RT Book, Section
A1 Maclaren, Noel Keith
A1 Kukreja, Anjli
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181420165
T1 Type 1 Diabetes
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181420165
RD 2024/04/19
AB Diabetes  is  the  name  given  to  a  collection  of  diseases  that  have  elevations  in  blood  glucose  levels  in  common.  Population  studies  have  defined  cutoff  levels  of  glycemia  that  are  eventually  associated  with  increased  microvascular  disease  such  as  retinopathy.  Two  replicate  fasting  levels  that  exceed  126  mg/dl  (>7  mM)  are  diagnostic  in  the  absence  of  symptoms.  Persons  with  fasting  levels  between  110  and  126  mg/dl  are  at  risk  of  diabetes  (impaired  fasting  glycemia).  Replicate,  2-h  glycemic  responses  >200  mg/dl  (>11.1  mM)  after  a  standard  oral  glucose  tolerance  test  indicates  diabetes  also.  This  stage  is  often  reached,  however,  before  the  fasting  glucose  levels  are  seen  to  rise.  Type  1  diabetes  comprises  those  forms  of  diabetes  that  are  primarily  due  to  insulin  deficiency,  however  a  relative  insulin  deficiency  also  is  part  of  type  2  diabetes,  which  is  however  less  severe,  though  it  is  compounded  by  degrees  of  insulin  resistance,  often  associated  with  obesity.  Long-term  type  2  diabetes  is  complicated  by  glucose  (glucosamine)  toxicity,  which  decreases  the  patients'  abilities  to  secrete  insulin  further,  leading  to  diagnostic  confusion  with  type  1  diabetes.  Whereas  type  2  diabetes  is  usually  strongly  familial,  type  1  is  much  less  so,  having  only  one  member  of  the  family  so  affected  in  90  percent  of  cases.The  immune-mediated  form  of  type  1  diabetes  (IMD)  is  most  common  amongst  Caucasian  races  and  is  presumed  present  when  autoantibodies  to  islet  cells  and/or  to  insulin  and/or  to  defined  islet  proteins  are  detected  in  the  presence  of  diabetes.  However,  an  insulin-deficient  type  of  diabetes  in  the  presence  of  the  risk  HLA  phenotypes  is  presumptive  evidence.  Adult  onset  IMD  is  characterized  by  a  gradual  decline  in  insulin  secretion  compared  to  children,  a  situation  readily  confused  with  type  2  diabetes  unless  autoantibodies  to  islet  cell  cytoplasm  (ICA)  and/or  to  glutamic  acid  decarboxylase  (GAD65)  can  be  detected.The  pathogenesis  of  IMD  involves  multiple  genetic  lesions  affecting  immunoregulation  against  self,  coupled  to  strong  influences  from  the  environment  affecting  penetrance.  Studies  from  rodent  models  of  the  disease  suggest  that  there  is  a  gene  dose  effect  of  quantitative  trait  loci,  with  accumulating  numbers  of  susceptibility  genes  compounding  the  risk.  There  are  protective  genes  also.  The  obligate  genes,  however,  are  those  encoding  DR  and  DQ  A  plus  B  chain  heterodimers.  Both  loci  are  involved  in  human  patients.  The  nonobese  diabetic  (NOD)  mouse  expresses  no  IE  (DR  homologous)  molecules  but  only  a  unique  recombinant  b/d  haplotype  IA  molecule  (DQ  homologous).  This  IAg7  is  a  poor  antigen  binder,  and  thus  may  allow  leakage  of  autoreactive  T  cells  from  the  thymus  into  the  peripheral  blood.  This  could  account  for  the  increased  propensity  to  develop  multiple  organ-specific  autoimmune  diseases  comprising  the  type  2  autoimmune  polyglandular  syndrome  of  which  IMD  is  a  part.  The  others  include  Addison  disease,  thyroid  autoimmune  disease  especially  Hashimoto,  atrophic  gastritis/pernicious  anemia,  vitiligo,  and  celiac  disease.  Further,  poor  expression  of  islet  cell  antigens  by  the  thymus  may  similarly  lead  to  defective  eradication  of  potentially  autoimmune-provoking  CD4+  T  cells.  Similarly,  some  studies  suggest  that  class-I  major  histocompatibility  complex  (MHC)  antigens  may  carry  some  relevant  genetic  information  in  addition  ...