News & Research

    USDA ARS Western Human Nutrition Research Center, Davis, California

Mechanisms underlying the pro-inflammatory effects of acylcarnitines & potential impacts on insulin action

General Research Subject: Type 2 Diabetes

Focus: Insulin Action

Type of Grant: Basic Science

Project Start Date: January 1, 2012

Project End Date: December 31, 2014

Diabetes Type: Type 2 diabetes

Research Description

A reduced ability of the pancreatic hormone insulin to trigger tissue uptake of blood sugar is an early event in the course of development of type 2 diabetes mellitus (T2DM). Abnormal fat combustion by fasting muscle is often correlated with insulin resistance, even in the pre-diabetic state, and altered fat metabolism also appears to diminish insulin action in liver, fat tissue, and the insulin-producing cells of the pancreas. Thus, the overarching aim of our research is to identify clinically-relevant metabolite biomarkers of dysfunctional fat metabolism, and to understand if at least some of these factors not only mark disease susceptibility but also participate in diabetes causation or exacerbation. Specific to this project is the goal to follow-up on initial results indicating that naturally-occurring acylcarnitine metabolites (fatty acids of differing chain-lengths, bound to an amino-acid-like molecule), which are elevated in the T2DM blood as by-products of inefficient fat metabolism, activate pro-inflammatory/insulin-resistance pathways through the specific pattern recognition receptors (PRRs). If true, this will have a profound influence on our understanding of diabetes pathophysiology and may provide new targets for preventive and therapeutic modalities.

Research Profile

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

Our research involves examination of inflammation in metabolically-relevant tissues, since some pathways of inflammation have been implicated in blunting insulin action (thus contributing to insulin resistance). Another aspect of the research aims to determine how specific metabolites that accumulate in tissues under conditions of inefficient fat metabolism can affect inflammation. The end-game of the work is to determine the specific molecular links between these metabolites and their targets, which in turn may contribute to insulin resistance. This knowledge can serve as a basis to design nutritional, pharmacological, or other interventions that can minimize the production or activity of high levels of the pro-inflammatory metabolites; for instance, by strategies that improve the efficiency of fat combustion in the tissues of persons with T2DM or pre-diabetes.

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

A reduced ability of the pancreatic hormone insulin to trigger tissue uptake of blood sugar is an early event in the course of development of type 2 diabetes mellitus (T2DM). Abnormal fat combustion by fasting muscle is often correlated with insulin resistance, even in the pre-diabetic state, and altered fat metabolism also appears to diminish insulin action in liver, fat tissue, and the insulin-producing cells of the pancreas. Thus, the overarching aim of our research is to identify clinically-relevant metabolite biomarkers of dysfunctional fat metabolism, and to understand if at least some of these factors not only mark disease susceptibility but also participate in diabetes causation or exacerbation. Specific to this project is the goal to understand how naturally-occurring acylcarnitine metabolites (fatty acids of differing chain-lengths, bound to an amino-acid-like molecule), which are elevated in the T2DM blood as by-products of inefficient fat metabolism, activate pro-inflammatory pathways that are implicated in blunting the proper activity of insulin in the body. Longer-term, this knowledge can serve as a basis to design nutritional, pharmacological, or other interventions that can minimize the production or activity of high levels of the pro-inflammatory metabolites; for instance, by strategies that improve the efficiency of fat combustion in the tissues of persons with T2DM or pre-diabetes. WHY IS IT IMPORTANT

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

Personally, I feel that as a nutritional biologist and physiologist, I can make a difference in generating research that is immediately translatable to the human condition. Diabetes, by its nature, requires knowledge that links the subcellular/molecular world, tissue and whole-body biology, and environmental factors, and this integrative aspect is a strength of our research team. The research award will enable us to pursue a new paradigm in the field, pro-inflammatory pathways emanating from metabolites associated with inefficient metabolism of fats, sugars, and amino acids. This research is "risky" in that it is newly-emerging, and the capability of ADA to advocate this type of science enables "out of the box" thinking that is needed to push our knowledge base forward from existing dogmas. IN

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

I envision that within the next 5 years, it will become appreciated that type 2 diabetes (at least newly-diagnosed T2DM) and pre-diabetes are exceptionally-responsive to nutritional intervention coupled to very modest increases in physical activity, with effects being independent of weight loss in a large percentage of affected individuals. We have evidence, for instance, that provision of a high-quality weight-maintaining diet in obese, sedentary insulin-resistant individuals markedly improves insulin levels within days. This perspective is important, since the field is now also well-positioned to leverage metabolite profiling to diagnose pre-diabetics in the clinic, moving beyond blood glucose as an outcome variable with limited predictive value (blood sugar increases come late in the game, whereas other markers in the blood seem to change in diabetes-prone individuals much sooner). Within 5-10 years, it will become commonplace for physicians to routinely order a metabolite and hormone profile screen during yearly physicals, to report on T2DM and insulin-resistance risk to patients (much like cholesterol tests are used today to report on cardiovascular disease risk). Once identified, pre-diabetics will be treated immediately through high-quality nutritional intervention and very modest increases in physical activity to prevent progression to T2DM.