Objective
The objective of this proposal is to use an epigenetic approach to stimulate the regeneration of insulin producing cells. The FDA approved drugs will be tested in a macaque model of Type 1 diabetes to assess their efficacy in resolving hyperglycaemia as assessed by blood glucose levels.
Background Rationale
Various strategies have been investigated to restore the insulin producing β-cell mass as a curative approach to diabetes. Whilst islet transplantations have resolved hyperglycaemia and led to insulin independence in Type 1 diabetic patients, a shortage of donors remains an impediment. Regeneration of β-cells has been investigated as a possible alternative source for islet transplantation. Previous studies conducted by us have shown that an epigenetic stimulation of the pancreatic ducts isolated from human donors allows for an increase in insulin levels. To this purpose, we aim to demonstrate this effect in a highly relevant macaque model of Type 1 diabetes, wherein administration of clinically approved drugs will be investigated for their potential in regenerating the destroyed β-cells of the pancreas.
Description of Project
Various strategies have been investigated to restore the insulin producing β-cell mass as a curative approach to diabetes. Whilst islet transplantations have resolved hyperglycaemia and led to insulin independence in Type 1 diabetic patients, a shortage of donors remains an impediment. Regeneration of β-cells has been investigated as a possible alternative source for islet transplantation. Previous studies conducted by us have shown that an epigenetic stimulation of the pancreatic ducts isolated from human donors allows for an increase in insulin levels. To this purpose, we aim to demonstrate this effect in a highly relevant macaque model of Type 1 diabetes, wherein administration of the clinically approved drugs will be investigated for their potential in regenerating the destroyed β-cells of the pancreas.
The FDA approved drugs will be tested in a macaque model of Type 1 diabetes to assess their efficacy in resolving hyperglycaemia as assessed by blood glucose levels. These studies will be conducted in non-human primates, which are more closely evolutionarily related to humans. Given that previous studies in closely related human exocrine tissue have demonstrated the successful restoration of β-cell markers, we anticipate that treatment of diabetic macaques with EZH2 inhibitors will result in the amelioration of high blood glucose levels, and a restoration of insulin production through newly formed β-cells.
Anticipated Outcome
Given that previous studies in closely related human exocrine tissue have demonstrated the successful restoration of β-cell markers, we anticipate that treatment of diabetic macaques with EZH2 inhibitors will result in the amelioration of high blood glucose levels, and a restoration of insulin production through newly formed β-cells.
Relevance to T1D
These studies will be conducted in non-human primates, which are more closely evolutionarily related to humans. Furthermore, these macaques will have their insulin producing cells destroyed using streptozotocin, which selectively targets β-cells. This means that their diabetic condition closely mimics the disease seen in Type 1 diabetic patients, where the immune system mediates destruction of β-cells.