American Diabetes Association Archives - Sanford Burnham Prebys

Tag: American Diabetes Association

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The Diabetes Story: Will new treatments lead to novel weight loss drugs?

AuthorGuest Blogger
Date

November 3, 2015

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Written by Jing Ping Lu, PhD

November is American Diabetes Month. Throughout the month, we will be highlighting our research contributions to this increasingly prevalent disease.

The growing epidemic of diabetes presents significant challenges for health care. It ranks 7th among the leading causes of death, and about one tenth of all health care dollars are spent on diabetes and its complications. According to the American Diabetes Association, 29.1 million Americans have been diagnosed with this metabolic disorder, and 1.4 million new cases were reported in 2013. With these statistics, the burden diabetes has on the health care system will continue to rise.

Opportunities to research the disease have also increased with the growing diabetic population. One particular area of emphasis is in understanding how glucose—a type of sugar—is broken down, or metabolized, in diabetic patients. Glucose is the major energy source our body uses to carry out activities. Glucose levels in the blood are kept constant by a hormone called insulin. After eating, the glucose level in the blood rises and signals insulin release. Insulin is like a key that opens up the locks on our cells so that glucose can enter. Glucose can then be stored in the form of glycogen and used later for energy. If our body does not make enough insulin, or insulin is not well recognized by the cell, then glucose levels will build up in the blood stream causing diabetes and other long-term complications.

Treating Diabetes Diabetic treatments are primarily developed to lower the amount of blood glucose by restoring the secretion of insulin or enhancing how well insulin works to promote the entry of glucose into cells. Another hormone called glucagon-like-peptide-1(GLP-1) has been shown to increase glucose-dependent stimulation of insulin release, and GLP-1 based drugs are used to treat diabetes. Julio Ayala, PhD, and his research team are working on projects that utilize GLP-1 based drugs to stimulate insulin secretion. These drugs come in two categories, GLP-1 analogs that mimic the action of GLP-1 and dipeptidyl peptidase 4 (DPP-4) inhibitors that prevent the breakdown of GLP-1 made in the body. Although both drugs can effectively lower glucose levels, one promotes weight loss while the other does not.

A new avenue for weight loss? Preliminary research performed in Ayala’s lab confirmed that the two drugs have different effects on food intake. “Interestingly, when targeted to specific regions in the brain, GLP-1 analogs reduce food intake to a greater degree than does native (natural) GLP-1. This may partly explain why GLP-1 analogs promote weight loss while DPP-4 inhibitors that increase native GLP-1 levels do not,” Ayala explained. “This leads us to speculate that even though both drugs bind to the same receptor in the feeding centers of the brain, they activate different molecular mechanisms in cells of the brain and this eventually results in different effects on food intake, and therefore, weight loss.”

As Ayala’s team continues to explore the mechanism of action, they hope to identify the critical steps that lead to the reduction in food intake. “Obesity is a leading risk factor for developing Type 2 diabetes. If we can discover the steps that GLP-1 analogs engage to promote weight loss, then drugs can be designed to specifically target these steps. This would provide a new avenue for designing drugs to treat obesity,” Ayala added, “and that could deliver a greater benefit to diabetes patients and contribute to decreasing the rise in Type 2 diabetes. We are excited to see the possibilities.”

Dr. Julio Ayala is an assistant professor at Sanford Burnham Prebys Medical Discovery Research Institute in Lake Nona, Fla and a recipient of an American Diabetes Association research award.

This post was written by Jing Ping Lu, PhD, a post-doctoral associate in Dr. Rastinejad’s lab in Lake Nona.

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Genes promote hardening of arteries in type 2 diabetes

Authorsgammon
Date

July 15, 2014

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Type 2 diabetes has become a national epidemic, affecting nearly 26 million children and adults in the U.S. and approximately 170 million worldwide. According to the American Diabetes Association, $245 billion in costs are associated with diabetes, and 1 in 5 health-care dollars is spent caring for diabetics. A significant portion of the health costs associated with diabetes are those attributed to complications of the disease—including heart attacks, heart failure, stroke, dementia, chronic kidney disease, and amputations of the lower limbs. These complications emerge partly from hardening of the arteries caused by calcium deposits—a process known as arterial calcification—and are much more common in type 2 diabetics than in non-diabetics.

Dwight Towler, MD, PhD, professor and director of the Cardiovascular Pathobiology Program at Sanford-Burnham, has been actively researching the molecular causes of arterial calcification for more than a decade. Finding a way to prevent cardiovascular calcification could improve the vascular health of type 2 diabetes and prevent many of the associated medical complications.

In Towler’s previous work, he found that the assumption that arterial calcification was a natural, passive process that happens when cells die was incorrect. Instead, he showed that when the metabolism is disturbed—as in diabetes—calcium deposits are made by an active process that happens when key regulatory proteins erroneously trigger bone-formation genes in the arteries. Today, he is focused on those regulatory proteins, coded in the DNA by the Msx genes. Under normal conditions, Msx genes are essential for the formation of bones and teeth in the skull. But, in inflammatory conditions such as those associated with type 2 diabetes, the genes trigger the formation of calcium deposits in the arteries.

In his most recent study published on July 16 in the journal Diabetes, in collaboration with Dr. Robert Maxson of the University of Southern California, Towler’s research team examined the impact of Msx genes in mice genetically engineered to develop diabetes when fed high-fat diets. Previously, Towler showed how high-fat diets up-regulated the Msx genes in the aorta and coronary vessels of these mice, and caused calcium deposits via the Wnt paracrine signaling cascade. Now the question was: What would happen if Msx genes were absent in these mice?

“We were pleased to find that down-regulation of the Msx genes did indeed reduce the arterial calcification and vascular stiffness associated with diabetes,” said Towler. Our results are important because currently, there are no drugs to treat cardiovascular calcification. We have now identified four signaling pathways that represent targets for new drugs to intervene and inhibit the process.”

As a board-certified internist, Towler is committed to advancing these research findings to improve patient health and health care. “Our next step is to biochemically and genetically validate these pathways in human vascular disease—and identify drugs that improve vascular structure and function in mice. We are starting with lead compounds already tested in humans for other indications to see if we can repurpose those drugs to minimize the time it takes to get a treatment to the patients that suffer from this devastating complication of diabetes,” added Towler.

The study was performed in collaboration with the Norris Cancer Center, University of Southern California (CA),  Washington University in St. Louis (MO), the Translational Research Institute for Metabolism and Diabetes (FL), and MD Anderson Cancer Center (TX).

Funding for the study was provided by NIH grants HL69229 and HL81138, the Barnes-Jewish Hospital Foundation, and Sanford-Burnham Medical Research Institute.