Dr. Leahy: One of the things that we cannot do in the diabetes biology world is try and separate tissues as if they work in isolation.  The glucose homeostasis system is this incredibly interactive system where the brain regulates the liver and it regulates beta cells and the beta cell carefully controls the hepatic glucose production and peripheral tissues are impacted by adipose sites and vice versa.  It goes on and on.  And the reason this is important is if you actually look at thiazolidinedione, the TZDs, the drugs that I think the average provider would say is a pure insulin sensitizer.  It’s the drugs we have to promote insulin sensitivity and they don’t have any impact on beta cells.  Well, that’s not so clear for two reasons. 

The first is there are lots of studies using TZDs in either pre-diabetes or early diabetes and you get an improvement in insulin sensitivity, of course.  But, in fact, the bottom line is they’re stabilizing beta cell function.  And the concept is that if the beta cell is being driven by this metabolic stress -- maybe some hyperglycemia, other metabolic factors, it over secretes and you get beta cell failure from over secretions. So now I come in with an insulin sensitizer -- I rest, quote, unquote, I rest the beta cell.  That actually allows the beta cell to remain healthy and so you stabilize beta cell function.  So many scientists actually look at these TZD intervention studies in early diabetes or pre-diabetes and conclude this insulin sensitizer stabilizes beta cell function.  So, is that a direct or indirect affect?  Well, clearly indirect affects occur.  There’s beta cell rest -- no one’s going to deny that. 

The other issue is, however, there may be direct effects.  I am a big believer, in part because it’s what I study in my laboratory -- that the signaling pathway which TZDs act on which is called PPAR-gamma that is expressed in beta cells, that’s active in beta cells -- I believe it controls important genes -- so maybe we’ll figure out with time there’s a direct affect.  But at least TZDs clearly do have either indirect or direct affects on beta cells as well as promoting insulin sensitivity.  So that’s that class of drugs. 

The same concept in theory could be thought about with metformin.  Now, metformin’s major physiological affect is to lower hepatic glucose production.  People may know that the drugs been available outside the U.S. for almost 60 years -- this is not a new drug.  And amazingly we really didn’t have a signaling pathway or direct mechanism that metformin worked on until a few years ago.  There’s still a little bit of debate, but it seems to work on a fuel sensing pathway called AMP kinase which is very active in adipose sites also in peripheral tissues.  But again, analogous to the TZD conversation AMP kinase is present in beta cells and is actually fairly active.  So, we think about metformin as a liver-specific drug.  We give it to try and control fasting blood sugars, which is a reflection of adipose glucose production.  Whether it would actually have good effects on beta cells over time, directly or indirectly -- don’t know.  Certainly, using metformin in pre-diabetes was clearly legitimized and many primary care doctors are aware of the diabetes prevention program -- the DPP study that used metformin in pre-diabetes and showed a reasonably good affect at prevention of diabetes. 

Now, there is a long, long list of other agents that are out there and for the most part they’re not used the same kind of way that the other drugs we’ve talked about are used in the United States.  There’s the alpha-glucosidase inhibitor.  They essentially slow carbohydrate absorption from the gut.  Amazingly, they’re used extensively in Asia and not used much in this country.  We have newer drugs that have come out.  There’s the cholesterol resin, which is now approved.  There’s a drug that we’ve used -- dopamine agonist, which has been used for prolactinomas that’s been recently approved.  There is this sort of long list, but I think the classic drugs we tend to think about are the sulfonylureas, metformin, TZDs and the incretin drugs and, of course, insulin. 

And just one sort of comment about insulin -- one of the reasons I think it’s so important that the primary doctors have an understanding of the importance of beta cell dysfunction and eventual failure in Type II diabetes is we have to sort of get away from the thinking about insulin therapy in this disease as a last resort and as somewhat a result of a patient’s unwillingness to follow a healthy lifestyle program and understand that some people are programmed for beta cell failure and they’re going to end up with failure requiring insulin no matter what.