Gettys, Thomas W., PhD
Mechanisms of enhanced insulin sensitivity by dietary methionine restriction
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Integrated Physiology\Amino Acid Metabolism, Integrated Physiology\Fatty Acid Metabolism, Integrated Physiology\Insulin Secretion and Islet Hormones
Type of Grant: Basic Science
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
Obesity is the product of a chronic positive energy balance, and the resulting accumulation of excess adipose tissue is strongly linked to disordered lipid metabolism, development of insulin resistance, and a cluster of co-morbidities called metabolic syndrome. The growing impact of metabolic disease has mobilized a coordinated effort by investigators to understand how dysregulation of energy homeostasis leads to disordered lipid metabolism and the development of insulin resistance. Dietary methionine restriction (MR) produces a highly integrated series of biochemical and physiological responses that improve biomarkers of metabolic health and result in a corresponding enhancement of insulin sensitivity. The beneficial responses are observed when dietary MR is initiated in growing animals but also when the dietary regimen is initiated after physical maturity. Our Preliminary Data make a compelling case that dietary MR acts in part through (a) centrally-mediated effects on energy expenditure, fat deposition, and adipocyte endocrine function, and (b) direct effects on peripheral tissues that remodel the integration of lipid metabolism between liver and adipose tissue. We hypothesize that the coordinated responses to dietary MR involve both hypothalamic and peripheral nutrient sensing systems which detect the decrease in circulating methionine and engage a combination of neurochemical and transcriptional mechanisms to produce the resulting phenotype. The most significant unanswered questions regarding dietary MR are: (1) How and where is the reduction in methionine sensed? (2) How is the sensing event linked to the highly beneficial physiological responses that are produced? (3) Can dietary MR reverse pre-existing obesity and/or insulin resistance?
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project will explore the underlying nutrient sensing and resulting transcriptional, biochemical, and physiological mechanisms that are involved in translating a reduction in dietary methionine into enhancement of tissue-specific as well as overall insulin sensitivity. In work recently published by our group, we have shown that dietary methionine restriction in humans with metabolic syndrome reduces hepatic lipid content and improves overall insulin sensitivity. The current project will explore the mechanistic details of these effects of the diet in pre-clinical studies, and these insights will be used to guide the next steps in our overall efforts to translate this work into an effective dietary formulation that can be used to treat individuals with metabolic disease. The critical unanswered question that this proposal will answer is how restricting dietary methionine content functions to improve biomarkers of metabolic disease and enhance insulin sensitivity.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our pre-clinical studies in rodents and our initial clinical study used diets that were formulated from individual amino acids to restrict the content of methionine in the diet. Although not a problem in rodents, the palatability of this elemental diet in humans is poor and this diminishes its broader use in individuals with metabolic disease. The proposed work will establish the exact range of methionine restriction that is most effective in improving insulin sensitivity in pre-clinical studies. We are simultaneously working with food scientists at our institution to develop the methods that will allow us to selectively deplete methionine from intact proteins that will be used to formulate highly palatable diets for patients with obesity and/or insulin resistance. Therefore, the fundamental knowledge that we will gain from our pre-clinical studies will guide the formulation of diets that limit methionine content to the exact degree that is most effective in improving the biomarkers of metabolic disease. This project will directly facilitate the translation of important new knowledge into the clinic and improve the health of individuals suffering from metabolic disease.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
For the last 27 years, I have worked as a basic scientist on the fundamental biology of adipose tissue, with an emphasis on understanding how dietary composition affects the signaling systems which regulate the energy storage and endocrine function of the adipocyte. During this time, my focus has been on animal models of obesity with the goal of identifying the specific mechanisms that influence energy balance and lead ultimately to the expansion of adipose tissue, development of obesity, and compromise insulin sensitivity. I was originally trained as a nutritionist/physiologist and have always known that dietary composition affected tissue-specific gene expression and the resulting metabolic phenotype of the animal. Scientific advances in recent years have begun to identify the specific nutrient sensing mechanisms that detect changes in individual components of the diet. More importantly, these advances are now showing us how this information is being translated to regulate tissue-specific transcriptional programs. In recent years, I have been involved in exploring how dietary restriction of a single essential amino acid (e.g. methionine) produces such a profoundly beneficial effect on biomarkers of metabolic disease and enhances insulin sensitivity. The present award will be the focus of the research efforts of my laboratory as we work to use the knowledge we will gain to translate this work into an effective dietary regimen for individuals with metabolic disease.
In what direction do you see the future of diabetes research going?
It is my view that metabolic disease culminating in diabetes is best defined as the failure of insulin to integrate the metabolism of carbohydrate and lipid between and among tissues. Although insulin functions to regulate fuel selection and storage in individual tissues, metabolically active tissues function as a syncytium such that compromised insulin action in a single initial site initiates a progressive deterioration of the integration of metabolism across all tissues. It is my view that future diabetes research should place more emphasis on understanding the initiation and pathological progression of metabolic disease in terms of how compromised insulin function in specific sites impacts the integration of metabolism across all tissues. This may provide knowledge that will guide the development of individual treatment strategies tailored to ameliorate, stop, or reverse the progression of metabolic disease. Relative to the current proposal, dietary methionine restriction has a profound effect on the integration of lipid metabolism between liver and adipose tissue while also significantly enhancing in vivo insulin sensitivity. Our goal is to explore how methionine restriction reciprocally alters lipid metabolism in each site and determine whether these transcriptional responses are essential to the tissue-specific improvements in insulin sensitivity.
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