News & Research

    Virginia Polytechnic Institute and State University, Blacksburg, Virginia

Skeletal muscle pro-inflammatory signaling and metabolic flexibility

General Research Subject: Insulin Resistance Pre Diabetes

Focus: Integrated Physiology, Integrated Physiology\Fatty Acid Metabolism, Integrated Physiology\Muscle, Nutrition-Clinical

Type of Grant: Clinical Science and Epidemiology

Project Start Date: January 1, 2013

Project End Date: December 31, 2015

Research Description

Skeletal muscle burns a significant amount of the fat and sugar that circulates in the blood stream. Ideally, when sugar is elevated in the blood stream, the muscle will either use it to make new energy or store it for later use.  Likewise, for fatty acids.  Skeletal muscle of obese and diabetic humans has been shown to inadequately use either sugar or fatty acids when they increase in the blood stream, and this has been termed metabolic inflexibility.  The cause of metabolic inflexibility is not known, but it is believed that eating more fat than the body needs for energy may be a contributing factor.  Metabolic inflexibility in skeletal muscle is bad because if the muscle does not use the sugar or fat, it will be stored elsewhere in the body and potentially lead to obesity and the resistance to insulin. 

We have performed a research study with nonobese, healthy humans during which we fed them a high fat diet for 5 days.  Interesting, only 5 days of a high fat diet is sufficient to cause the skeletal muscle to become metabolically inflexible just like that observed in obese and diabetic humans.  We are proposing addition studies to feed healthy humans a high fat diet for 5 days in effort to better understand what causes metabolic flexibility.  We are speculating that a high fat diet causes the intestines to release a substance called endotoxin that causes muscle to become metabolically inflexible.  We will test this notion in our proposed studies.

Research Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?

The inability for skeletal muscle to adapt fuel oxidation to fuel availability is termed metabolic inflexibility, a well characterized feature of disease states such as obesity, metabolic syndrome, and type 2 diabetes (T2D). The mechanism(s) responsible for skeletal muscle metabolic inflexibility are not known. Recently, there has been growing interest in the role of gut permeability and blood endotoxin in the pathology of metabolic derangements associated with obesity and T2D. Rodent studies have revealed direct links between the gut microbiome and metabolic disease, as well as associations between elevated blood endotoxin and metabolic dysregulation, both at the whole body and tissue level. High fat feeding in rodents is known to elicit elevated levels of blood endotoxin, a phenomenon that is termed metabolic endotoxemia.

In humans, obesity and T2D are associated with increased blood endotoxin and single meals have been shown to elevate blood endotoxin, but to date, there is no evidence in humans that high fat feeding results in metabolic endotoxemia. Moreover, there are no established links between gut permeability, metabolic endotoxemia, and skeletal muscle metabolic function in humans. We are proposing to utilize a model of acute high fat feeding in healthy humans to study the interplay between gut function, blood endotoxin, and skeletal muscle pro-inflammatory signaling and metabolic adaptability.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

The proposed studies will: 1) address a void in the literature by determining if high fat feeding increases gut permeability and blood endotoxin in humans as observed in rodents; 2) ascertain if there is a link between gut function, blood endotoxin, and skeletal muscle pro-inflammatory status and metabolic adaptability; and 3) establish mechanistic targets for future human interventions.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?

Early in my graduate training in exercise physiology, I became intensely interested in the metabolic flexibility of skeletal muscle, e.g., the ability to rapidly change substrate oxidation to meet ATP demand when transitioning from states of physical inactivity to activity, and vice versa; as well as the ability to alter substrate oxidation to meet substrate supply when oscillating between fed and fasting conditions.   Consumption of macronutrients that far exceed ATP demand and the inability of skeletal muscle to adapt to increased substrate supply are hallmark characteristics of metabolic diseases, such as obesity and type 2 diabetes. 

The overarching objective of my research program is to discern the signals that initiate metabolic inflexibility in skeletal muscle as a result of excess energy consumption.  The current project affords us the opportunity to test the hypothesis that pro-inflammatory signaling in skeletal muscle is essential for metabolic adaptation to increased energy flux, but a chronic pro-inflammatory state is deleterious to this process.

In what direction do you see the future of diabetes research going?