TY  - CHAP
M1  - Book, Section
TI  - Insulin Action, Insulin Resistance, and Type 2 Diabetes Mellitus
A1  - Taylor, Simeon I.
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  - Diabetes  mellitus  is  a  syndrome  characterized  by  elevated  levels  of  glucose  in  the  plasma.  The  American  Diabetes  Association  has  recently  proposed  revised  criteria  for  the  diagnosis  of  diabetes:  (a)  a  fasting  plasma  glucose  level  >126  mg/dl,  or  (b)  a  plasma  glucose  level  >200  mg/dl  at  2  h  after  the  ingestion  of  oral  glucose  (75  g),  or  (c)  random  plasma  glucose  >200  mg/dl.Diabetes  is  a  heterogeneous  clinical  syndrome  with  multiple  etiologies.  Type  1  diabetes  is  caused  by  destruction  of  pancreatic  beta  cells,  most  often  by  autoimmune  mechanisms.  Type  2  diabetes  (the  most  common  form  of  diabetes,  accounting  for  >90  percent  of  patients)  is  caused  by  a  combination  of  two  physiological  defects:  resistance  to  the  action  of  insulin  combined  with  a  deficiency  in  insulin  secretion.  Although  the  molecular  basis  of  the  common  form  of  type  2  diabetes  has  not  been  elucidated,  it  is  thought  to  result  from  genetic  defects  that  cause  both  insulin  resistance  and  insulin  deficiency.  Type  2  diabetes  generally  has  onset  after  the  age  of  40.  Unlike  type  1  diabetes,  type  2  diabetes  is  usually  associated  with  relatively  mild  hyperglycemia,  and  ketoacidosis  seldom  develops.  Gestational  diabetes  mellitus  is  a  form  of  diabetes  that  has  its  initial  onset  during  pregnancy,  and  resolves  after  the  end  of  the  pregnancy.Insulin  exerts  multiple  effects  upon  target  cells—especially  skeletal  muscle,  liver,  and  adipose  tissue.  In  general,  insulin  promotes  storage  of  fuels  (e.g.,  glycogen  and  triglyceride),  and  inhibits  the  breakdown  of  stored  fuel.  To  accomplish  these  general  physiological  functions,  insulin  exerts  multiple  specific  actions  upon  target  cells.  For  example,  insulin  promotes  recruitment  of  glucose  transporters  from  intracellular  vesicles  to  the  plasma  membrane,  thereby  stimulating  glucose  transport  into  skeletal  muscle  and  adipocytes.  Insulin  also  regulates  many  metabolic  enzymes,  either  by  increasing  or  decreasing  the  level  of  protein  phosphorylation.  In  addition,  insulin  regulates  the  level  of  intracellular  metabolites  that  regulate  enzyme  activity  by  allosteric  mechanisms.  Finally,  insulin  regulates  the  level  of  gene  expression—inducing  the  expression  of  some  genes  (e.g.,  hepatic  glucokinase)  and  inhibiting  expression  of  other  genes  (e.g.,  phosphoenolpyruvate  carboxykinase).The  biologic  actions  of  insulin  are  mediated  by  a  cell  surface  receptor.  The  receptor  possesses  an  extracellular  domain  that  binds  insulin,  and  an  intracellular  domain  that  possesses  tyrosine-specific  protein  kinase  activity.  Insulin  binding  activates  the  receptor  tyrosine  kinase,  leading  to  autophosphorylation  of  the  receptor  as  well  as  phosphorylation  of  several  intracellular  proteins  (e.g.,  insulin  receptor  substrates  -1,  -2,  -3,  and  -4).  Insulin-stimulated  tyrosine  phosphorylation  ultimately  leads  to  the  activation  of  multiple  downstream  signaling  pathways.  Among  these,  activation  of  phosphatidylinositol  3-kinase  is  the  most  important  in  mediating  the  metabolic  actions  of  insulin.  Increasing  the  cellular  content  of  phosphatidylinositol  3,4,5-trisphosphate  activates  phosphoinositide-dependent  protein  kinases  (e.g.,  PDK-1).  PDK-1  phosphorylates  and  activates  multiple  downstream  protein  kinases,  including  protein  kinase  B,  atypical  protein  kinase  C,  and  p70  S6  kinase.  Activation  of  these  protein  kinases  is  responsible  for  mediating  many  of  the  ultimate  metabolic  actions  of  insulin,  including  translocation  of  GLUT4,  activation  of  glycogen  synthesis,  and  suppressing  gluconeogenesis  by  inhibiting  transcription  of  the  gene  encoding  phosphoenolpyruvate  carboxykinase.Although  the  primary  causes  of  insulin  resistance  have  not  yet  been  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/24
UR  - ommbid.mhmedical.com/content.aspx?aid=1181420088
ER  -