Linking diet and metabolism to diabetes risk

Project Title: A New Homeostatic Mechanism for Metabolic Control
Institution: Duke University
Pathway Project Publications: 1
Promoted to Senior Research Associatie in 2017

Major accomplishments:

The association of branched chain amino acids (BCAA) and related metabolites with metabolic diseases is among the strongest reported for any biomarker. However, mechanisms that explain the links between elevated BCAA and altered lipid and glucose homeostasis have not been forthcoming.  With the support of the Pathway award we demonstrated that BCAA abundance influences skeletal muscle insulin sensitivity in a manner that involves alteration of fatty acid utilization due to mechanisms related to skeletal muscle nitrogen trafficking.

We have also uncovered a regulatory axis in liver that integrates the breakdown of BCAA with glucose and lipid production. Thus our findings suggest that elevated BCAA not only cause skeletal muscle insulin resistance but also report on the activity of a molecular axis that controls both glucose and lipid homeostasis.

We have extended the field's understanding of the reach of this signaling node by demonstrating that components of this axis exist in multiple cellular locations alongside key proteins involved in BCAA metabolism as well as glucose and lipid handling. We also employed bioinformatics to identify common short amino acid sequences or 'motifs' that are present in proteins regulated by this novel signaling node. Importantly, we show that therapeutic interventions targeting this axis have a robust impact on glucose control and levels of liver fat in severely obese insulin resistant rats. These findings are described in one manuscript published in the journal Molecular Metabolism in 2016 and two additional manuscripts currently under peer review.

Impact statement:

Type 2 diabetes is a complex disease that involves perturbation of normal control mechanisms for all of the major macronutrients. Indeed, we now know that perturbed protein (amino acid) and fatty acid utilization in addition to glucose metabolism are features of insulin resistance and diabetes and that each contributes to the development of complications associated with this disease. The Pathway program is currently supporting my work to understand an original and previously unanticipated finding of a molecular regulatory node that integrates control of glucose, lipid, and protein metabolism. Although much more needs to be learned, an exciting long-term outcome of this work could be the development of targeted approaches for improving metabolic functions across the nutritional landscape in individuals with type 2 diabetes via a single intervention. Importantly, the support provided by the Pathway award in terms of the financial provisions, specialized mentoring from the esteemed members of the mentor advisory group, and interaction with industry partners ensures that we have the necessary resources available to make the most of our initial discovery.

This award also comes at a critical time in my career development, as I prepare to launch my own independent laboratory. On this note, the remarkable financial support provided by the Pathway Initiator Award serves as a strong foundation on which I can begin to build my research group. It is noteworthy that the conditions stipulated by the award have strengthened my ability to negotiate strong institutional support that will further enhance the experimental capabilities and resources available to my group as we work to develop new approaches to improve the healthspan of persons with diabetes.