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Trigger  2  –Insulin  secretion    

 
Glucose  homeostasis-­‐Insulin  and  Glucagon    
Normal  blood  glucose  range  is  4  to  7  mM
...
5mM,  is  desired
...
   
Insulin  acts  by  three  mechanisms-­‐inhibiting  lipolysis,  increasing  glucose  uptake  
and  decreasing  hepatic  gluconeogenesis  and  glycogenolysis
...
 This  signals  through  PKB  and  PDK1  to  mobilise  GLUT  4  
receptors  to  the  membrane
...
   
Insulin  signalling  also  increases  glucokinase  transcription-­‐this  lowers  glucose  
concentration,  as  glucokinase  (which  has  a  high  Km)  phosphorylates  glucose  to  
G6P
...
 
 

 

 

 
Regulation  of  Insulin  Secretion    
Insulin  is  stored  in  VERY  large  quantities  in  beta  cells
...
   
Several  factors  affect  it:    
• Glucose  via  Glucose  Stimulated  Insulin  Secretion  (GSIS)
...
 This  causes  intracellular  

 

calcium  excretion  from  ER  which  allows  SNARE  mediated  vesicle  fusion  
with  da  membrane
...
 It  is  observed  to  have  numerous  effects-­‐inhibiting  
beta  cell  apoptosis,  increasing  insulin  gene  transcription,    
GLUT2  transporters  have  a  low  affinity  for  glucose-­‐this  makes  them  responsive  
to  only  higher  or  lower  concentrations  of  glucose  in  the  blood,  compared  to  
GLUT4  transporters
...
 
Mutations  are  associated  with  a  lower  affinitity  and  a  higher  blood  glucose  range
...
 The  paper  suggests  that  there  should  be  4  classes  
of  diabetes  resulting  from  gene  mutations  (instead  of  just  MODY/neonatal  
diabetes):    
1
...
 This  leads  to  a  
reduction  in  insulin  secretion  but  otherwise  beta  cells  are  healthy
...
 High  dose  sulphonylureas  
appear  to  correct  all  of  these
...
Gene  mutations  in  glucokinase  can  lead  to  stable  and  mild  fasting  
hyperglycaemia,  detected  usually  in  young  patients
...
   
3
...
 Low  
dose  sulphonylureas  are  usually  recommended
...
Diabetes  that  is  associated  with  extrapancreatic  diseases  (eg  renal  disease  
and  deafness)  can  result  from  several  other  mutations,  and  usually  
requires  early  treatment  with  insulin    
 
Diagnostic  tests  and  criteria  for  diabetes    
Standard  UK  criteria  (or  WHO  guidelines)    
Diabetes  symptoms,  plus  one  from:    
·
Random  venous  plasma  glucose  of  11
...
1mM  or  
greater,  two  hours  after  the  sugar    
Two  of  these  tests  will  usually  be  performed  on  separate  days  to  confirm  a  
diagnosis  alongside  symptoms    
   
Hb1AC    
A  HbA1C  reading  of  greater  than  6
...
 Without  symptoms  of  diabetes,  
the  test  should  be  repeated  and  if  the  result  is  less  than  this  level,  the  patient  
should  be  marked  as  high  risk  for  diabetes
...
g
...
 
Those  who  don’t  produce  insulin  (e
...
 in  type  1  diabetes)  will  have  lower  serum  c  
peptide,  which  is  produced  post  translationally  from  insulin
...
 They  can  also  be  used  to  confirm  removal  of  
insulinomas  (pancreatic  tumours)    
Normal  levels  of  serum  c  peptide  are  roughly  5  times  greater  than  insulin  levels
...
51-­‐2
...
17-­‐0
...
   
Autoantibodies    
4  common  antibodies:    

·

ICA  is  islet  cell  cytoplasmic  antibody
...
 The  most  common  antibody  used  to  detect  type  1,  
found  in  about  80%  of  patients
...
 Insulin  is  the  only  antibody  thought  to  be  highly  
specific  for  children  (though  some  is  produced  elsewhere  e
...
 macroglia)
...
 Detects  for  a  protein  known  
to  be  in  beta  cells  but  not  specific  to  them
...
 Another  antibody  against  beta  
cell  antigens,  but  is  not  specific
...
   
Diagnosing  monogenic  diabetes    
                       People  with  many  monogenic  forms  of  diabetes  (e
...
 KCNJ11  mutations)  
will  present  very  early  on,  much  earlier  than  the  normal  age  range  for  type  1-­‐for  
example,  within  the  first  year  of  life
...
diabetes
...
uk/About_us/What-­‐we-­‐say/Diagnosis-­‐ongoing-­‐
management-­‐monitoring/New_diagnostic_criteria_for_diabetes/  
Insulin  analogues    
Two  analogues  are  currently  available:    
The  first  is  rapid  acting
...
 The  amino  acid  sequence  can  be  changed  to  
interfere  with  this  to  absorb  much  faster  and  make  action  have  a  much  more  
rapid  onset
...
 There  are  two  types-­‐Glargine,  which  has  additional  
arginine  to  change  solubility  and  slow  absorption,  and  detemir,  which  uses  
additional  lysines  to  increase  binding  to  albumin,  reducing  degradation
...
     
                       The  patch  is  a  6mm2  array  of  121  needles,  each  of  which  contains  3  key  
components-­‐the  insulin,  glucose  oxidase  and  a  polymer
...
 More  insulin  is  therefore  released  in  response  to  higher  
glucose  concentrations
...
nature
...
html?WT
...
 Made  up  of  a  
glucose  sensor  (under  the  skin),  which  is  attached  to  a  wireless  transmitter,  
which  send  its  signal  to  the  insulin  pump
...
   
Can  still  be  quite  limiting  in  terms  of  movement  (with  a  sensor  under  the  skin  
etc),  but  having  a  computer  constantly  monitor  insulin  stop  the  need  for  constant  
injections
...
 Allo-­‐transplants  feature  beta  cells  
from  deceased  patient  organs
...
 This  is  done  by  
feeding  a  catheter  into  the  hepatic  portal  vein,  and  forcing  islets  into  the  liver
...
 They  are  then  infused  into  the  liver  as  with  allo-­‐transplantation
...
   
http://www
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nih
...
aspx    
 
Beta  cell  regeneration    
                       Beta  cell  regeneration  involves  trying  to  produce  a  functional  beta  cell  
mass  from  cells  already  in  the  pancreas-­‐e
...
 alpha  cells  (which  secrete  glucagon)  
or  exocrine  pancreatic  cells
...
 Certain  GI  
hormones,  such  as  gastrin,  can  induce  these  states
...
   
 
In  type  1  diabetes  where  the  beta  cells  have  been  destroyed  a  logical  response  is  
to  try  and  regenerate  their  beta  cells
...
 This  can  be  achieved  by  using  a  strategy  of  re-­‐
expressing  key  regulators  of  beta  cell  development  such  as  Ngn3,  Pdx1,  MafA
...
 When  this  was  carried  out  in  mice  the  cells  
were  reprogrammed  to  cells  which  related  to  beta  cells  and  functioned
...
 
However  with  type  1  diabetes  they  might  still  be  destroyed  by  the  immune  
response
...
   
Induced  pluripotent  stem  cell  –  from  adult  cell  reverted  back  into  a  stem  cell
...
 

 

Disadvantages:  cost,  time,  can’t  be  used  for  autoimmune  diseases,  use  of  virus  to  
integrate  pluripotency  factors  therefore  mutagenesis

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