Research on New Type 2 Treatment Targets Insulin Source
Incretins, a type of hormone produced in the gastrointestinal tract, have been investigated extensively for their potential as effective treatments for type 2 diabetes. We are just preparing to go to the American Diabetes Association conference in Washington, D.C., the biggest meeting of doctors globally every year, and there is NO hotter topic at hand! So we wanted to take some time to fill you in on GLP-1, a promising new branch of type 2 diabetes treatment and the focus of the 1st Amsterdam Diabetes Forum, held this past spring in Amsterdam, Netherlands. While there are many drugs already available for the treatment of type 2 diabetes, over two-thirds of people with the disease continue to have suboptimal glucose control, and incretin therapies offer benefits matched by no other type 2 diabetes treatment currently available.
Type 2 diabetes, the most prevalent form of the disease, is thought to be caused by dysfunction of the insulin producing cells of the pancreas, the beta cells, which can result from years of untreated insulin resistance. Diabetes occurs when our beta cells fail to compensate for the increasing glucose levels due to insulin resistance. As type 2 diabetes is caused by both insulin resistance and beta cell failure, treatments for the disease must target either the insulin resistance component by improving efficiency of insulin action, or the beta cell function component increasing beta cell mass and thus promoting increased insulin secretion. Incretins present an emerging line of treatment for improving beta cell function.
Incretins are natural gut hormone peptides that lower blood glucose levels after meals by increasing insulin release from the beta cells of the pancreas and suppressing glucagon release from the alpha cells. Two incretins are crucial to improving beta cell function: glucose insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). GIP does not appear to be a promising treatment target because diabetic beta cells are relatively resistant to the action of GIP. However, beta cells in people with diabetes are sensitive to the effects of GLP-1, and thus GLP-1 is an effective therapeutic target. One barrier that researchers first came upon when studying GLP-1 for clinical development is that its half-life in the blood is only 1-2 minutes (it only stays active in the body for a very short time), because it is quickly broken down by the enzyme DPP-IV. However, researchers have found two solutions to this problem: development of GLP-1 analogs, which have a very similar structure to natural GLP-1 and provide all the same benefits without being broken down by DPP-IV, and development of DPP-IV inhibitors, which are drugs that prevent DPP-IV from degrading natural GLP-1.
Following a meal, GLP-1 is secreted by endocrine cells of the intestine, and this normally enhances insulin release from the beta cells of the pancreas and inhibits glucagon release. In healthy individuals, glucagon is only released from the pancreas when blood sugar levels are low and glucagon secretion is shut off after meals by insulin and by GLP-1. In those of us with diabetes, however, GLP-1 and insulin levels are low, which results in high glucagon levels. This combination of hormonal signals mistakenly tells the body that it is starving when it really is not. Thus, the liver continues to pump out glucose, even after a meal, and this is thought to be a major cause of post-prandial hyperglycemia in diabetes.
During the Amsterdam conference, Susan Bonner-Weir Ph.D. (Joslin Diabetes Center) presented a review of beta cells in type 2 diabetes. Normally when a person grows (whether during childhood or through weight gain), the beta cells of the pancreas grow to match the person's increased metabolic needs. Surprisingly, some individuals are able to maintain euglycemia even in the most extreme cases of obesity; thus, diabetes only ensues when beta cells cannot maintain the appropriate mass.
GLP-1 to the rescue! Maybe. GLP-1 treatment might preserve or increase beta cell mass in humans. In rats and mice, GLP-1 treatment is known to increase beta cell mass. Unfortunately, it has been difficult to determine the effects of GLP-1 treatment on human beta cell mass, as it is hard to directly measure how many beta cells we have without taking out some of the pancreas.
There are two strategies currently on the market to enhance GLP-1 function. The first is direct stimulation of GLP-1 receptors by GLP-1 analogs such as Byetta. These GLP-1 receptor agonists (molecules that activate a receptor are called agonists) are small protein fragments. Since small proteins like insulin and GLP-1 are rapidly degraded by our digestive systems, we have to inject these drugs like insulin. Although you would probably prefer not to take a medication by injection, these drugs have powerful benefits. GLP-1 analogs significantly increase insulin secretion, lower A1c levels, cause substantial weight loss, and may even promote beta cell growth.
The other strategy on the market to enhance GLP-1 function is the inhibition of DPP-IV. Since the DPP-IV enzyme naturally breaks down GLP-1 very quickly, DPP-IV inhibitor drugs work by preventing the breakdown of natural GLP-1 in the body. Because the effect of GLP-1 can only go as high as the amount of GLP-1 secreted by the body, some of the extra effects that are observed with GLP-1R agonists are not observed with DPP-IV inhibitors—both good effects like weight loss and appetite suppression and bad effects, such as nausea. DPP-IV inhibition can be achieved by once- or twice-daily oral dosing.
In some ways DPP-IV inhibitors have an advantage over the injectable GLP-1 analogs because they are well tolerated, oral drugs, and improve A1c and other metabolic parameters; on the other hand, they do not lower A1c as much as GLP-1 analogs and they lack the very key positive effects of GLP-1 analogs, like weight loss and appetite suppression. Also, it has been reported that patients can avoid nausea and improve fasting glucose levels with GLP-1 analogs by taking four mini-doses (e.g., 5 micrograms of Byetta) rather than two regular doses.
As was put forward by several presenters at the conference, and perhaps most clearly by Carolyn Deacon, Ph.D. (Panum Institute in Copenhagen), incretins appear to be an ideal target for diabetes treatment for several reasons:
- First, incretins increase insulin secretion and decrease glucagon secretion; this is good for those of us with diabetes, since we do not produce enough insulin and produce too much glucagon.
- Second, incretins work only after eating a meal, which means that the chances of developing hypoglycemia are very low (insulin will only be released if you have food in your system).
- Lastly, the inhibition of DPP-IV will only raise the levels of endogenous incretins, which prevents the possibility of activating incretin receptors in a non-physiologic (and possibly dangerous way).
Overall, we believe GLP-1 analogs show the greatest promise for the treatment of type 2 diabetes, and many experts believe that these incretin enhancers and mimetics will change the paradigm of treating diabetes. Certainly, GLP-1 analogs offer benefits that no other drugs do: improvement in A1c and postprandial glucose levels along with sustained weight loss. Although more data is needed, GLP-1 analogs may also increase beta cell mass, making it possible to reverse some of the damage to beta cells that occur in type 2 diabetes. The drawback to GLP-1 treatment is that these drugs (exenatide and liraglutide) must be injected, although we find from reports from doctors who have patients on the therapy that most patients aren't too troubled by this – and the ones that are may be able to try DPP-IV inhibitors eventually, though that is not as potent. Overall, GLP-1 inhibitors may be an excellent new drug to ask your doctor about if you suffer any weight problems – they have some tantalizing benefits, such as weight loss, and might ultimately show, in our view, to be an ideal adjunct to nearly every diabetes therapy.
Kelly Close is editor in chief of diaTribe (www.diaTribe.us), a free online newsletter for patients looking for more information on products and research.
NOTE: The information is not intended to be a replacement or substitute for consultation with a qualified medical professional or for professional medical advice related to diabetes or another medical condition. Please contact your physician or medical professional with any questions and concerns about your medical condition.
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