Wice, Burton M, PhD
The use of xenin-25 to probe alpha and beta cell dysfunction in humans with type 2 diabetes
General Research Subject: Type 2 Diabetes
Focus: Integrated Physiology, Integrated Physiology\GLP-1, GIP, and Other Gut Hormones, Islet Biology, Islet Biology\Hormone Secretion and Exocytosis
Type of Grant: Clinical Science and Epidemiology
Project Start Date: January 1, 2013
Project End Date: December 31, 2015
Diabetes Type: Type 2 diabetes
Type 2 diabetes (T2D) has become a worldwide epidemic and there is a substantial need to clarify causes and identify potential treatments for this disease. These findings would provide profound health and economic benefits. Hormones released from the intestines and pancreas are involved in regulating blood glucose levels. Those released from the intestine are known as "incretins" and the two major incretins are called GLP-1 and GIP. The hormones released from the pancreas include insulin, which reduces blood glucose levels, and glucagon which increases blood glucose levels. The incretin hormones cause changes in the release of pancreatic hormones and slow the release of nutrients from the stomach (gastric emptying), which in turn impacts blood glucose levels.
Drugs which mimic GLP-1 action are successful in treating T2D, but mimicking GIP has not been an effective therapy. Xenin-25 (Xen) is a protein which is also produced in the intestine and previous experiments have shown that the combination of Xen and GIP increases insulin release under specific conditions in humans without T2D, but these effects are lost in those with T2D. Experiments in mice showed that Xen also enhances GIP action on increasing insulin release and that communication from nerves (neurotransmitters) are needed for this action. Thus, humans with T2D may not respond to neurotransmitters and this impairment may lead to the development of T2D. The proposed studies will test if neurotransmitters are needed for Xen and GIP to increase insulin release and slow gastric emptying in humans.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?
Peptides (termed incretins) secreted by intestinal enteroendocrine (EE) cells increase insulin secretion from the pancreatic islet â-cell following ingestion of a meal. Critically, this effect occurs only in the presence of elevated blood glucose which prevents continued insulin release and subsequent hypoglycemia once blood glucose levels return to normal. Glucagon-Like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP) are the two incretin hormones that have been most intensively studied to date. In addition to increasing glucose-dependent insulin secretion, incretins also lower blood glucose levels independent of their effects on the beta-cell. Humans with T2D have a blunted response to endogenously released incretin hormones and thus, insulin secretion is not sufficient to normalize plasma glucose levels. This project is designed to determine why the incretin response is blunted in persons with T2D.
We have shown that a hormone called xenin-25 increases the incretin response in humans without T2D but is inactive in those with T2D. Moreover, we have shown in mice that the effects of xenin-25 on insulin secretion are mediated by neurons rather than a direct effect on insulin-producing beta cells. Thus, the goal of this study is to identify the specific subtypes of neurons that mediate the effects of xenin-25 in humans without T2D. This will hopefully allow us to identify novel approaches to bypass the defective neurons and thus, restore the response to endogenous incretins in humans with T2D.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The world wide epidemic of T2D has emphasized the urgent need to develop new and improved approaches to the prevention and treatment of this condition. Recently approved therapies that are now playing a major role in the treatment of T2M exert their beneficial effects through the incretin system. However, some aspects of the incretin system are impaired in persons with T2D. We have shown that a hormone called xenin-25 increases the incretin response in humans without T2D but is inactive in those with T2D.
We have also shown in mice that the effects of xenin-25 on insulin secretion are mediated by neurons rather than a direct effect on the islet beta cell. Thus, it is important to identify the specific subtypes of neurons that mediate the effects of xenin-25. The goal of these studies is to identify the neurons that mediate the effects of xenin-25 on insulin secretion in humans. This will hopefully allow us to identify novel approaches to bypass the defective incretin response and thus, normalize blood glucose levels in humans with T2D.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
An American Diabetes Association Statement points out that in the United States alone, greater than 17.5 million persons have been diagnosed with T2D with an associated yearly economic burden exceeding $245 billion. The incidence of the disease is increasing rapidly on a worldwide basis with staggering impact on cost of healthcare and quality of life. Thus, there is an urgent need to develop new and improved approaches to the prevention and treatment of T2D - the issue addressed by this research.
Previous studies from my laboratory suggest that defective neuronal rather than incretin signaling may be a major defect in humans with T2D. This award will allow my laboratory to conduct studies that are designed to identify which neurons are defective in humans with T2D.
In what direction do you see the future of diabetes research going?
T2D results from insulin deficiency- both impaired insulin production and secretion as well as insulin resistance by peripheral tissues. Therefore, future research must address 4 issues. First, it is critical elucidate the molecular mechanisms that regulate insulin production and secretion and why this is defective in humans with T2D; Secondly, it is critical elucidate the molecular mechanisms that regulate survival of the insulin-producing pancreatic islet beta-cell so that insulin production and release can be retained. Thirdly, research must be conducted to identify the molecular mechanisms that cause insulin resistance in the peripheral tissues so that less insulin is required to maintain glucose homeostasis. Finally, it is important to understand how hyperglycemia causes cell and tissue damage that ultimately leads to the serious and fatal complications resulting from T2D. With this information, we can hopefully develop novel drugs that maintain beta-cell function, reduce insulin resistance and/or enhance insulin action, and reduce or prevent complications from hyperglycemia.
For persons with insulin-dependent diabetes, we must think about ways to replace insulin. This will require 1) a search for novel drugs that mimic insulin action, 2) generation of a sufficient supply of islets that can be used for transplants, 3) development of gene therapy techniques to engineer insulin production by non-beta-cells, or generation of new beta-cells from pluripotent stem cells.
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