PHRD5015 Lecture 12 - Diabetes & Insulin Resistance

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PHRD5015 Lecture 12 - Diabetes & Insulin Resistance
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2013-10-29 22:05:00
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PHRD5015 Diabetes Insulin Resistance
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Diabetes & Insulin Resistance
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  1. percentage of US w/ diabetes as of 2010
    8.3%
  2. risk for developing diabetes for an obese person compared to non-obese
    10 times greater
  3. health consequences of diabetes (7)
    • 1) heart disease/stroke
    • 2) hypertension
    • 3) blindness/eye problems
    • 4) kidney disease
    • 5) neuropathy
    • 6) amputations
    • 7) dental disease
  4. cells responsible for removing glucose from the blood during feed
    muscle cells
  5. induces movement of GLUT4 containing vesicles to the cell surface
    insulin
  6. tissue (other than muscle) that upregulates GLUT4 expression & takes care of remaining blood glucose load
    adipose tissue
  7. how insulin keeps blood sugar low
    promotes GLUT4 expression in muscle & adipose tissue
  8. muscle & adipose GLUT4 levels are _____ in diabetics
    lower
  9. 2 reasons diabetics have high blood glucose
    • 1) muscles aren't taking up glucose at meal times
    • 2) liver is continuously making too much glucose all the time
  10. AGE
    • advanced glycosylation endproducts
    • reactive glucose slowly adducts to proteins
    • protein function is altered
  11. RAGE
    receptor for AGEs
  12. natural ligand for RAGE
    • HMG1- high mobility group I protein
    • can function as DAMP
  13. activation of ____ promotes the activation of NF-B
    RAGE
  14. glycosylation if collagens in the ECM results in...
    • increase in stiffness
    • in vessels -> leads to hypertension, decreased O2 transport, inappropriate interactions with LDLs/HDLs -> heart disease
  15. glycosylation of kidney proteins leads to...
    • decreased kidney function
    • renal tubule cells undergo apoptosis
  16. promotes inflammation mediated damage to heart & kidney tissues
    activation of RAGE
  17. formed when glucose levels are high
    sorbitol
  18. formed when glucose levels are at normal/low conditions
    glucose-6-phosphate
  19. converts glucose to glucose-6-phosphate
    hexokinase
  20. converts glucose to sorbitol
    aldose reductase
  21. hexokinase affinity and capacity/speed of conversion
    high affinity; low capacity/speed
  22. aldose reductase affinity and capacity/speed of conversion
    low affinity; high capacity
  23. proof for the importance of aldose reductase in diabetes complications
    aldose reductase knockout mice are resistant to diabetic retinopathy
  24. production of sorbitol uses up _____.
    NADPH
  25. needed for the processing of glutathione
    NADPH
  26. cells of diabetic patients have less ____ -> less protection from ROS
    reduced glutathione (GSH)
  27. VEC of diabetic patients secrete less ____ -> increased BP
    NO
  28. causes relaxation if vascular smooth muscle
    NO
  29. glucose derivative that plays important role in maintaining osmolar balance
    sorbitol
  30. 2 molecules that decrease in response to increase in sorbitol
    • 1) myo-inositol
    • 2) taurine
  31. 2 mobile osmolytes
    • myo-inositol
    • taurine
  32. loss of this type of cell is seen early in diabetic retinopathy
    pericytes
  33. pathophysiology of diabetic retinopathy (5 steps)
    • 1) loss/apoptosis of pericytes
    • 2) basement membrane thickening
    • 3) microaneurysms form
    • 4) glial cells invade
    • 5) angiogenesis of leaky vessels
  34. proposed mechanism for basement membrane thickening in diabetic retinopathy
    sorbitol alters myoinositol & taurine levels -> increased PKC levels -> increased synthesis of ECM components
  35. proposed mechanism for pericyte apoptosis in diabetic retinopathy
    sorbitol depletes NADPH -> decreased glutathione reductase activity -> oxidative stress
  36. proposed mechanism for glial infiltration in diabetic retinopathy
    sorbitol depletes NADPH -> decreased glutathione activity -> inflammasome generated signals attract glial cells
  37. insulin resistant
    can't respond to a given amount of insulin as readily as a healthy counterpart
  38. points in life where insulin resistance increases
    • puberty
    • pregnancy
    • as we age
    • with inactivity
    • increased weight gain
  39. points in life when insulin resistance decreases
    • with exercise
    • with weight loss
  40. hyperinsulinemia
    • state of requiring higher levels of secreted insulin to clear glucose properly after a meal
    • metabolic syndrome
  41. negative health consequences of hyperinsulinemia (6)
    • 1) dyslipidemia
    • 2) hypertension
    • 3) cardiovascular disease
    • 4) polycystic ovary syndrome
    • 5) non-alcoholic fatty liver disease
    • 6) increased risk of cancer
  42. dyslipidemia
    high fasting triglycerides & low HDL/cholesterol
  43. 2 resulting states in insulin resistant patients
    • 1) hyperinsulinemia
    • 2) hypertriglyceridemia
  44. insulin promotes the resorption of...
    sodium in the renal tubules of the kidney
  45. mechanism/effect of insulin-induced blood pressure change
    insulin promotes resorption of Na+ -> increased Na+ -> water retention -> increased BP
  46. (3) risk factors for cardiovascular disease
    • 1) high plasma triglyceride levels
    • 2) low HDL levels
    • 3) hypertension
  47. most common endocrine abnormality for insulin resistant women
    PCOS - polycystic ovary syndrome
  48. inhibits release of mature egg from the ovary
    secretion of testosterone by the ovary
  49. remains sensitive to insulin in insulin resistant patients
    • 1) liver
    • 2) ovaries
  50. effect of increased triglyceride synthesis by the liver
    increased triglyceride accumulation in hepatocyte eventually leading to damage & initiation of inflammatory response -> non-alcoholic fatty liver disease
  51. how insulin functions as a grown factor
    IRS-1 can activate Ras (and the MAPK cascade)
  52. cancers linked to insulin resistance (3)
    • 1) breast cancer
    • 2) endometrial cancer
    • 3) prostate cancer
  53. diabetes occurs when the ______ can no longer produce sufficient insulin for glycemic control
     cell
  54. what renders cells unable to produce insulin?
    dyslipidemia causes damage to cells, decreasing their secretory capacity and cell mass due to apoptosis
  55. cells sense
    • glucose
    • free fatty acids
  56. largest endocrine organ in the body
    adipose tissue
  57. hormones secreted by adipose tissue
    adipokines
  58. 6 adipokines
    • 1) leptin
    • 2) adiponectin
    • 3) resistin
    • 4) plasminogen activator inhibitor 1 (PAI-1)
    • 5) visfatin
    • 6) inflammatory signaling molecules (TNF, IL-1)
  59. how adipose tissue regulates metabolism
    through adipokines
  60. -secreted by adipose tissue to inhibit eating
    -acts on hypothalamus
    -functions as main homeostatic regulator of body weight
    leptin
  61. -most abundant adipokine
    -serves as an insulin sensitizer
    -secretion is associated with inflammatory disease
    adiponectin
  62. how adiponectin serves as an insulin sensitizer
    stimulates fatty acid oxidation via AMP-activated protein kinase (AMPK)
  63. increased levels of this adipokine are predictive of coronary artery disease
    adiponectin
  64. resulting effects of oxidative stress
    • detection by inflammasomes -> send out inflammatory signals (IL-1)
    • NF-B activation -> induction of inflammatory genes (TNF)
  65. scaffold associated with Pro-IL-1 cleavage and IL-1 secretion in inflamed adipocytes
    NLRP3-Asc1-Casp1
  66. marker for macrophages in mouse fat tissue
    CD68
  67. critical for macrophage recruitment as obesity develops
    inflammasome signaling
  68. association of TNF and fat
    high fat -> high TNF
  69. TNF can cause insulin resistance in ____ and ____.
    hepatocytes & adipocytes
  70. co-culture of muscle and adipose cells renders muscles sensitive to ____ so that they develop insulin resistance.
    TNF
  71. results of hepatocytes treated with TNF and insulin (4)
    • 1) decreased insulin receptor number 
    • 2) decreased autophosphorylation of insulin receptor
    • 3) decreased IRS-1 phosphorylation
    • 4) decreased Akt activity
  72. 2 kinases that can induce insulin resistance by phosphorylating IRS-1
    • 1) JNK
    • 2) IKK
  73. phosphorylation at this location on IRS-1 results in poor activation of PI3K and Akt
    Ser307
  74. adipocytes from obese individuals release ___.
    (powerful mediators of insulin resistance)
    free fatty acids
  75. treatment with acipimox (anti-lipolytic drug) decreases ___ and ____.
    free fatty acid levels & insulin resistance
  76. GPR
    free fatty acid receptors
  77. binds omega-3 fatty acids
    GPR120
  78. scavenges an adaptor molecule from TNF pathway leading to decreased IKK and JNK activation
    GPR120
  79. preferentially expressed in  cells, binds FFA released by adipose tissues expanded via obesity
    GPR40
  80. promotes inflammation when bound to FFA released by obesity-expanded adipose tissues
    GPR40
  81. type of fat that plays a greater role as the mediator of insulin resistance
    visceral fat
  82. type of fat less capable of inducing insulin resistance
    subcutaneous (peripheral) fat
  83. type of fat that contains more macrophages
    visceral fat
  84. (2) inflammatory signaling molecules secreted by adipocytes
    • MCP-1
    • leukotriene B4
  85. type of macrophages associated with an active inflammation and are found in obese fat tissue
    M1
  86. type of macrophage associated with down-regulation of the immune response
    M2
  87. gene expressed in macrophages found in adipose tissue
    CD11c
  88. 2 ways in which omega-3 FAs combat metabolic syndrome
    • 1) bind/activate GP120 leading to inhibition of NF-B (central activator of inflammation)
    • 2) create active prostaglandins and inactive thromboxanes to shift the eicosanoid balance towards the anti-inflammatory state
  89. insulin independent way to activate the AMPK-induced mobilization of GLUT4
    exercising
  90. 4 major metabolic processes affected by insulin
    • 1) increase glucose use by muscle
    • 2) decrease protein catabolism & amino acid secretion in muscle
    • 3) decrease FA & glycerol mobilization/secretion in adipose 
    • 4) decrease gluconeogenesis in liver
  91. 4 responses of insulin in metabolic processes in the insulin resistant patient
    • 1) liver gluconeogenesis insensitive to insulin
    • 2) liver FA production remains sensitive to insulin
    • 3) adipose GLUT4 expression insensitive to insulin
    • 4) adipose fat storage remains sensitive to insulin
  92. insulin resistance in adipose tissue results in
    increased FFA release

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