Columbia Technology Ventures

Knock-in mouse model with labeled insulin provides essential tool for diabetes research and drug development

Diabetes mellitus affects more than 25 million people in the United States, and 90-95% have type 2 diabetes, which is characterized by insulin resistance in peripheral tissues as well as a defect in insulin secretion by beta cells. Currently, there is no cure for type 2 diabetes. Research into the expression and secretion of insulin by beta cells in the pancreas will be important for the development of future treatments for diabetes. This technology is a knock-in mouse model with GFP inserted into the insulin 2 locus. The ability to use fluorescent imaging to visualize endogenous expression of insulin will provide a valuable tool in the investigation of events that affect insulin expression in vivo. This technology can also serve as an in vivo model for drug development.

GFP-labeled insulin in knock-in mouse allows in vivo investigation of insulin production and secretion

Insulin’s key role in glucose metabolism contributes to the development of diabetes, but investigation of insulin production in vivo has been limited due to the absence of precise animal models. Most insulin mouse models consist of transgenic mice expressing transient or variable labeling of insulin-related proteins, which can cause misleading expression. The knock-in mouse described in this technology contains a GFP knocked into its endogenous insulin locus, which ensures that all the regulatory mechanisms that control insulin expression remain intact. Unlike other transgenic mice, this mouse line faithfully recapitulates the expression of insulin, which will be useful for further investigations into the mechanism of glucose metabolism and treatments for diabetes.

The accurate fluorescent labeling of insulin in this knock-in mouse strain was demonstrated by staining the GFP and the insulin individually and ensuring that they co-localized. Furthermore, they looked for the appropriate presence of GFP in known locations of insulin expression (i.e. pancreatic islet cells) as well as the absence of GFP in areas like the brain, kidney, and liver of the transgenic mice.

Lead Inventor:

Argiris Efstratiadis, Ph.D.

Applications:

  • Animal model to investigate genetic and environmental factors that cause insulin level and expression changes
  • Ability to track insulin production and secretion will provide insight into effectiveness of various drug compounds for diabetes treatment
  • Further in vivo investigation into insulin-secreting beta cells, which are labeled by the GFP
  • The labeling of cells that interact with insulin will allow precise extraction of these cells for ex vivo experiments
  • Identification of novel proteins that interact with insulin, which may serve as therapeutic targets for diabetes

Advantages:

  • Directly labels insulin in vivo such that the GFP is restricted only to the cells where insulin is found
  • All regulatory elements in the insulin gene are kept intact, so expression can’t be falsely altered by other local factors (like in transgenic mice)
  • Any genetic or environment modifications to the endogenous insulin will be accurately represented by the GFP label

Patent information:

Patent Pending

Tech Ventures Reference: IR 2363

Related Publications:

*C Talchai, S Xuan, T Kitamura, RA DePinho, D Accili. Generation of functional insulin-producing cells in the gut by Foxo1 ablation. Nature Genetics, Vol. 44, Mar. 2012, pp. 206-212.