
    - Adipose tissue
      - Triglyceride Storage
        Lipoprotein lipase induced insulin
        hydrolyze triglycerides in circulating lipoproteins
        fatty acids to the adipocytes
        increase glucose transport via GLUT4
        provides glycerol phosphate for fatty acid esterification
        hormone-sensitive lipase inhibited by insulin
  - Paracrine effects
    - inhibits α cell secretion of glucagon
    - somatostatin secreted by δ cells inhibit glucagon secretion.

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Description: Medicina Mind Map on Insulin, created by Valentina Ardila Mora on 04/10/2020.
Created by: Valentina Ardila Mora
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Insulin

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