May 14, 2006

Zyprexa's Weight Gain: Does What You Eat Matter More Than How Much?

The authors of this article have an interesting hypothesis, upon which I speculate wildly.  But it is fascinating: 


GLUT5, is found primarily in the small intestine (though also in muscle and kidneys.)  What's interesting about it is that it transports fructose, which in turn directly stimulates additional GLUT5 mRNA  expression.  You eat fructose, this increases the expression of GLUT5 in the intestinal villi, which increases the transport of fructose.  So the more fructose you eat, the more readily you can absorb it.


Now fructose doesn't stimulate insulin secretion.  Since insulin regulates leptin, fructose actually reduces leptin.  Fructose increases ghrelin. So you get hungry.  Fructose goes to the liver and is metabilized to acyl glycerols, and consequently result in  increased triglycerides.


So you have a situation in which Remeron and Zyprexa (and high dose Haldol) cause an increase in GLUT5 expression; if they are also eating fructose (read: high fructose corn syrup) this is causing an additional expression in GLUT5, and hunger, and increased triglycerides...  if one wants to conduct a useful experiment, find out if the people who gain the most weight on Zyprexa are those who consume the most  high fructose corn syrup (and not just those who eat the most.)  In other words, can you gain weight on Zyprexa if you are eating Atkins?


(NB: there are many who want to believe that Zyprexa causes weight gain by increasing leptin; and so fructose and GLUT5 lowering leptin seems confusing.  Zyprexa, as shown above,  actually decreases leptin, acutely.  (And clozaril has either no effect, or minimal lowering.)  Letpin only increases with increased fat-- i.e. as a consequence of fat, not as the cause of fat.  Those who have found increases in serum leptin do so only after chronic administration, and resultant weight gain (for example, in a study of 13 schizophrenics on Zyprexa who showed a small increase in leptin after 4 weeks-- and after a 2 kg weight gain; or 6 week animal study finding increased fat and leptin.   The question, as noted by the authors, is whether the acute hypoleptinemia and hypoglycemia is what triggers hunger and an ultimate increase in fat, leptin, glucose and insulin. )