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Published on: June 15, 2013
Induction of insulin secretion in engineered liver cells by nitric oxide
Latha Muniappan1, Sabire Ozcan
1Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, 741 South Limestone, BBSRB, Lexington, KY 40536, USA. latha.muniappan@uky.edu
Background:
Type 1 Diabetes Mellitus results from an autoimmune destruction of the pancreatic beta cells, which produce insulin. The lack of insulin leads to chronic hyperglycemia and secondary complications, such as cardiovascular disease. The currently approved clinical treatments for diabetes mellitus often fail to achieve sustained and optimal glycemic control. Therefore, there is a great interest in the development of surrogate beta cells as a treatment for type 1 diabetes. Normally, pancreatic beta cells produce and secrete insulin only in response to increased blood glucose levels. However in many cases, insulin secretion from non-beta cells engineered to produce insulin occurs in a glucose-independent manner. In the present study we engineered liver cells to produce and secrete insulin and insulin secretion can be stimulated via the nitric oxide pathway.
Results:
Expression of either human insulin or the beta cell specific transcription factors PDX-1, NeuroD1 and MafA in the Hepa1-6 cell line or primary liver cells via adenoviral gene transfer, results in production and secretion of insulin. Although, the secretion of insulin is not significantly increased in response to high glucose, treatment of these engineered liver cells with L-arginine stimulates insulin secretion up to three-fold. This L-arginine-mediated insulin release is dependent on the production of nitric oxide.
Conclusion:
Liver cells can be engineered to produce insulin and insulin secretion can be induced by treatment with L-arginine via the production of nitric oxide.
Insights
Engineered liver cells can produce insulin for type 1 diabetes treatment. Insulin secretion is stimulated by L-arginine through nitric oxide production, offering a novel therapeutic approach.
Area of Science:
- Cell Biology
- Endocrinology
- Metabolic Diseases
Background:
- Type 1 Diabetes Mellitus (TDM) involves autoimmune destruction of insulin-producing pancreatic beta cells, leading to hyperglycemia and complications.
- Current TDM treatments often struggle with sustained glycemic control, driving research into alternative therapies like surrogate beta cells.
- Engineered non-beta cells may offer a solution, but achieving glucose-responsive insulin secretion remains a challenge.
Purpose of the Study:
- To engineer liver cells to produce and secrete insulin.
- To investigate methods for stimulating insulin secretion from these engineered cells.
Main Methods:
- Adenoviral gene transfer was used to express human insulin or key beta cell transcription factors (PDX-1, NeuroD1, MafA) in liver cells (Hepa1-6 cell line and primary cells).
- Insulin secretion was measured under varying glucose conditions and in response to L-arginine.
- The role of nitric oxide in L-arginine-stimulated insulin release was assessed.
Main Results:
- Engineered liver cells successfully produced and secreted insulin.
- Insulin secretion was not significantly increased by high glucose alone.
- Treatment with L-arginine stimulated insulin secretion up to threefold, dependent on nitric oxide production.
Conclusions:
- Liver cells can be successfully engineered for insulin production.
- L-arginine can induce insulin secretion from these engineered cells via the nitric oxide pathway.
- This approach presents a potential strategy for developing surrogate beta cells for TDM treatment.
