Decoding the logic of metabolite pool size control - despite decades of progress in metabolomics, understanding what determines metabolite concentrations in cells remains a fundamental unsolved problem

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Duke University $807,500 on August 15, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847).

The project, titled "Decoding the Logic of Metabolite Pool Size Control," develops an integrated metabolic control discovery platform to understand the molecular mechanisms that regulate metabolite concentrations in cells. The research will systematically discover molecular components that sense and respond to metabolite perturbations, use computational approaches to reconstruct how these components function as control circuits, and validate discovered circuits in increasingly complex biological systems ranging from cell lines to human organoids. The work addresses the central hypothesis that metabolite dysregulation in diseases such as diabetes—characterized by elevated branched-chain amino acids—represents corrupted control circuits rather than simple pathway failures.

Duke University's Office of Research Administration Division is the awardee. Work is performed in Durham, North Carolina, with a period of performance from August 15, 2026, through May 31, 2031. The award is structured as a project grant, the standard assistance type for investigator-initiated research under this NIDDK program.

While we can measure thousands of metabolites with unprecedented accuracy, we lack an understanding of the control logic that maintains their precise concentrations, such as keeping blood glucose at 5 MM regardless of the feeding state or maintaining ATP levels constant despite thousand-fold changes in energy demand. This proposal aims to decode the control circuits governing metabolite pool size homeostasis, moving beyond descriptive metabolomics to reveal how cells compute and maintain specific metabolite set points. The project will develop an integrated metabolic control discovery platform through three iterative steps. First, the project will systematically discover the molecular components that sense and respond to metabolite perturbations across multiple regulatory layers. Second, computational approaches will reconstruct how these components work together as control circuits, distinguishing true regulators from coincidental responders. Third, discovered control circuits will be validated in increasingly complex biological systems, from cell lines to human organoids, establishing their functional importance and therapeutic potential. The central hypothesis is that metabolite dysregulation in diseases like diabetes-where branched-chain amino acids show a 2- to 3-fold elevation-represents corrupted control circuits rather than simple pathway failures. The proposed research aims to transform metabolism from a descriptive to a predictive science, enabling the rational manipulation of metabolite pools for therapeutic benefit. By revealing the fundamental principles of metabolite homeostasis, this work addresses a critical barrier between observing metabolic diseases and treating them, aligning with niddk's mission to improve prevention, diagnosis, and treatment of diabetes and metabolic diseases.