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McGill University
PHGY 210
Anne- Marie Lauzon

WEEK  2   Monday,  January  10 ,  2011   PHGY  210   Dr.  White     Endocrine  Control  of  Calcium  Homeostasis   • Calcium  ions:   o Play  a  key  role  in  many  fundamental  biological  processes   o Essential  structural  component  of  the  skeleton   § Normal  blood  clotting   § With  Na  and  K  helps  maintain  transmembrane  potential  of  cells   § Calcium  is  important  in   excitability  of  nervous  tissue   § Contraction  of  muscles   § Release  of  hormones  and  neurotransmitters   • Concentration  in  cellular  and  extracellular  fluid  is   ~  10  mg/100ml   o In  circulation  50%  free,  50%  bound  to  albumin   o ~99%  of  body  calcium  is  in   skeleton/bone.  Part  of  this  is  loosely  bound   o Bone  serves  as  a  calcium  reservoir   • Hormonal  Control   o Maintenance  of  plasma  calcium  is  achieved  by  exchange  between  bone   &  plasma  under  influence  of   hormones   o Hormones  also  affect  intestinal  absorption  of  calcium  and  excretion  by  kidneys     Three  Particularly  Important  Hormones   1. Parathyroid  hormone  (PTH) :  a  protein  produced  by  parathyroid  glands   a. It  serves  to  increase  circulating  levels  of  calcium   2. Calcitonin:  a  protein  produced  by  the  parafollicular  of  “C”  cells  of  the  thyroid  gland   a. It  lowers  the  circulating  levels  of  calcium   b. “anti-­‐parathyroid  hormone”   3. Vitamin  D:  a  steroid   a. It  increases  the  circulating  levels  of  calcium     The  Calcium  Cycle:   • Calcium  is  obtained  in  the  diet  from  milk,  cheese,  eggs,  butter,  etc   • It  is  absorbed  form  the  digestive  tract   in  the  duodenum  and  upper   jejunum  of  the  intestine   o Intestinal  Ca  absorption  is  increased  by  Vit  D  and   PTH   • Calcium  circulating  in  plasma :   o Some  calcium  will  be  deposited   in  bone  or  cells  of  other  tissues   § Calcitonin  increases  deposition  in  bone   o Some  will  go  through  the  kidney  and  be  excreted  in  the  urine   § Calcitonin  increases  this  calcium  loss   o When  plasma  concentration  is   below  10  mg/100ml  then  PTH  will  stimulate  reabsorptio n  of  calcium   from  the  intestine  and  kidney  and  increase  removal  of  calcium  from  the  bone   –  this  is  called  bone   resorption   o Therefore,  stable  blood  calcium  levels  are  dependent  on  exchange  of  calcium  between  bone  and   plasma  under  the  influence  of  the  above   hormones     Parathyroid  Hormone   • Secreted  from  parathyroid  chief  cells  that  are  embedded  in  the  surface  of  the   thyroid   • There  are  4  parathyroid  glands  located  at  the  back  of  the  thyroid  gland     1   WEEK  2   • If  parathyroids  are  removed,  there  is  a  drop  in  calcium  levels  resulting  in  tetanic  convulsions  and  death   • Structure   o 84  amino  acid  mature  polypeptide,  however  only  the  N-­‐terminal  34  amino  acids  are   important  for  full  activity   o Synthesized  as  part  of  a  larger  precursor  protein,   preproparathyroid  hormone .  Proteolytic  cleavage   renders  the  mature  form  of  PTH   o Short  half  life  –  3  to  18  minutes  (depending  on  the  person)     Functions  of  PTH   • Increase  the  concentration  of  plasma  calcium   o 1)  Bone  Resorption:  increases  bone  demineralization  thereby   increasing  calcium  concentration  in   body  fluids   o 2)  Kidney:  increase  resorption  of  calcium  in  proximal  convoluted  tubule   o 3)  Vitamin  D  Synthesis:   stimulate  conversion  of  25-­‐hydroxyvitamin  D3  to  the  biologically  active  form   of  Vitamin  D  (1,25  D3)  primarly  in  the  kidney   § 25  hydroxyvitamin  D3  has   a  long  half-­‐life  since  it  is  a  storage  form  and  not  biologically   active  form   o 4)  Gut:  PTH  and  1,25D3  facilitate  the   absorption  of  Ca  from  the  gut   • Control  of  PTH  release   o Controlled  directly  by  the  circulating   concentration  of  calcium   • Mechanism  of  PTH   activity   o Binds  to  its  cognate  receptor  on  target   cells   o Stimulates  adenylyl  cyclase  to   increase   production  of  cAMP     Problems  with  Parathyroid  Gland  Function   1. HYPOFUNCTION   a. Hypoparathyroidism :  low  levels  of  PTH  in  circulation   b. Symptoms:   i. Low  plasma  calcium  (hypocalcemia)   ii. Production  of  biologically  active  Vitamin  D  is   decreased   iii. Tetany  –  Convulsions  (more  serious  clinical  manifestations)   .  If  Calcium  <  7mg/100  ml,  increased  neural  overexcitability  leading  to  muscle   spasms   . Muscles  contract  spontaneously  and  remai n  contracted   . Spasms  of  laryngeal  muscles  can  lead  to  death  (asphyxiation)   c. Treatment   i. Administration  of  vitamin  D  and  Calcium  supplements   ii. Not  feasible  to  give  PTH  because  it  is  a  protein  and  needs  to  be  injected   2. HYPERFUNCTION   a. Hyperparathyroidism :  caused  by  adenoma  of  parathyroid  glands   b. Symptoms:   i. High  levels  of  circulating  PTH  and  high  production  of  1,25  D3   (biol.  active  Vit.  D)   ii. High  PTH  stimulates  bone  resorption  and  calcium  resorption  from  kidney   iii. 1,25  D3  increases  calcium  absorption  in  the  intestines   iv. Both  of  these  lead  to  ELEVATED  CALCIUM  in  circulation   . Leads  to  kidney  stones  (common  symptom)   . In  severe  cases,  can  get  cardiac  arrhythmias,  depressed  neuromuscular  excitability,   calcium  deposition  on  walls  of  blood  vessels,  and  cartilaginous  regions  of  bones       2   WEEK  2   c. Treatment   i. Surgery  to  remove  the  parathyroids  (not  necessarily  all  4  glands),  and  replacement   ++ therapy  for  1,25D3  and  Calcium     Vitamin  D   • Available  from  limited  dietary  sources  such  as  cod  liver  oil  and  fatty   fish   • Synthesized  from  a  cholesterol  metabolite  (technically  it  is  not  a  vitamin   then)   • Synthesis  involves  several  tissues  (Skin,  liver,  and  kidney)   • Synthesis   o 1)  UVB  light  +  7-­‐dehydrocholesterol  (skin)   o 2)  25-­‐hydroxylation  in  liver   o 3)  1-­‐hydroxylation  in  kidney  and  several  peripheral  tissue   § yields  1,25  dihydroxyvitamin  D3   • Can  have  local  synthesis  of  1,25  D3  in  different  tissues  that  are   measured  in  different  ways.   • Physiological  Function   o 1)  1  Function:  increase  calcium  absorption  in  the  intestine   o 2)  Regulates  the  immune  system   –  has  an  anti-­‐inflammatory  role   o 3)  Has  anti-­‐cancer  properties  (colon  cancer)   • Regulation  of  Vitamin  D  Synthesis  In  the  Kidney   o Increased  in  low  calcium  conditions  (where  PTH  is  increased)   o Decreased  by  high  calcium  levels   • In  northern  countries,  absence  of  UVB  may  lead  to  vitamin  D   deficiency   o Deficient  bone  mineralization   –  manifests  as  Rickets  in  growing  individuals   § If  missing  the  receptor  you  lose  normal  hair  function  and  can’t  treat  it   § If  you  have  a  deficiency  in  synthesis  you  can  give  supplements   o More  severe  in  dark -­‐skinned  people   § 6  fold  difference  in  ability  of  light  skinned  people  compared  to  dark  skinned  in  Vitamin  D   production   • Synthesis  can  also  be  defective  with  renal  failure   o Deficient  1-­‐hydroxylation  in  kidney   • Low  vitamin  D  in  Adults  leads  to   osteomalacia  (soft  bone  –  bone  defect)   o Not  enough  mineral  in  bone,  compared  to  osteoporosis  where  there  is  not  enough  proteinaceous   matrix     Calcitonin   • 32  Amino  acid  calcium-­‐lowering  peptide  hormone     o All  32  a.a.  are  necessary   • It  lowers  plasma  calcium  by  promoting  transfer  of  Calcium   from  blood  to  bone   ++ • Increases  urinary  excretion  of  Ca   • Regulation:   o Rise  in  plasma  calcium  increases  release  of  calcitonin   o Decrease  in  plasma  calcium  decreases  release  of  calcitonin   • Less  important  biologically  than  PTH  or  1,25  D3   o Absence  of  calcitonin   doesn’t  compromise  calcium  homeostasis     Adrenal  Glands   • Located  adjacent  to  the  upper  surface  of  kidneys   • Heavier  in  males   • Two  distinct  tissues:   cortex  and  medulla     3   WEEK  2   • Comparison  of  Cortex  and  Medulla   o A)  Histologically:   § Cortex  contains  large  lipid  containing  epithelial  cells   § Medulla  has  chromaffin  cells  with  fine  brown  granules   when  fixed  with  potassium  bichromate   o B)  Origin:   § Cortex  is  derived  from  mesoderm   § Medulla  is  derived  from  the  neural  crest   o C)  Function:   § Cortex  produces  steroid  hormones   • Glucocorticoids  (ex:  cortisol  in  humans,   corticosterone  in  rodents)   • Mineralocorticoids  (ex:  aldosterone)   • Progestins   § Medulla  produces  catecholamines,  epinephrine,  and  norepinephrine,  and  some  peptide   hormones  (ex:  enkephalins,  dynorphins,  and  atrial   natriuretic  peptides)     Adrenal  Cortex   • 3  morphologically  and  functionally  different  layers  *not  going  to  ask  to   differentiate  between  the  names*   o zona  glomerulosa  (mostly  mineralocorticoids  like  aldosterone)   o zona  fasciculate  (mostly  glucocorticoids  like  cortisol)   o zona  reticularis  (produces  glucocorticoids,  progestins,  androgens,   and  estrogens   • Layers  produce  different  sets  of  hormones  because  they  have  different   enzymes  present  in  them  -­‐  *don’t  need  to  memorize  structures  to  the  right*   • Activity  in  the  zona  fasciculate  and  zona  reti cularis  is  controlled  by   pituitary  hormone  adrenocorticotropin  (ACTH)   • 18-­‐hydroxylase  is  present  only  in  the  zona  glomerulosa   o important  to  the  synthesis  of  mineralocorticoids   α • 17 -­‐hydroxylase  is  absent  in  the  zona  glomerulosa  because  it  does  not  produce  glucocorticoids   • The  adrenal  cortex  hardly  stores  its  hormones,  they  are   released  into  the  blood   almost  immediately     Molecular  Mechanisms  of  Action  of  Steroid  Hormones   • Functions  to  regulate  (increase/decrease)  transcription  of  hormone/receptor-­‐ specific  target  genes   • Regulated  genes  vary  between  tissues  and  relate  specifically  to  the  functions  related   to  each  steroid  hormone  as  well  as  the  physiological  function  of  that  tissue   • Steroid  receptor  is  found  unbound  in  the  cytoplasm  wit h  a  carrier,  but  upon   binding  the  steroid  it  will  translocate  to  the  nucleus  and  regulate  transcription     Physiological  Roles  of  Adrenal  Hormones   • Aldosterone:   o Responsible  for  sodium  metabolism   + § Increases  reabsorption  of  Na  by  the  kidney   o Also  affects  the  plasma  concentration  of  K  and  H    (decreases)   § Loss  of  K  and  H occurs  in  the  urine  to  balance  the  reabsorption  of  Na   § Because  aldosterone  stimulates  production  of  a  particular  exchanger           4   WEEK  2   Glucocorticoids   • Cortisol  in  humans   • Corticosterone  in  rodents   • 1)  SALT  RETENTION   o Some  activity,  but  it  is   less  effective  than  aldosterone   o In  some  conditions,  they  can  have  low  affinity  for  mineralocorticoid  receptors   o Can  be  important  under  pathological  conditions  when  plasma  cortisol  remains  elevated   • 2)  EFFECTS  ON  PROTEIN  AND  CARBOHYDRATE  METABOLISM   o Stimulate  synthesis  of  gluconeogenic  enzymes  in  hepatocytes  and  a  number  of  enzymes  that   breakdown  proteins  in  muscle  and  other  tisues   § Leads  to  release  of  amino  acids  that  enter  the  liver  and  are  converted  to  glucose  and   glycogen  through  gluconeogenesis   o Decreases  glucose  uptake  by  muscle  and  adipose  tissue   o Decreases  glycolysis   (glucose  oxidation)   § All  of  these  result  in  INCREASE  OF  BLOOD  GLUCOSE  LEVELS  that  then  causes   an  increase  in   insulin  secretion   o Increased  blood  glucose  because  of  excess  glucocorticoid  activity  is  called   adrenal  diabetes   § Prolonged  cases  can  lead  to  destruction  of  Beta  cells  of  pancreas  ie:   diabetes  mellitus   • 3)  LIPID  METABOLISM   o Glucocorticoids  maintain  or  increase  levels  of   lipolytic  enzymes  in  adipose  tissue  cells   o Augments  lipolytic  action  of  other  hormones   § Ex:  epinephrine   o Lipids  are  used  as  fuel   § Excess  glucocorticoids  results  in   hyperlipidemia  and  hypercholesterolemia   • 4)  ANTI-­‐INFLAMMATORY  /  IMMUNOSUPPRESSIVE  ACTIONS  OF  GLUCOCORTICO IDS   o Reduce  inflammatory  response   at  sites  of  injury   o Cause  atrophy  of  the  lymphatic  system   o Decreases  levels  of  circulating  lymphocytes   –  reduce  antibody  formation   § Used  in  organ  transplantation     o Glucocorticoids  also   decrease  histamine  formation  –  decrease  allergic  reactions     • 5)  EFFECTS  OF  GLUCOCORTICOIDS  ON  BONE   o Decrease  in  protein  matrix   because  of  protein  catabolic  effect   § Increased  loss  of  Ca  from  bone  manifests  as   osteoporosis  (recall  the  definition  of  osteoporosis  above)     Control  of  Glucocorticoid   Secretion   • Controlled  by  pituitary  adrenocorticotropin  (ACTH)  –  39  amino  acid   polypeptide   o Synthesized  as  proopiomelanocortin  (POMC)   • Feedback  control  of  cortisol  secretion  is  controlled  by  the  hypothalamus   and  anterior  pituitary   • In  humans,  only  cortisol  exerts  negative  feedback  for  ACTH  release   o Enzyme  deficiencies  (ex:  lack  of  11 β-­‐hydroxylase)  prevent   cortisol  production  so  ACTH  secretion  is  not  regulated  anymore   § Referred  to  as  congential  adrenal  hyperplasia   • Treatment:     o Administration  of  cortisol   § a)  Corrects  deficiency   § b)  Normalizes  secretion  of  ACTH           5   WEEK  2   Mechanism  of  Action  of  ACTH   • Binds  specific  ACTH  receptor  on   membranes  of  zona  fasciculate  and  zona  reticularis  cells   • Stimulation  of  andenylyl  cyclase  –  increased  production  of  cAMP   • Activate  steroidogeneic   enzymes  to  increase  synthesis  and  release  of  steroid  hormones     Daily  Rhythm  of  Pla sma  Cortisol  and  ACTH   • Diurnal  rhythm  of  ACTH  and  cortisol  secretion   o Minimal  at  midnight,  maximum  in  the  morning   • Rhythm  may  be  independent  of  sleep   • Rhythm  is  abolished  by  stre ss  and  Cushing’s  disease   • Responsible  for  Jetlag     Glucocorticoids  and  Stress  Responses   • A  variety  of  stress  stimuli  (psychological  or  physical)  induce  a  significant  increase  in  synthesis  and   release  of  CRH,  ACTH,  and  cortisol   o Ex:  pain,  fear,  exercise,   hunger,  cold,  hemorrhage,  etc   • Release  of  cortisol  during  stress  can  be  ADVANTAGEOUS   o Provides  energy  and  amino  acids  through  breakdown  of  tissue  proteins  (especially  under   conditions  where  normal  feeding  isn’t  feasible   –  starvation)   • Can  also  be  DISADVANTAGE OUS   o Cortisol  inhibits  wound  healing   • Prolonged  stress  maintains   constantly  high  levels  of  glucocorticoids  that  would  lead  to  increased   blood  glucose  (diabetes  mellitus),  decreased  immune  responses  (susceptibility  to  infections),  loss  of   bone,  etc.         6   WEEK  2   Wednesday,  January  12 ,  2011   PHGY  210   Dr.  White     Pathophysiology  of  Adrenal  Cortex   • ADDISON’S  DISEASE:  hypofunction   o Characterized  by  failure  of  the  adrenal  cortex  to  produce   adrenocortical  hormones   o May  involve  total  destruction  of  the  gland   o Mostly  due  to  atrophy  of  the  adrenal  glands  due  to   tuberculosis  infection   § Also  involves  the  medulla  as  well  as  the  cortex   o Results  in  glucocorticoid  and  mineralocorticoid  deficiencies   o Glucocorticoid  deficiency   § Low  blood  sugar  (particularly  between  meals )   § Decreased  lipolysis   § Decrease  in  gluconeogenesis   § This  leads  to  a  lack  of  energy,  muscle  weakness,  and  an  inability  to  take  stress   o Mineralocorticoid  deficiency   § Since  these  stimulate  sodium  reabsorption  in  kidney   –  low  sodium  in  the  plasma  –   “Hyponatremia”   § Will  also  have  decrease  in  Chlorine  and  water  reabsorption   § All  of  these  are  lost  in  the  urine  causing:   • Decrease  in  ECF   • Decrease  in  Plasma  Volume   • Decreased  cardiac  output   § Recall,  when  sodium  is  reabsorbed,  potassium  and  protons  are  pumped  out  instead   + + § Here,  we  have  an  increase  in  K  and  H  that  is  reabsorbed  from  urine   o Mineralocorticoid  deficiency  is  the  more  dangerous  consequence  of  adrenal  hypofunction   § Addison’s  disease  patients  will  die  of  shock  7  days  after  a  complete  absence  of   mineralocorticoids   o Treatment:  Administration  of  hormones   § (Glucocorticoid)  Cortisol  à  carbohydrate  metabolism   § (Mineralocorticoid)  Aldosterone  à  controls  electrolyte  blood  levels   • CUSHING’S  DISEASE:  hyperfunction   o Characterized  by:  hyperplasia  of  the  adrenal  cortex  due  to  increased   circulating  levels  of  ACTH   § Similar  to  non-­‐toxic  goiter  in  the  sense  that  there  is  no  negative   feedback  loop  of  TSH  on  the  thyroid  à  causes  hyper-­‐production  of   hormones  in  this  case   o Excessive  production  of  glucocorticoids  as  well  as  increased  production  of   mineralocorticoids  (opposite  of  Addison’s  Disease)   o Effects  of  Glucocorticoid  increase:   § Increase  in  blood  glucose  (adrenal  diabetes)   § Increase  in  insulin  secretion   • If  prolonged,  can  cause  cells  to  burn  out  leading  to  Frank   Diabetes  Melitus  (permanent   –  Life  long)   § Decrease  in  protein  synthesis   § Increase  in  protein  breakdown   • Can  get  osteoporosis  due  to  the  loss  of  protein  from  bone   o Effects  of  Mineralocorticoid  increase:   § Increase  in  Na -  ‐  hypernatremia   § Increase  in  chlorine  and  water  reabsorbed  from  urine  as  well     7   WEEK  2   § Leads  to:   • Increase  in  ECF   • Increase  in  Plasma  Volume   • Hypertension  (high  blood  pressure)   § Decrease  in  K  (hypokalemia)  and  decrease  in  H  (Alkalosis)   o Leads  to  an  increase  in  sex  hormones  and  Androgens  à  can  cause  masculinity  in  females   o Diagnosis  based  on:   § Puffiness  of  face  (water  retention)   § Masculinizing  effect  on  females   § Hypertension  (water  retention  and  elevated  sodium)   § Increase  blood  glucose   § Increased  steroid  metabolites  in  urine  (above  basal  levels)   o Treatment:   § Surgery:  subtotal  removal  of  adrenal  cortex     The  Pancreas  as  an  Endocrine  Organ   • Located  behind  the  stomach   • Has  both  endocrine  and  exocrine  functions   o 99%  of  pancreas  is  exocrine   –secretes  digestive  enzymes   o Scattered  within  the  exocrine  pancreas  are  small  areas  of  endocrine  structures  called   Islets  of   Langerhans  –  these  are  a  compact  mass  of  cells  with  very  good  vascularization   • ~  60%  of  cells  in  Islets  of  Langerhans  are  Beta -­‐Cells  –  these  synthesize  insulin   • ~  25%  are  alpha-­‐cells  –  these  synthesize  Glucagon   o There  are  small  numbers  of  other  types  of  cel ls  ex:  Delta  cells  that  synthesize  somatostatin  and  other   hormones   • Insulin  and  Glucagon  are  small  protein  hormones  that   control  blood  glucose  concentrations   • Insulin  is  more  important  than  glucagon  –  insulin  deficiency  and/or  absence  compromises  the  well   being  of  the  individual  significantly .  If  untreated,  may  be  fatal.   o Insulin  DECREASES  blood  glucose  levels   o Glucagon  INCREASES  blood  glucose  levels   o Loss  of  glucagon  can  be  compensated  for  by  glucocort icoids,  but  insulin  loss  does  not  have  a  backup     Actions  of  Insulin   • Insulin  controls  blood  glucose  concentrations   –  it  is  the  only  hormone  that  acts  to  primarily  decrease   blood  glucose  levels   o Glucose  is  always  present  in  the  blood.   Even  while  fasting,  have  80mg/100mL  ~  5mM,  however,   there  is  very  little  free  in  tissues   o Glucose  does  not  diffuse  very  readily  into  most  cells ,  except  in  the  brain,  and  must  be  transported   § Glucose  is  hydrophilic   –  not  lipid  soluble   o A)  In  the  liver  and  muscle  cells,  glucose  is  converted  into  glycogen   o B)  In  the  adipose  tissue,  it  is   converted  into  fat  and  stored  for  later  use   o C)  In  many  cells  of  the  body  it  is   oxidized  to  produce  energy   • Insulin  Receptor   o Membrane  receptor   –  stimulates  insertion  of  glucose  transport   proteins  from  the  cytoplasm  to  the  plasma  membrane   § Results  in  increased  glucose  uptake     Insulin  Deficiency   • Results  from  autoimmune  destruction  of   Beta-­‐cells  of  Islets  of  Langerhans  –   leads  to  Diabetes  Mellitus   o Here,  most  tissues  cannot  take  up  glucose  efficiently  and   glucose  accumulates  in  circulation   • Occurs  even  if  no  g lucose  is  in  the  diet  because  the  body  resorts  to  gluconeogenesis    -­‐-­‐  the  breakdown  of   non-­‐structural  proteins  to  amino  acids  and  synthesis  of  g lucose     8   WEEK  2   • Under  these  conditions,  free  fatty  acids  (FFA)  becomes  the  principal  source  of   energy  –  increased  lipolysis.  Usually  into  4  carbon  short -­‐chain  fatty  acids.   • However,  fat  inefficiently  used   –  incomplete  oxidation  of  FFA  and  increased   circulating  acetoacetic  acid  and  Beta-­‐hydroxybutyric  acid  (metabolic  acidosis)   and  acetone  (ketosis  –  acetone  smell  in  breath  of  untreated  diabetics)   • Leads  to  decreased  blood  pH  that  causes  diabetic  coma  and  even  death,   unless  appropriate  treatment  is  provided     Other  Symptoms  of  Diabetes  Mellitus   • Increase  in  blood  glucose   • At  >  180mg%,  glucose  spills  over  into  urine,  causing  glycosuria   • Leads  to  loss  of  water  in  urine  causing  polyurea  –  dehydration  and  increased  thirst  (called  polydipsia)     • As  mentioned  above,  untreated  d iabetes  leads  to  ketosis  and  metabolic  acidosis   • Administration  of  insulin  injections  is  needed  to  restore  the  individual  back  to  normal   • In  diabetic  comas,  acidosis  and  associated  electrolyte  imbalances  must  be  corrected  in  addition  to  insulin   administration     Causes  of  Diabetes  Mellitus   • Diabetes:  comes  from  “running  through”  in  Greece  –  term  was  used  to  describe  the  symptom  of  polyuria   • Mellitus  referred  to  “sweet”   –  distinguishes  from  urine  polyuria  that  is  produced  by  people  suffering  from   anti-­‐diuretic  hormone  (ADH)  deficiency  called   Diabetes  Insipidus   • In  adults,  diabetes  mellitus  may  be  of  two  types  due  to  a  deficiency  of  Insulin  (TYPE  1    -­‐-­‐  insulin   dependent  diabetes  mellitus )  or  hypo-­‐responsiveness  to  Insulin  (TYPE  2  –  insulin  independent  diabetes   mellitus.     TYPE  1  or  INSULIN  DEPENDENT  DIABETES  MELLITUS   • A)  Destruction  of  Beta  cells  f  pancreas   –  impairs  synthesis  of  insulin   o Most  cases   o Autoimmune  disease   o Treatment:  administration  of  insulin  and  dietary  monitoring   • B)  Defective  insulin  release   o Treatment  –  drugs  stimulating  insulin  release  can  be  administered  with  proper  diet   • When  insulin  is  administered  as  a  diabetes  treatment,  dose  control  is  im  ant o Too  much  insulin  =  severe  decrease  in  blood  glucose  content   o When  glucose  reaches   20-­‐30  mg/100ml,  the  availability  of  glucose  for  the  brain  is  not  sufficient.   The  individual  may  fall  into  a   coma  known  as  an  insulin  shock  or  hypoglycemic  coma   § Must  be  treated  with   immediate  administration  of  glucose  otherwise  death  or  permanent   brain  damage  may  occur     TYPE  2  or  INSULIN-­‐INDEPENDENT  DIABETES  MELLITUS   • Insulin  levels  are  normal  or  abnormally  high !   • Problem  is  hypo-­‐responsiveness  of  target  cells  to  insulin   o Insulin  resistance  develops  often  due  to  the  decreased  number  of  insulin  receptors  on  target  cells   • Associated  with  obesity  due  to  overeating   • Prolonged  high  insulin  levels  decrease  the  number  of  receptors   –  downregulation  of  receptors   • Treatment:   o Proper  diet  and  exercise   § Decrease  in  caloric  intake  (can  be  done  medicinally),  this  decreases  insulin,  leads  to   upregulation  of  receptors   § Insulin  receptors  increase  in  response  to  frequent  endurance  exercise   (regardless/independent  of  changes  in  body  weight)       9   WEEK  2     Juvenile  Diabetes  Mellitus   • Juvenile  diabetes  mellitus  appears  in  childhood  and  is   insulin  dependent   • The  beta  cells  DO  NOT  produce  insulin   o Usually  the  auto-­‐immune  type  of  diabetes!   • Treatment:  Administration  of  insulin     Measurement  of  Glucose  Tolerance   • How  do  we  diagnose  diabetes?     o Glucose  Tolerance  Test:   § Glucose  tolerance  is  decreased  in  diabetes   (low  or  absence  of  insulin)   o   Glucose  tolerance  is  increased  in   hyperinsulinism   • After  a  fast  (overnight)  of  12  hours,  a  patient  is  given  0.75  to  1.5  g  of  glucose/kg  of   body  weight   • Blood  is  taken  before  administration,  and  at  30 -­‐60  minute  intervals  th ereafter  for  3  to   4  hours.  Glucose  is  measured.   • Blood  glucose  in  a  normal  individual  increases  in  ~  1  hour  from  80  mg  /  100  ml,  to       130  mg/ml.   o After  ~2-­‐3  hours,  it  returns  to  normal   • In  a  diabetic,  the  increase  in  blood  glucose  is  greater  than  normal  and  returns  to   normal  more  slowly     Control  of  Insulin  Secretion   • Efficient  feedback  control  of  insulin  release  is  essential  to  avoid  hypoglycemia   • Several  mechanisms:   o A)  Most  important,  beta  cells  respond  to  levels  of  blood  glucose  secreting  little  or  no  insulin   when  blood  glucose  is  low,  but  secreting  much  more  when  the  blood  glucose  is  high   o B)  Also,  gastrin  release  and  vagal  impulses  to  the  beta  cells  induce  insulin  release ,  as  a  result,   insulin  starts  to  leave  the  pancreas  even  before  the  blood  glucose  begins  to  rise  during  meals   § Signals  the  beta  cells  as  a  response  to  the  act  of  eating     Glucagon   • A  peptide  hormone  that  is   synthesized  and  released  by  alpha  cells  of  the  pancreas   • Metabolic  functions  are  opposite  of  insulin’s   –  resembles  those  of  epinephrine   • Raises  blood  sugar  by   promoting  glucogenolysis  (breakdown  of  glycogen)  and  gluconeogenesis   (synthesis  of  glucose  from  carbon  units)  in  the  liver   • In  adipose  tissue,  glucagon  increases  rate  of  lipolysis  leading  to  increased  concentration  of  free  fatty  acids   (FFA)  in  circulation   • Glucagon  interacts  with  a  G-­‐protein  coupled  membrane  receptor,  stimulating  the  activity  of  adenylyl   cyclase,  increasing  the  production  of  cyclic  AMP   • Glucagon  release  is  controlled  by  the  concentration  of  glucose  in  circulation   o Low  Blood  Glucose  content  stimulates  alpha-­‐cells  of  pancreas  thereby  increasing  synthesis  and  release   of  glucagon   o High  Blood  Glucose  content  would  decrease  release  and  decrease  synthesis  of  glucagon   • Glucagon  is  not  as  important  as  insulin   o Other  hormones  can  increase  blood  glucose  content ,  such  as  cortisol  (glucocorticoids),  as  well  as   epinephrine,  norepinephrine,  etc.     Growth  Hormone     • Produced  by  anterior  lobe  of  the  pituitary   • Also  known  as  Somatotropin  (STH)   • Responsible  for  growth       10   WEEK  2   • IT  is  a  single  chain  polypeptide  with  species   specificity—ex:  only  human  GH  works  in  humans,  rat  and   bovine  GH  does  not.   • Increases  protein  synthesis  in  many  tissues  (Bone,  muscle,  kidney,  and  liver)  by   enhancing  a.a.  uptake   by  cells  and  accelerating  transcription  and  translation  of  mRNA   • Also  increases  the  rate  of  lipolysis  and  utilization  of  free  fatty  acids  as  a  source  of  energy   o This  is  a  direct  effect  of  GH,  it  is  NOT  MEDIATED  BY  SOMATOMEDINS   • Somatomedins:   o These  are  the  many  effects  of  GH  mediated  by  substances  produced  by  the  liver  and  would  lead  to   under  stimulation  of  GH   –  somatomedins  are  the  end  organ  hormones  resulting  from  GH  
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