TY  - CHAP
M1  - Book, Section
TI  - β-Cell Dysfunction in Type 2 Diabetes: Pathophysiological and Genetic Bases
A1  - Kahn, Steven E.
A1  - Porte, Daniel
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - β-Cell  dysfunction  is  an  integral  component  of  the  pathogenesis  of  the  hyperglycemia  of  type  2  diabetes  mellitus.  This  dysfunction  is  associated  with  decreased  insulin  secretion  as  well  as  a  decline  in  the  release  of  the  newly  identified  β-cell  secretory  product  islet  amyloid  polypeptide  (IAPP  or  amylin).  Production  of  these  hormones  by  the  islet  β-cell  requires  the  packaging  of  their  respective  propeptides  (proinsulin  and  proIAPP)  into  secretory  granules,  where  they  undergo  processing  by  the  proprotein  convertases  (proconvertase  1/3  (PC1/3)  and  proconvertase  2  (PC2))  to  yield  their  mature  products  insulin  and  IAPP  and  the  inert  C-peptide,  the  latter  as  a  byproduct  of  proinsulin  processing.  Proinsulin  processing  is  incomplete,  and  small  amounts  of  proinsulin  are  released  along  with  insulin  and  C-peptide  when  secretory  granule  exocytosis  is  stimulated  by  glucose  and  nonglucose  secretagogues.Glucose-induced  exocytosis  of  the  secretory  granule  requires  entry  of  glucose  into  the  cell  via  the  facilitative  glucose  transporter  Glut-2  followed  by  its  phosphorylation  by  glucokinase.  The  subsequent  metabolism  of  glucose  results  in  the  production  of  adenosine  triphosphate(ATP),  which  raises  the  ATP/adenosine  diphosphate  (ADP)  ratio  within  the  cell  and  closes  the  specific  ATP-sensitive  potassium  channel.  In  the  case  of  the  nonglucose  secretagogues,  these  act  via  the  membrane  phosphodiesterases  or  by  activation  of  adenylate  cyclase  through  the  guanine-nucleotide  binding  proteins  (G-proteins).  All  of  these  mechanisms  are  dependent  on  the  mobilization  of  calcium  from  the  extracellular  space  or  from  intracellular  stores.Glucose  directly  stimulates  insulin  secretion  in  a  complicated  manner  involving  at  least  two  phases.  In  addition  to  stimulating  insulin  release  directly,  glucose  also  potentiates  the  β-cell  response  to  other  secretagogues.  The  secretory  responsiveness  of  the  β-cell  is  also  modulated  by  other  factors  including  the  sensitivity  of  the  peripheral  tissues  to  insulin.  The  nature  of  this  modulation  is  compatible  with  a  feedback  loop  such  that  β-cell  function  increases  reciprocally  as  insulin  sensitivity  declines.  Knowledge  of  the  nature  of  this  relationship  is  important  in  the  interpretation  of  β-cell-function  testing  in  vivo.In  type  2  diabetes,  β-cell  dysfunction  is  manifest  as  an  absence  of  the  early  (first)  phase  of  glucose-induced  insulin  and  IAPP  secretion  and  a  reduction  in  the  later  (second)  phase  response.  In  addition,  the  ability  of  glucose  to  potentiate  the  β-cell’s  response  to  nonglucose  secretagogues  is  diminished.  Finally,  oscillatory  insulin  release  is  also  abnormal  in  subjects  with  type  2  diabetes.  Many  of  these  changes  in  β-cell  function  can  be  demonstrated  in  subjects  at  high  risk  of  developing  type  2  diabetes  at  a  time  when  their  glucose  tolerance  is  essentially  normal.  These  individuals  include  women  with  a  history  of  gestational  diabetes  or  with  polycystic  ovary  syndrome,  older  subjects,  first-degree  relatives  of  individuals  with  type  2  diabetes,  and  subjects  with  impaired  glucose  tolerance  (IGT).The  etiology  of  the  β-cell  dysfunction  of  type  2  diabetes  is  incompletely  understood.  Both  genetic  and  environmental  factors  are  important.  Islet  mass  is  reduced  by  the  deposition  of  islet  amyloid  which  predominantly  replaces  β-cells.  These  amyloid  deposits  are  comprised  primarily  of  IAPP.  A  single  amino  acid  substitution  in  IAPP  has  been  described  in  a  few  Japanese  subjects,  but  this  change  does  not  explain  the  development  of  islet  amyloid  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/24
UR  - ommbid.mhmedical.com/content.aspx?aid=1181419855
ER  -