Newly Identified Biochemical Pathway Could Be Target for Insulin Control

Now researchers at Duke Medicine and the University of Alberta are reporting the identification of a new biochemical pathway to control insulin secretion from islet beta cells in the pancreas, establishing a potential target for insulin control.

The study, published online Sept. 24 in the journal Cell Reports, results from a field of work called metabolomics, which uses mass spectrometry instruments to measure and trace intermediate molecules in key metabolic pathways of cells and tissues.

“The Duke group focused on metabolites in islet cells that changed in response to elevated external glucose concentrations,” said co-senior author Christopher B. Newgard, Ph.D., director of the Sarah W. Stedman Nutrition and Metabolism Center and the Duke Molecular Physiology Institute. “We found a strong increase in an intermediate in the purine/nucleotide metabolic pathway -- known as adenylosuccinate, or S-AMP -- in islets stimulated with glucose.”

Impairment of S-AMP production was shown to interfere with normal glucose-stimulated insulin secretion. The Duke and University of Alberta Diabetes Institute teams were also able to demonstrate that S-AMP is capable of rescuing impaired insulin secretion in islets from people with Type 2 diabetes.

Newgard said the collaborative effort between the Duke and Alberta teams also yielded a separate finding, reported online Sept. 21 in the Journal of Clinical Investigation, which describes another molecular pathway that could be a potential metabolic target for insulin control.

In that study, the research teams identified a process that works essentially like a dimmer switch to adjust how much or how little insulin is secreted when blood sugar increases. This dimmer switch appears to be broken in Type 2 diabetes, but the researchers found that its function can be restored.

“For the moment, we have two separate mechanisms, but with further study we may find that they are more connected,” Newgard said. “Whether they are independent, additive or synergistic is unknown, so we are eager to bring the two projects together to see where that may lead.”

In addition to Newgard, study authors from Duke include Jessica R. Gooding; Mette V. Jensen; Brett R. Wenner; Danhong Lu; and Ramamani Arumugam.

Patrick E. MacDonald, Ph.D., of the Alberta Diabetes Institute, led the work at the University of Alberta, along with Xiaoqing Dai and Mourad Ferdaoussi.

The National Institutes of Health (DK046492-22 and K01GM109320-02) and the Canadian Institutes of Health Research (MOP 244739) funded the research.