Dr. Leahy: We’ve even moved earlier in our thought process trying to define what’s happening at even earlier stages of the disease, before blood sugars even reach the pre-diabetes stage.  And probably one of the most important research accomplishments are genetic studies -- the ability to start to do very, very precise genome-wide genetic studies -- and Type II diabetes has been right up there with these types of kinds of studies. 

And as it stands right now we have at least 20 genetic mutations that have been identified to raise the risk of Type II diabetes.  There’s some debate about a few of these, but most of them appear to be in the beta cell and appear to be related to either impairing beta cell function or beta cell mass.  So that’s probably where we start, and I think a lot of people think that maybe people who carry these mutations either don’t grow enough healthy beta cells early in their life or the beta cells they do have are just not normally functional. 

What happens later is either an ongoing process of these either genetic or environmental defects so maybe the genetic defect makes beta cells die earlier than they ordinarily would.  So that’s speculation, but someone reaches an age where beta cell mass has slowly been falling and it reaches a stage where even in a normal environment it just can’t keep up anymore.  Or alternatively, it may be that as one gets heavier and exercises less and eats more of a western diet, then we face all sorts of metabolic issues potentially related to things like increases in free fatty acids or other lipid-related detrimental effects. 

It could be related to the beginnings of a rising glucose that is fairly modest, but from a cell point of view is not modest at all in promoting oxidative stress or endoplastic reticulum stress.  It could be other kinds of environmental factors we haven’t even identified. There is some feeling out there, there may be toxins in the environment or some other environmental issues that are actually detrimental for beta cell function. 

Early in the course of the disease these metabolic changes that we’re all now facing as we westernize put more of a stress on beta cells.  Probably the best legitimized concept is as beta cells compensate and work, in some people that becomes overwork and that actually leads to a beginning of the end which is beta cells compensate, but they can’t do it long enough, they start to fail and that’s the initial part of the slippery slope.