Doliba, Nicolai M.
The effects of fatty acids on neuro-hormonal regulation of insulin secretion
General Research Subject: Obesity
Focus: Integrated Physiology\Fatty Acid Metabolism, Integrated Physiology\GLP-1, GIP, and Other Gut Hormones, Islet Biology\Hormone Secretion and Exocytosis
Type of Grant: Basic Science
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
Carbohydrates, fats and proteins are the main nutrients that an organism needs to live and grow. However, consumption of a high-fat diet and high intakes of saturated fat are associated with impaired secretion and action of insulin, a hormone secreted by pancreatic beta-cells, and as result leads to an increased risk of type 2 diabetes. In addition to nutrients insulin secretion is stimulated by many hormones and neurotransmitters. Acetylcholine, the neurotransmitter of the parasympathetic nervous system, plays a significant role in the regulation of insulin secretion in pancreatic beta-cells. Preliminary studies on mouse pancreatic islets have shown that even acute elevation of free fatty acids (end products of a fat digestion) results in inhibition of acetylcholine stimulated insulin secretion. It was also found that fatty acid leads to the depletion of intracellular storage capacity of calcium in the cellular organelle named endoplasmic reticulum (ER). Because the action of acetylcholine depends on activation of cell membrane receptor (M-cholinoreceptor) and intracellular calcium metabolism, it was proposed that either interference of fatty acids with signaling through the receptor and/or emptying of intracellular calcium stores by fatty acids results in reduced acetylcholine-stimulated insulin secretion. The current project is designed to test this hypothesis and to uncover the intracellular mechanisms of these effects. The study will also evaluate whether these effects occur under chronic elevation of fatty acids. The final goal of this project is to test if fatty acid has similar effects in human pancreatic islets which may contribute to our knowledge about etiology of type 2 diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The goal of the current project is to reveal the mechanisms by which a high-fat diet and high intakes of saturated fat may lead to impaired secretion and action of insulin, a hormone secreted by pancreatic beta-cells, and as result to an increased risk of type 2 diabetes. In addition to the main nutrients (carbohydrates, fats and proteins) insulin secretion is stimulated by many hormones and neurotransmitters. Acetylcholine, the neurotransmitter of the parasympathetic nervous system, plays a significant role in the regulation of insulin secretion in pancreatic beta-cells. Preliminary studies on pancreatic islets have shown that even acute elevation of free fatty acids (end products of fat digestion) results in inhibition of acetylcholine stimulated insulin secretion. Because acetylcholine contributes significantly to insulin secretion and therefore to maintaining optimum glucose balance in humans, uncovering the mechanisms by which elevated fatty acids affect this regulation may have a great impact on conceptual approaches for exploring Type 2 diabetes-associated impairments in beta-cell functions or attempting their treatment. If free fatty acids do indeed attenuate acetylcholine-mediated insulin secretion, then a lack of compensatory insulin release in Type 2 diabetes mellitus and perhaps also refractoriness (unresponsive to medical treatment to stimulate insulin secretion) could be explained.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
In the long-term, we hope that our project will help to better understand the mechanisms by which high-fat diet leads to impairment of insulin secretion and development of type 2 diabetes. This study could benefit the patient with diabetes in two ways: 1) it could help to indentify new therapeutic targets and strategies for the treatment and management of diabetes and obesity; 2) it can help to design a better diet and give patients a reason to abide by it. Both may improve the quality of the life for people with type 2 diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have been involved in diabetes research for most of my scientific career. Because diabetes is a major, and global, health problem, I believe it is very important to conduct my research in the diabetes field. Additional motivation to do research in this area came from the powerful interrelation between basic science and clinical medicine. I have previously received ADA research funding which has greatly helped me establish a strong foundation for my diabetes research. I have been a member and supporter of the ADA for more than 17 years and participated in numerous annual meetings and other activities. This award is particularly important and special to me because I would like to develop an independent career in field of diabetes.
In what direction do you see the future of diabetes research going?
I think that collaboration amongst diverse scientists and disciplines will make tremendous progress in indentifying new therapeutic targets and strategies for the treatment and management of diabetes and obesity. I also think that the drug development should focus on beta-cell protection from overstimulation by high glucose and fat which occurs in obesity and type 2 diabetes. We should also better educate the public about proper nutrition and the role of exercise.
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