DCI, Myo inositol and metformin

Metformin  has a dose dependent    absorption  in humans   and its   bioavailability  is  limited to 50-60 %   because   the amount    available   may result    from pre  systemic    clearance  or binding to the intestinal wall.

Therapeutic regimens of metformin    administration are not well  standardized   and its dose   should probably be adjusted  according   to the patient’s   BMI   and insulin  resistance .

For example it was  demonstrated   that nonobese  women with PCOS  respond better than obese women to metformin    treatment   at a dosage  of 1,500   mg/ day   for 6 months   Nonobese    women in fact  showed a statistically   significant    decrease   in serum androgen    level   and fasting insulin level and also an  improvement  in menstrual  cyclicity    . Moreover   it is    possible   that women    who did not respond   to metformin   1.5 g dose  per day   might show  clinical   changes   if the dose is increased  to 2 g.

Common   side effects are gastrointestinal   such as   diarrhea nausea vomiting   bloating  abdominal  discomfort flatulence and  unpleasant metallic taste   in the mouth.

Lactic   acidosis   and hypoglycemia are very rare.

To reduce  these side  effects. It is recommended to start  metformin  with a low   dose  and then   gradually  increase  within a period  of  4-6 weeks.

Metformin  may cause vitamin  B12  malabsorption  and so  every   patient   should be  monitored for signs   and symptoms  of vitamin  B 12     deficiency    numbness paresthesia  macroglossia  behavioral     changes   and pernicious anemia.

Metformin   prescription      should be avoided  in women   with renal   insufficiency   congestive  heart     failure    sepsis   or hepatic   dysfunction

Therefore   testing  of hepatic  and renal    function is  necessary  in advance   of prescription  and thereafter yearly   testing  is indicated.

However   it has been   demonstrated    that metformin use for up to 6 months  dose not adversely affect renal   or liver   function    in  a large   sample  of  PCOS   women even   those with   mildly  abnormal    baseline    hepatic  parameters

Metformin –How long to prescribe?? The length  of metformin  treatment  in PCOS  patients   is not   standardized but   data present in literature    showed that   after a  long term   metformin treatment   drug suspension  is related   to a quick   reversion  of its beneficial  effect  on peripheral  insulin sensitivity.

The    insulin  resistance  is associated  with

Abnormally low levels  of DCI  in urine  plasma   and insulin target  tissues  

Excessive MI  urinary  excretion

Intracellular  MI  deficiency   in  insulin sensitive  tissues 

In the contrary  more recently    Nestler  proposed that in a woman   with PCOS   an initial   genetic   or environmental    insult  causing  insulin    resistance   leads to  a compensatory   hyperinsulinemia. The latter   induces a defect   that increases  renal   clearance of  DCI   and this  lead to a reduction   in circulating   DCI and its   availability     to tissue. The consequence   is an intracellular   deficiency   of DCI  and of DCI – IPG   a mediator of insulin action

Diminished release  of DCI IPG  in response   to stimulation   by insulin    results  in a further   decrease   in insulin  sensitivity  .

 Moreover  defective DCI-  IPG  release  in response    to insulin   could be due to a  qualitative    defect in the insulin signaling mechanism  that  activates  DCI IPG  mediator     release   from the membrane   there may  be a primary     defect  in the union  of the insulin   receptor  B unit to the G protein   or a defect   in  G protein activation   of phospholipase.