Endocrine: DM Pathophysiology

  1. Type 1 DM Risk Factors
    Genetic predisposition

    Autoimmune trigger
  2. Type 2 DM Risk Factors
    • FH§ 
    • BMI > 25
      Sedentary lifestyle
    • Race/ethnicity (non-white Americans)
    • Previous pre-diabetes (IGT or IFG)
    • Gestational Diabetes Mellitus or baby > 9 lbs
    • Hypertension
    • Low HDL, ­ HighTG
    • PCOS, acanthosis nigricans
    • Vascular disease
  3. Insulin Synth
    • Proinsulin (A chain, B chain and C peptide)
    • C-peptide cleavage creates active insulin
    • C-peptide & insulin stored & co-secreted
    • Beta cells also secrete islet amyloid polypeptide
    • (IAPP) or amylin
  4. Beta Cell – Fasting
    • membrane remains mostly polarized
    • -> very little Ca influx; incretin levels low

    Basal insulin released to maintain euglycemia and glucose supply to muscle, fat, liver
  5. Beta Cell – Fed
    Extracellular Glu conc inc along w/incretin

    Glu trans into cell by GLUT2 (insulin indep.)

    Glu undergoes glycolysis -> pyruvate;

    Pyruvate enters the mitochondria -> ATP

    Inc ATP -> closed ATP-dep. K+ channels

    K+ channel closure depolarizes membrane

    Depolarization allows Ca channels to open

    Ca influx occurs

    Inc intracellular Ca -> migration of insulin secretory granules to membrane -> release
  6. Insulin action
    After secretion, ½ of insulin destroyed by liver

    Remaining insulin enters circulation

    Binding insulin to its receptor stims a cascade
  7. Fasting
    • -> Dec insulin
    • -> Inc glucagon
    • -> Inc glucose production
    • -> Dec uptake by fat/muscle
    • -> Inc ­ lipolysis
  8. Fed
    • -> Inc insulin
    • -> Dec glucagon
    • -> Dec glucose production
    • -> Inc uptake by fat/muscle
    • -> Dec ­ lipolysis
  9. Type 1 DM Pathophys
    Islet cell autoantibodies

    Activated lymphocytes in islets/lymph/circ

    T-cells proliferate on exposure to islet protein

    Presence of cytokines within islets
  10. Autoimmune targets in Type 1 DM
    • Insulin
    • Glutamic acid decarboxylase (GAD)
    •      o Glutamate to GABA
    • Tyr phosphatases (ICA-512/IA-2)
    • Phogrin
    •      o insulin secretory granule protein
  11. Type 2 DM Pathology
    • Beta cell dysfunction (postprandial)Excessive Hepatic glucose production (fasting)
    • Insulin resistance (postprandial)

    Tissues of greatest concern: muscle, liver, adipose, pancreas

    • Genetic predisposition?
    • * Insulin signaling – possibly
    • * Obesity & fat distribution – highly likely
  12. Type 2 DM Pathology Stages

    Insulin resistance (hyperinsulinemia)

    Impaired glucose tolerance (postprandial)

    Type 2 Diabetes Mellitus (fasting)
  13. Hyperinsulinemia
    -> downreg of insulin receptors and tyrosine kinase activity at receptors that remain

    likely 2o to a postreceptor signaling defect

    Ex: insulin binds receptor, but translocation of GLUT4 does not occur
  14. Obesity
    contributes to insulin resistance (inc. FFA & adipokines)

    • Inc FFA ->
    •      Dec Glu utilization
    •      Inc hepatic Glu prod.
    •      Dec beta cell function (insulin production)
    •      Dec adiponectin (insulin sensitizer)

    Adipokines responsible for creating the inflammatory state associated with DM
  15. Insulin secretion
    Inc FFA and dietary fat impairs beta-cell fxn

    Init. comp. inc. to maintain euglycemia -> hyperinsulinemia

    • Over time, Glu-stim'd secretion becomes
    • impaired -> postprandial hyperglycemia

    Next, glucose toxicity impairs beta-cell fxn

    Oxidative metabolism of Glu -> prod of reactive O2 spp (normally quickly detoxified)

    Beta cells have limited O2 detox proteins

    Chronic hyperglycemia -> large amounts of reactive O2 spp that dmg the cells -> Early apop & impaired gene transcription

    Hyperglycemia worsens

    Beta-cell mass declines

    Bye-bye insulin production
  16. Hepatic glucose/lipid production
    • Insulin resistance -> impaired control of
    • gluconeogenesis -> fasting hyperglycemia & dec postprandial glycogen storage

    Endogenous Glu prod is accel'd in pts w/ type 2 DM despite hyperinsulinemia b/c of hepatic insulin resistance

    Insulin resistance -> inc FFA from adipocytes -> inc lipid synth -> ­ Inc VLDL/TG & Dec HDL
Card Set
Endocrine: DM Pathophysiology
Pathophysiology of Diabetes Mellitus