How Poisonous Lizard Saliva Transformed Diabetes Treatment

By Susan L. Samson, MD, PhD, FRCPC, FACE

When I was finishing my training as an endocrinology fellow, I was fascinated by the account of the discovery of incretin hormones. In 1992, endocrinologist and scientific researcher Dr. John Eng of the Bronx Veteran’s Administration Medical Center identified a protein in the saliva of the Gila (pronounced HEE-la) monster, a giant poisonous lizard found primarily in the deserts of the southwestern U.S. and northern Mexico. He found that the protein stimulated the release of insulin following a meal.

Because the food intake was necessary to trigger the insulin release (it did not happen if calories were given intravenously or through blood vessels), the term incretin, or “gut hormone” was given to these hormones, as they were triggered by food entering the gut.

Incretin hormones help decrease blood sugar levels in several ways. They increase the amount of insulin released from the pancreas in relation to an increase in blood sugar, which in turn helps the glucose move from the blood across cell membranes and into the cells of the body.

They also decrease the typical release of a hormone named glucagon that occurs with food intake, but which acts against insulin to raise blood sugar. So, the less glucagon, the better insulin acts in the body.

Perhaps the most desirable feature of incretins is that they decrease appetite. Interestingly, they reduce the speed that food leaves the stomach, so food can look good, smell good and taste good, but you feel full faster and thus eat less – perhaps up to 20 percent fewer calories, according to some studies. This phenomenon not only affects the stomach, but also has a not-well-understood but direct effect on the brain’s satiety or “fullness” centers.

Through additional research studying the lizard protein, as well as a naturally occurring human incretin called glucagon-like peptide (GLP-1), physicians now have a number of highly effective incretin-based choices for the treatment and management of diabetes mellitus.

At this time, there are three short-acting (daily or twice daily) and two long-acting (weekly) injectable incretin medications to choose from. There also are pill forms of oral, incretin-based medications available in the U.S., nicknamed “gliptins.” Gliptins inhibit the enzyme dipeptidyl peptidase 4 (DPP4), which breaks down naturally occurring human GLP-1, thus allowing one’s own GLP-1 to circulate longer to lower blood sugar. The pill form is weaker in its effects on blood sugar than the injectable forms, but there is work being done on making a pill form of the GLP-1 drug that may be available in the next few years.

As with any drug, there can be potential side effects with incretin medication, the most common being nausea. This tends to be mild, seldom leads to vomiting, and typically lessens very quickly (if present) over the next injections. The longer-acting injectables usually cause less nausea than the shorter forms

Also, there are warnings about a very unusual form of thyroid cancer that has been reported in rats and mice given this medicine. However, in more than 10 years of studies and use in the market, there has yet to be a report of a monkey or human developing this type of cancer with the drug.

If there is a history of medullary thyroid cancer in the family or in your own history, it is recommended these drugs not be used. There is also concern about the possibility of developing pancreatitis, a painful inflammation of the pancreas gland, a large, flat gland located behind the stomach in the upper abdomen. So, if you are taking the medication and experience abdominal pain, it is advised that you stop the drug and contact your healthcare team promptly.

Pancreatic cancer has been raised as another concern, although it has not been well recognized that just having diabetes (specifically Type 2) can more than double your risk of developing cancer compared to a person without diabetes.

When taking gliptins, it is important to keep hydrated as there have been reports of kidney function being affected by these drugs when people are on diuretics (medications designed to increase the amount of water and salt expelled from the body as urine) or become significantly dehydrated. These are all important issues that should be discussed thoroughly with your endocrinologist to help you balance the benefits and risks of taking these medications.

The use of injectable incretin medications and gliptins is becoming more common not only because of the very beneficial effect on blood sugar control, but also on lowering blood pressure and contributing to better cholesterol levels over time. These improvements can significantly decrease the risk of eye, kidney and nerve complications associated with diabetes.

However, there is another sinister complication of diabetes, one that falls under the category of cardiovascular disease. including heart attacks, strokes and hardening of the arteries in the legs. Diabetes is a known “cardiovascular risk equivalent” which, loosely translated, means that that the risk of having a cardiovascular problem such as a heart attack or stroke in a person with diabetes is similar to someone who is not diabetic, but has already had a heart attack or stroke or leg vessel disease. Unfortunately, older research studies found that simply lowering blood sugar does not decrease cardiovascular events, in contrast to clearly helping decrease diabetes-related eye and kidney disease.

The good news is there is accumulating evidence from recently published studies that injectable incretin therapies can have a very positive effect on cardiovascular health in individuals with Type 2 diabetes mellitus (the form of diabetes where one’s own insulin does not work as it should, plus the pancreas produces increasingly less insulin over time). The volunteers who participated in these studies were in a very high-risk category: they had already had a heart or stroke event, or they had multiple health problems (e.g., kidney disease, heart failure).

The LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) included over 9,000 volunteers who were followed for almost four years. There was a 20 percent decrease in cardiovascular death in the treated group of study volunteers using a daily injection of liraglutide.

The positive effects on cardiovascular events using another injectable medication, semaglutide, were evaluated in the SUSTAIN-6 trial. The rate of heart attacks, strokes, or deaths from a cardiovascular event was reduced by 25 percent in the semaglutideusing group after just two years. Semaglutide (not yet FDA-approved for use in patients in the U.S.) is chemically similar to liraglutide, but is a once-weekly injection. There may be an oral form of semaglutide available in the future.

To be fair, not all study trials have shown these types of positive effects. There are some that have shown no harm, meaning results were the same for those using incretin versus those who did not.

At this point, we wait for more clinical trials to understand if positive effects on heart disease and stroke can be extended to more of the injectable incretin therapies. As a physician, it would be wonderful to know that I can treat the blood sugar levels while simultaneously decreasing your cardiovascular risk at the same time.