Sanford-Burnham research on type 2 diabetes
With the long-term goal of identifying novel pharmaceutical targets to treat and prevent type 2 diabetes, scientists at Sanford-Burnham are researching the molecular and genetic underpinnings of insulin production, glucose metabolism and the regulation of both processes. Since aggressive cardiovascular disease is the leading cause of death among type 2 diabetics, researchers are also determining how diabetes affects other organ systems.
Hormones and Diabetes
Insulin is a hormone, but other hormones also play a big part in controlling hunger, insulin production and fat storage. At Sanford-Burnham, scientists are using genetic and biochemical approaches to better understand GLP-1, a protein secreted by the gut that enhances insulin secretion in response to nutrient intake. GLP-1’s receptor is also expressed in brain regions involved in the control of glucose metabolism, food intake and motivated behavior, making it an attractive target for anti-diabetic therapies.
Blood glucose levels also control the availability of orexin, a hormone that negotiates hunger and sleep-wake cycles. After a meal, high levels of glucose in the blood lower orexin levels, making you feel sleepy. After you fast all night while sleeping, low blood glucose levels trigger the production of more orexin, which makes you feel awake and hungry in the morning. This simple regulation is disrupted in type 2 diabetes and obesity. Sanford-Burnham researchers are now trying to understand how faulty regulation and abuse of sleep-wake cycles contribute to the development of diabetes and obesity.
Glucose and Fat Metabolism
A multi-disciplinary group was formed at Sanford-Burnham’s Lake Nona, Orlando campus to study the cell’s control of metabolism and the biochemical reactions that turn nutrients into energy and burn that energy to sustain life. This team investigates how the complex interactions between cells and organs affect caloric intake and energy balance. An important focus of their research is the cellular cross-talk and regulatory mechanisms that turn genes on and off to control metabolism.
For example, scientists are studying the molecular mechanisms by which obesity induces insulin resistance in diabetes. They have identified a cellular communication network required for insulin-stimulated glucose uptake and the relocation of a glucose transporter from cellular storage to its functional location on the cell membrane. One research group is using animal genetics to mimic human diseases and to define the determinants and metabolic conditions that promote obesity and diabetes and related disease processes, such as metabolic syndrome.
Others at Sanford-Burnham are using fruit flies as a simplified model to study glucose and fat metabolism. They are following the ‘thrifty gene hypothesis’, which suggests that certain genetic variations were selected during evolutionarily recent times of famine and that these genes are now contributing to the obesity and diabetes epidemic. Scientists are using various genetic approaches to identify these factors.
There isn’t just one heart disease – there are many different ‘flavors’ that can result from diabetes, high blood pressure or other causes. Our scientists are now finding that the molecular mechanisms leading to each type of heart disease are different. For example, the heart has an incredible capacity to switch back and forth between burning sugar and burning fats to generate energy, and that balance gets shifted differently depending on the type of heart disease. Whereas the diabetic heart sucks up fat, the hypertensive heart prefers sugars. Researchers at our Lake Nona campus believe that clearly defining each distinct pathway to heart disease and heart failure will help them develop new therapies tailored to the specific cause.
In another effort to develop personalized medicine for diabetics, Sanford-Burnham researchers are evaluating several genetic markers in diabetic and non-diabetic people who have experienced heart attacks. Heart patients are traditionally treated with a type of drug called a beta-blocker. However, initial results reveal that diabetic patients with different variations in a particular gene respond differently to beta-blockers. For some people, beta-blockers are extra beneficial, while those with a different genetic makeup were more likely to experience harmful side effects from the drug.
Insulin and muscle
Muscles are the primary site for converting sugar to energy and therefore are of particular interest to scientists seeking to understand glucose management in diabetes. Insulin resistance in skeletal muscle is a key feature of the pre-diabetic state and a precursor to type 2 diabetes and cardiovascular diseases.
Several laboratories are researching genes that regulate metabolism in skeletal muscle and are developing techniques to better understand how insulin resistance develops. They use these tools to develop and test new strategies to activate fat oxidation as a means to improve insulin action and reduce body weight. These tools also allow scientists to explore the origins of reduced fat oxidation – a key feature of patients with type 2 diabetes and their children.
Sanford-Burnham scientists in Lake Nona recently created a new model to study diabetes, obesity and exercise: the couch potato mouse. These mice lack a protein coactivator called PGC-1 in their muscle tissue. Without it, their muscles develop normally but they are unable to exercise. Surprisingly, these mice are not obese and their muscle cells respond normally to insulin, meaning they are not at increased risk for developing diabetes despite their sedentary lifestyles. These researchers are now investigating what happens when they boost PGC-1 activity intermittently, as normally occurs when a person exercises. These studies will increase our understanding of the complicated links between exercise, obesity and diabetes and may unlock new therapeutic targets for metabolic diseases.
For more information
National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)
Part of the National Institute of Health (NIH)
American Diabetes Association (ADA)
Florida Hospital Diabetes Institute