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Chemical Biology of Diabetes

Small-molecule discovery is a key activity within type 2 diabetes (T2D) research. Newly discovered or synthesized molecules:

  • help the Diabetes Research Group understand the biological basis of diabetes
  • serve as candidates for testing therapeutic hypotheses in vivo
  • may potentially become lead compounds for clinical development

The group’s overall approach leverages human “experiments of nature” to identify new targets for therapeutic intervention. As genetic loci associated with diabetes are uncovered within the human genome and validated through extensive molecular, cellular, and physiological studies, researchers aim to transition knowledge of the mechanisms underlying disease risk into assay development and high-throughput compound screening.

The Diabetes Research Group uses a wide range of biochemical, cell-based, and protein-binding techniques to measure chemical modulation of key genetic targets. Once the scientists identify active small molecules, they take a variety of cell-based approaches to confirm activity, assess specificity of action, and understand the mechanism of action of compounds within cells. Together, these methods move them closer to their ultimate ambition to advance the understanding and treatment of diabetes.

In addition to genetic targets, one area of focus for small-molecule discovery is pancreatic beta cell biology. Beta cell death, and the consequent deficiency in insulin secretion, is a key feature of type 1 diabetes. Beta cell dysfunction is also a hallmark of T2D, resulting in the inability of patients to compensate for high blood glucose levels. A chemical intervention capable of restoring glycemic control in patients with diabetes would have enormous clinical impact. To that end, we have developed phenotypic cell-based assays to identify compounds capable of a number of activities, such as: 

  • increasing human beta cell proliferation
  • protecting beta cells from the inflammatory processes of diabetes progression
  • inducing beta-cell transdifferentiation
  • enhancing glucose-dependent insulin secretion from beta cells
  • targeted delivery of small molecules to the beta cell in vivo

Several compounds are now undergoing preclinical testing for efficacy in rodent models of diabetes.

Projects