I got this link from a comment that George posted.
FoxO1 is a transcription factor ( you can see a video here of what it does ). Its job is to enter the nucleus in cells, read the DNA sequence it binds to, and start churning out the peptides that that particular DNA sequence codes for. And it just so happens that FoxO1 codes for the enzymes involved in gluconeogenesis.
These particular enzymes are rate-limiting unfortunately, I.E. they determine the rate at which the process happens. The more of these enzymes you have active, the higher your rate of hepatic glucoenogenesis. So, loosely speaking we have........
High FoxO1 activity -> lots of gluconeogenic enzymes floating around -> high rate of hepatic glucose production.
The problem is further compounded by the fact that FoxO1 seems to cause insulin resistance in muscle, it causes muscle to start up-taking fat and burning it and ignore glucose oxidation, this will result in decreased muscle glucose uptake aswell. Recall that muscle is the primary site for peripheral glucose disposal after a meal. All the glucose in your blood after you eat a potato has to go somewhere, and if it doesnt get disposed of in muscle because of a high FoxO1 activity making muscle insulin resistant, it probably ends up being disposed of in adipose tissue.
Disposing of alot of glucose in adipose tissue promotes fat tissue growth ( obesity ). Remember the high levels of leptin seen in fat people being atleast partly a consequence of glucose going down the lipogenesis pathway inside adipocytes? Where did all that glucose come from anyway?
Answer: it got rejected from muscle because muscle is insulin resistant because of a high FoxO1 activity.
Suddenly it all seems so clear, the idea that fat tissue growth "protects" you from diabetes would appear to be a very real phenomenon. Actually, I wouldnt really say fat tissue growth is "protecting" you, but rather it is masking the problem. The fat tissue is sucking up all the glucose that isnt being disposed of in muscle.
FoxO1 is where we finished with the recent Lustig paper, In it, Lustig talks about selective hepatic IR, where insulin is suppose to suppress gluconeogenesis after eating a potato, insulin is suppose to stop FoxO1 from entering the nucleus and therefore stop it from doing its job of making gluconeogenic enzymes during a time when blood glucose is naturally elevated because we've just eaten some glucose. The problem seen in metabolic syndrome is that insulin fails to properly suppress FoxO1 in response to potato eating.
It is also likely that hyper-activity of FoxO1 is causing the elevated fasting blood sugar in MetSyn.
The question that Lustig couldnt answer, and the question that may well be the answer to the whole diabesity epidemic is, why is the FoxO1 transcription factor so hyper-active?