Gettys, Thomas W., PhD
Role of UCP1 in the inter-organ lipid cycle engaged by dietary methionine restriction
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Insulin Action, Insulin Action\Insulin Resistance, Insulin Action\Metabolism, Insulin Action\Transgenic Models
Type of Grant: Mentor Based Minority Postdoctoral Fellowship
Project Start Date: July 1, 2013
Project End Date: June 30, 2016
Obesity and diabetes affect quality of life of a large portion of the national population and have a significant economic impact on healthcare. Understanding the precise molecular events that lead to obesity, insulin resistance, type 2 diabetes, and metabolic syndrome will translate into more effective treatments. Dietary restriction of the essential amino acid, methionine, has been proven to profoundly reduce body weight and body fat, and improve insulin sensitivity. These effects occur in spite of increased food intake.
The Gettys lab has demonstrated that methionine restriction (MR) also increases expression of uncoupling protein 1 (UCP1), a protein that may be involved in mediating the beneficial effects of MR. In order to determine the role of UCP1 in the effects of MR on metabolism, wild-type mice and mice lacking UCP1 will be placed on control and MR diets. The effects of MR on insulin sensitivity and lipid metabolism in both groups of mice will be determined. The results of this study will greatly contribute to our understanding of the mechanisms by which MR exerts its beneficial health effects. This will ultimately aid in the development of the MR diet as a therapy for obesity, insulin resistance, type 2 diabetes, and metabolic syndrome.
Mentor: Thomas Gettys, PhD Postdoctoral Fellow: Desiree Wanders, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The current training project will provide support for an outstanding postdoctoral fellow to pursue a deeper understanding of the physiological mechanisms of enhancement of in vivo insulin sensitivity in a preclinical model by a novel diet that specifically limits dietary methionine. The scientific focus of this award is to understand how dietary methionine restriction remodels the integration of lipid metabolism in peripheral tissues. Given that disordered lipid metabolism in liver, muscle and adipose tissue are central components of the development of insulin resistance and diabetes, the present work will provide important new insights into whether the corrections in lipid metabolism produced by methionine restriction are central to the enhancement of insulin sensitivity produced by the diet. More importantly, the information obtained through this proposal will guide our efforts to continue our development of methionine restriction as a dietary treatment for obese patients with lipid disorders that are insulin resistant.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
Our laboratory conducted the first clinical trial to evaluate the efficacy of dietary methionine restriction in patients with metabolic syndrome. This trial was conducted using a medical food lacking methionine that was developed by Abott Labs for patients with hypermethionemia. This medical food was designed to provide the full daily protein requirement, and although it lacks methionine it does contain cysteine which functions to spare and partially substitute for methionine. In our clinical trial, the presence of methionine ameliorated the full effectiveness of the diet to produce the full effects of methionine restriction documented in our preclinical studies. However, our clinical trial did show an improvement in hepatic lipid metabolism that improved the overall metabolic health of the patients. Our laboratory has since developed an approach to selectively delete both methionine and cysteine from intact proteins that will solve the problem encountered in our first clinical trial. The present training award will provide a deeper understanding of how dietary methionine restriction works to improve lipid metabolism that will be important in guiding our next clinical trial using the methionine/cysteine-depleted proteins that we have developed.
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 4 yrs, I have been involved in exploring how dietary restriction of methionine produces such a profoundly beneficial effect on essentially all biomarkers of metabolic disease, including in vivo insulin sensitivity. My laboratory has employed the versatility and power of pre-clinical studies to obtain a fundamental understanding of how this dietary approach functions to produce these improvements. The present award will be used to train an outstanding junior scientist in my laboratory who will become an important future contributor to translating the insights obtained during her training into an effective and safe dietary approach to the treatment and improvement in the lives of patients suffering from some degree of insulin resistance and metabolic disease.
In what direction do you see the future of diabetes research going?
Metabolic disease culminating in diabetes in best defined as the progressive failure of insulin to integrate the metabolism of carbohydrate and fat between and among tissues. Although insulin functions to regulate fuel selection and storage in individual tissues, these tissues in fact function as a syncytium such that compromised insulin action in a single initial site initiates the progressive deterioration in the ability of insulin to coordinate fuel utilization and 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 tissues impacts the integration of insulin function across all tissues. This may provide knowledge that will guide the development of specific treatment strategies tailored to slow, 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 improving overall insulin sensitivity. It is my view that understanding the integrative effects of this diet will be essential to understanding how it improves in vivo insulin sensitivity.
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