Sunday, May 11, 2008

Diabetes and Your Small Intestine

In the last post, I introduced you to the remarkable antidiabetic effect of gastric bypass surgery. It rapidly reverses diabetes in 83% of patients, and it seems to be due to bypassing the upper small intestine specifically, rather than caloric restriction. This points to a special role of the upper small intestine in regulating food metabolism. I told you I was going to look into the mechanism of why this effect happens, and here's the short answer:

It's complicated and no one understands it completely.

Now for the long answer. Nutrient homeostasis is very important and we have sophisticated ways of coordinating it among different tissues. Part of the small intestine's job is telling the body that nutrients are on their way into the bloodstream. Two ways it conveys this signal are by secreting hormones into the bloodstream, and by sending signals to the brain and liver via parasympathetic nerves.

The small intestine secretes dozens of hormones, one category of which is called the incretins. Incretins by definition increase the secretion of insulin by the pancreas, among other things. They were discovered when researchers realized that oral glucose elicits more of an insulin response than intravenous glucose. The reason is that cells in the upper small intestine secrete incretins when they detect glucose.

There are two known major incretin hormones that are secreted by the small intestine, GIP and GLP-1. There was a recent study by the lab of Blanca Olivan which looked into the levels of incretins in patients who had undergone Roux-en-Y gastric bypass, a common type in which 95% of the stomach and part of the upper small intestine is bypassed.

Their results are very interesting! Compared to controls losing an equivalent amount of weight on a low-calorie diet, the bypass patients saw a HUGE increase in their oral glucose tolerance test (OGTT) GLP-1 secretion (9.8 vs 112.5 pmol/L), a large increase in GIP secretion, and a corresponding increase in insulin secretion (575 vs 769 pmol/L). Two-hour OGTT blood glucose levels went from borderline diabetic to "normal", by American Diabetes Association standards. Fasting glucose and insulin dropped substantially. The bypass group gained considerable glucose control, better than the matched controls on a low-calorie diet.

It looks like part of the mechanism involves whipping the pancreas to produce more insulin in response to glucose. It also affected fasting insulin, although that could simply be due to calorie restriction because it went down in both groups. Interestingly, non-diabetic patients who get a Roux-en-Y bypass often get reactive hypoglycemia, where their pancreas overproduces insulin after a meal and they get dangerously low blood sugar. Dr Mary-Elizabeth Patti calls it "diabetes reversal in people who don't have diabetes". So the effect doesn't seem to be specific to people with diabetes.

There is some suggestion that the effect on incretins is due to bypassing the duodenum, which is part of the upper small intestine. Here's how the (very sophisticated) reasoning goes: when the duodenum doesn't get glucose dumped on it, that somehow increases release of incretins by the small intestine further along the line.

There's actually an antidiabetic drug that mimics GLP-1; it's called Byetta. There's another that inhibits the breakdown of GLP-1 called Januvia. A second effect of GLP-1 is to delay stomach emptying, which both drugs do. They have been effective for some diabetics.

Well this turned into a long post, so I'll follow up on the parasympathetic (nerve) signaling of the small intestine next time.