Balancing act: New findings raise questions about blood sugar control. Credit: iStockphoto

For people with diabetes, balancing blood sugar presents a complex challenge. Danger lurks at both extremes of glucose monitor readings: when sugar levels spike too high, the risks of diabetic complications such as nerve damage worsen. In contrast, if they fall too low, the risk of heart attack seems to increase—a danger recently suggested when researchers noticed that people on intensive insulin regimes had a higher rate of such events. (The discovery led them to abruptly end this intensive treatment regime within the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in February 2008.)

Future diabetes prevention and treatment could perhaps solve this conundrum by sidestepping insulin treatments entirely through drugs that mimic the beneficial effects of hormones naturally secreted in a healthy gut. To build a case for this approach, John Dixon of the Monash University Medical School in Melbourne, Australia cites a recent study from his group suggesting that a form of weight-loss surgery called gastric banding, which reduces stomach size, might help reverse type 2 diabetes (J. Am. Med. Assoc. 299, 316–323; 2008).

Participants in the trial ate less and lost weight. Most notably, 73% of the subjects in the study who had type 2 diabetes went into remission after the surgery (compared with 13% in the control group). Dixon, who also serves as president of the Australian and New Zealand Obesity Society, suspects that the surgery—which involves placing a band at the top of the stomach—might reverse diabetes by altering the nerve signals sent from stretch receptors in the stomach to the brain stem and the hypothalamus region. The brain then relays the message to the gut, which secretes hormones producing a feeling of fullness, he says.

Future medicines directed at this pathway, in which the vagal nerve transmits signals from the top of the stomach to the brain, could mimic the band's effect without an invasive surgical procedure. This noninvasive, drug-based approach would probably reach more people.

Although drugs targeted at this specific brain pathway have not yet hit the market, two medications that work through other gut hormone pathways are already available. The US Food and Drug Administration (FDA) has approved two related drugs, exenatide and pramlintide, to act in conjunction with other diabetes medications. Exenatide, an analog of a gut hormone called GLP-1, slows the emptying of the stomach and also seems to help boost natural insulin secretion, leading to lower blood glucose levels. And pramlintide, a synthetic version of the pancreatic hormone amylin, promotes the sensation of feeling full.

Now, scientists such as Dixon are investigating a third potential hormonal medication for diabetes called 'peptide YY', also known as PYY. Like exenatide and pramlintide, PYY seems to help regulate blood sugar and promotes the sensation of feeling full, but it also helps promote absorption of water and electrolytes in the colon. According to Dixon, PYY seems to have a much longer-lasting effect on appetite than either of these two already approved hormone treatments and could perhaps help control diabetes by promoting weight loss. Additionally, obese people do not seem to develop resistance to PYY as they apparently do to leptin, another appetite-suppressing hormone (N. Engl. J. Med. 349, 941–948; 2003).

Dixon claims that, with more research, bypassing glycemic control and going right to the underlying signaling pathways could be the future of diabetes treatment and prevention. But these hormones can cause nausea and it may take a while for such hopes to materialize, especially for young people. Even as the rates of obesity and type 2 diabetes in adolescents continue to climb, physicians using the gut hormone approach in young people must do so off-label. The FDA has not approved exenatide, pramlintide or gastric banding for children and teens, although clinical trials currently in progress could change this.

“Gastric banding looks promising for the treatment of diabetes in young people,” says Francine Kaufman, a researcher at the Keck School of Medicine at the University of Southern California in Los Angeles and past president of the American Diabetes Association. “But less invasive and potentially reversible methods would be a better way to alter gut hormones,” she adds.

Kaufman is currently leading the largest ongoing clinical trial with young people involving established methods of glycemic control—The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) trial studies how children and teens respond to diabetes interventions including metformin and lifestyle therapy. According to Kaufman, safety concerns about intensive blood sugar lowering are not an issue in the trial because, unlike the original ACCORD trial, the study lacks an intensive-treatment arm.

Until more clinical evidence shows otherwise, the American Diabetes Association stands behind the three proven prevention strategies to treat the disease—lifestyle modification and use of the drugs metformin and acarbose—along with other conventional treatments, such as insulin shots. At least for the foreseeable future, many experts do not expect gut hormone therapy to supplant these treatments.

But, given the debate surrounding blood sugar control, researchers such as Dixon see medicines derived from gut hormones as a promising solution. He maintains hope that the hormone treatments could one day help drive the disease into remission: “The best treatment for diabetes is stopping the disease altogether.”