Dr. Engel is Clinical Professor of Medicine, Albert Einstein College of Medicine. Within the past three years, Dr. Engel has received research support from and been on the Speaker's Bureau of Eli Lilly and Amylin.

Resistance to insulin, the hormone that controls how our bodies handle sugar, is considered to be the primary defect of Type 2 diabetes, and is usually the result of obesity and/or a genetic predisposition. But most individuals with insulin resistance are able to maintain normal blood sugar levels by pumping out extra insulin. It is only when this increased production does not occur that problems arise.

Until recently, medical scientists suspected that the cells in the pancreas, where the insulin is produced, just wore down and couldn't produce enough insulin. But now researchers believe this process is more complicated than cell "exhaustion" and may reflect other functions that these specialized cells are supposed to handle that are not working properly.

We now know, for example, that these specialized pancreas cells, named beta cells, receive a chemical "signal" from the entry of the blood sugar, or glucose, into the cell, which through a series of steps leads to the release of insulin. In some individuals with diabetes, the signal simply does not work — the rising blood sugar does not effectively stimulate insulin release.

Until recently, medical scientists suspected that the cells in the pancreas, where the insulin is produced, just wore down and couldn't produce enough insulin. But now researchers believe this process is more complicated...

Researchers have now identified other products manufactured by our bodies that stimulate the beta cells to release insulin. The term "incretins" refers to secretory products of the intestine that influence beta cell function. These proteins, GIP and GLP-1, enhance insulin secretion.

GIP is a 42-amino acid peptide that is secreted by the K-cells of the intestine located primarily in the small intestine. After a meal, scientists found that blood levels of GIP rise within minutes. GIP was also found to have a variety of effects on fat metabolism.2 Though GIP seems to operate in healthy individuals, it has limited usefulness for diabetic individuals with higher than normal blood sugar levels.

GLP-1, in contrast, works in everyone. GLP-1 exists in two forms, a 30- and a 31-amino acid peptide, and is secreted by the L-cells of the large bowel and the last section of the small bowel. Most amazingly, GLP-1 is secreted within minutes of eating food even though these distant L-cells have not been in contact with food. This rapid response to food ingestion implies that some kind of nerve pathway is involved. As with GIP, GLP-1 levels are low in the fasting state, rise after eating but, unlike GIP, GLP-1 can affect insulin secretion even in patients with Type 2 diabetes. What this means is that GLP-1 may help diabetics individuals better regulate their blood sugar through more effective insulin release.

In addition, animal studies have demonstrated other very helpful effects on pancreatic beta cell function including making more beta cells and reducing the number of beta cells that die.4 The net result of these actions is to increase the mass of beta cells and, thus, increase insulin secretory capacity. GLP-1 also controls another enzyme, glucagon, that left unchecked would raise blood sugar levels too high.

GLP-1 Effects on Nutrient Intake and Digestion
An underappreciated phenomenon in patients with diabetes is the impact of high blood sugar on rates of stomach emptying. Patients with diabetes have accelerated gastric emptying. The accelerated emptying can result in an increase in the rate of absorption of dietary carbohydrate. GLP-1, however, can delay gastric emptying, which then tends to limit the rate of rise in glucose levels after meals. Additionally, GLP-1 directly inhibits appetite through the central nervous system. These varied effects thus complement the ability of GLP-1 to enhance insulin secretion.

Therapeutic Implications
The recognition of the key role played by GLP-1 in glucose regulation has led to attempts to develop drug therapies that mimic or enhance GLP-1 activity. Exenatide, a naturally occurring product, originally isolated from the saliva of the Gila monster, is very similar to human GLP-1. It is administered by subcutaneous injection, typically at a dose of 10 mcg twice a day. By itself or in combination with either sulfonylureas, metformin or combination sulfonylurea/metformin, exenatide can lower blood glucose levels. Remarkably, exenatide also causes weight loss in contrast to the weight gain typically seen with insulin, as well as with most oral antidiabetic medications.