LMP301 2014 Lecture 13.pdf

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University of Toronto St. George
Laboratory Medicine and Pathobiology
Kenneth Yip

  Lecture  13:  Diabetes   Diabetes  in  Canada   -­‐ Diabetes  takes  several  years  before  it  is  actually  diagnosed   o Can  be  on  the  verge  of  being  diagnosed,  but  not  diabetes  yet   -­‐ 2.4  million  of  Canadians  with  Diabetes   -­‐ 570,000  Canadians  have  undiagnosed  type  2  diabetes   -­‐ 6  million  with  pre-­‐diabetes  or  at  risk  of  Type  2  diabetes   -­‐ $17.4  billion  estimated  economic  impact  (cost  to  health  care  system)     Diabetes  mellitus  (DM)   -­‐ common  endocrine  disorder   -­‐ characterized  by:  hyperglycemia  (lots  of  glucose  in  blood)   -­‐ cause:  lack  of  insulin  secretion  OR  lack  of  insulin  action  OR  both     Glucose  Metabolism   1) insulin  binding  to  receptor   o 3-­‐4  insulin’s  will  bind  to  a  receptor  in  the  presence  of   glucose   2) protein  activation  cascade   o this  activates  a  cascade  of  proteins   3) translocation  of  Glut-­‐4  to  membrane   4) influx  of  glucose  (liver,  brain  –  main  glucose  intak e)   5) Glycogen  synthesis  –  some  glucose  stored  as  glycogen   6) Glycolysis     7) Fatty  acid  synthesis     Glucose  Homeostasis   -­‐ blood  glucose  maintained  with  narrow  limits   Fed  State:   -­‐ liver  removes  70%  of  glucose  load  (whatever  we  ingest,  70%  will  be  removed  by  the  liver)   -­‐ glucose  is  oxidized  and  converted  to  glycogen   -­‐ excess  glucose:  converted  to  VLD  lipoprotein  in  liver  AND  then  transported  to  adipose  tissue   Fasting  State:   -­‐ plasma  glucose  is  low   -­‐ glycogen  breakdown   -­‐ gluconeogenesis  (from  glycerol,  lactate,  pyruvate,  amino  acids)   o glycogen  is  first  used,  as  its  being  used  up,  you  move  onto   glycerol,  lactate,  pyruvate,  amino  acids   -­‐ utilize  glucose  within  12 -­‐17  hours,  then  we  enter  fasting  state   -­‐ nowadays,  humans  are  never  really  in  a  fas ting  state  (constantly  taking  up  sugar  and  converting  it  to  fat  and   storing  it)         Glucose  Homeostasis  –  Hormonal  Regulation   -­‐ Lower  of  glucose:   o Insulin  (produced  by  Pancreas  β-­‐cells)   § Main  goal:  lower  glucose  in  plasma,  and  into  cells   -­‐ Increase  of  glucose  into  plasma:   o Glucagon  (pancreas  α-­‐cells)   o Growth  hormone  (anterior  pituitary)   o Adrenaline     o Cortisol  (adrenal)     Insulin   -­‐ Synthesized  in  pancreas  (β-­‐cells)   -­‐ Small  protein:  MW=5808   -­‐ Composed  of  two  amino  acid  chains  connected  with  disulfide  links   -­‐ Synthesized  as  insulin  pre-­‐pro-­‐hormone  (MW-­‐  11,500)  cleaved  to  proinsulin       (MW=9000)  and  further  cleaved  to  insulin  (Active)       Insulin  and  Glucose  Metabolism   -­‐ insulin  inhibits  glycolysis  and  ketogenesis  –  promotes  glucose  uptake   -­‐ insulin  inhibits  somatostatin   -­‐ insulin  inhibits  synthesis  of  glucagon     Metabolic  Effects  When  there  is  Lack  of  Insulin   -­‐ decrease  in:   o glucose  uptake  in  muscle   o glucose  uptake  in  the  liver   o synthesis  of  glycogen  in  the  liver   o glycolysis   o synthesis  of  protein  (amino  acids  need  to  be  utilized  to  produce  glucose)   o uptake  of  ions  (K+  and 4  )   -­‐ increase  in:   o gluconeogenesis  (glucose  synthesis  from  amino  acids,  pyruvate,  lactate)   o glycogenolysis  (break  down  of  glycogen)   o lipolysis  (break  down  of  fat)   o ketogenesis  (reduce  ketones)   o proteolysis  (break  down  of  proteins)     Classification  of  Diabetes  Mellitus     -­‐ Type  1  Diabetes   o Autoimmune  disease   § Antibodies  destroy  pancreatic   β-­‐cells  (which  produces  insulin)   o Autoimmune  destruction  of  pancreatic   β-­‐cells   o Insulin  Deficiency   o Accounts  for  10-­‐15%  of  all  diabetics  (a  less  common  type  of  diabetes)   o Common  in  the  young  –  diagnosed  early  on  in  life   -­‐ Type  2  Diabetes   o Resistance  of  peripheral  tissues  to  the  action  of  insulin   § Individuals  have  insulin,  but  cells  are  not  responding  to   insulin  =  no  regulation  of  plasma  glucose   o Insulin  level  normal  or  high  –  body  tries  to  reduce  glucose,  but  cells  are  not  responding  to  insulin   o Common  between  40  and  80  y ears  old   o Accounts  for  85%  of  all  diabetics  –  more  common  type  of  diabetes   o Now  seen  in  adolescents  and  children  (because  of  obesity)   o Obesity   -­‐ Gestational   o Glucose  Intolerance  during  pregnancy   o At  the  end  of  pregnancy,  normal  ability  to  metabolize  glucose  comes  back  (but  not  always)   -­‐ Other   o Genetic  diseases  leading  to  defective  pancreatic   β-­‐  cells  OR  other  genetic  diseases  of  the  pancreas  OR  other   endocrine  organs  (hemochromatosis,  Cushing’s,  Pheochromocytoma  etc .)     Complications  of  Diabetes  Mellitus   -­‐ Microangiopathy     o small  vessel  are  being  destroyed/effected  due  to  high  levels  of  glucose   -­‐ retinopathy  (eye  disease)   -­‐ nephropathy  (kidney  problems   –  can  lead  to  kidney  failure)   -­‐ neuropathy  (peripheral  nervous  system  affected)   -­‐ macroangiopathy  (disease  in  larger  vascular  system)     Diagnosis  of  Diabetes  Mellitus   -­‐ measure  blood  glucose   o fasting  plasma  glucose  (FPG)  >  7.0  mmol/L   o random  plasma  glucose  (PG)  >   11.1mmol/L   § not  necessarily  during  fasting  period       § thirsty  (constant  need  of  water)   § at  the  SAME  TIME,  if  they  have:   polyuria  (high  volume  and  frequency  of  urine),  polydipsia,  weight   loss  (not  enough  glucose  intake  from  cells)   à  consistent  with  diagnosis  of  diabetes   o oral  glucose  tolerance  test  (OGTT)     § used  when  there  is  ambiguity  in  results   § 75  grams  of  glucose  à  measure  random  plasma  glucose  (PG)  2  hours  later   § if  results  in  >11.1mmol/L  =  diabetes   § Confirm  with  repeat  testing  on  another  day   § Hard  to  diagnose  fasting  plasma  glucose   –  need  to  challenge  the  system  to  see  if  body  responds   normal     Diagnostic  Criteria     FPG  (mmol.L)     2  hours  later  OGTT   PG  (mmol/L)   Normal   4.0  –  6.0     <  7.8   Glucose  kept  at  tight  range   Impaired  Fasting  Glucose   6.1  –  6.9       (IFG)   during  fasting  -­‐  just  above  the  normal  range,  but  not   diabetic  yet   -­‐  just  above  normal,  but  just  below  diabetic  state   Impaired  Glucose  Tolerance   <  6.1   AND   7.8  –  11   (IGT)   Below  6.1,  but  after  2  hours,  they  have  a  problem  with   metabolizing  glucose   -­‐  fastin
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