De León-Crutchlow Laboratory

Research in the De León-Crutchlow Lab focuses on the molecular genetics and pathophysiology of monogenic disorders of insulin regulation resulting in hyper and hypoglycemia, the role of the entero-insular axis, and how these mechanisms can be applied toward developing novel therapies.

The laboratory contributions from the examination of human islets isolated from surgical specimens from infants with congenital hyperinsulinism revealed a complex pathophysiology in which the primary KATP channel defect leads to secondary consequences affecting gene expression, fuel metabolism, and insulin secretion, both triggering and amplifying pathways. Follow-up studies focus on examining the role of ion channels other than the KATP channels in the regulation of insulin secretion.

A particular interest in the lab involves interactions between the gut and the pancreatic beta cell under pathologic conditions. The lab team demonstrated that the GLP-1 receptor is constitutively active in pancreatic islets isolated from a mouse model of hyperinsulinism (SUR-1-/-), and that pharmacologic antagonism of the GLP-1 receptor (GLP-1R) ameliorates hypoglycemia in SUR-1-/- mice and blunts abnormalities of insulin secretion in cultured mouse and human hyperinsulinism islets.

The De León-Crutchlow Lab also examines novel mechanisms of disease affecting insulin regulation and resulting in diabetes. Contributions from the laboratory include describing neonatal diabetes due to inactivating mutations in neurogenin-3, activating KATP channel mutations, and inactivating mutations of GATA6.

Project Highlights

• Role of ion channels TMEM16A and Kv7.1 in the regulation of insulin secretion in normal and hyperinsulinism islets: ongoing studies using mouse models aim at elucidating the role of these channels in terminating insulin secretion after stimulation.
• Identification and characterization of novel genetic loci associated with hyperinsulinism: through a combination of deep genotyping and phenotyping of humans and pancreatic islets our team aim at identifying novel mechanism of disease in hyperinsulinism.