Objective
We have observed that in patients with type 1 diabetes, and those at risk of future diabetes, the immune system reacts against a modified insulin protein, namely oxidized insulin. We have preliminary data suggesting that the production of oxidized insulin by beta cells reflects their stress. Our goal is to develop a novel molecule (antibody) that will specifically recognize a modified insulin, or oxidized insulin. Armed with this tool, we will address three fundamental questions: 1) can oxidized insulin, measured in blood, alert doctors that beta cells are stressed, and perhaps reflect the ongoing immune attack on them? 2) can oxidized insulin impair sugar metabolism by interfering with the action of normal insulin? 3) Is oxidized insulin found in the pancreas affected by type 1 diabetes, especially in stressed beta cells? The ultimate goal of this research is to progress to the production of novel therapeutic molecules that can specifically recognize stressed beta cells making oxidized insulin and at the same deliver therapeutic signals, selectively to stressed beta cells, and possibly fend off the immune cells that attack them. Given that insulin is solely and abundantly produced in beta cells, oxidized insulin represents an ideal target for localized and selective delivery of therapies, which would allow for increased safety and efficacy.
Background Rationale
Type 1 diabetes is caused by loss of the insulin-producing pancreatic beta cells mediated by the immune system. However, beta cells themselves play a role in their own demise by making and accumulating modified proteins that the immune system recognizes as foreign, leading to their elimination by the immune system. Indeed, our studies have shown that this modified insulin is a target of immune responses in patients with type 1 diabetes. This oxidized insulin is produced by beta cells, probably in stressed beta cells, and is also released in the blood. The proposed project is geared towards generating a novel molecule (antibody) to specifically study and measure oxidized insulin. Oxidized insulin represents an ideal target for localized and selective delivery of therapies, which would allow for the generation of novel therapies with increased safety and efficacy, which remains an unmet need.
Description of Project
Type 1 diabetes is caused by loss of the insulin-producing pancreatic beta cells mediated by imbalanced activation of the immune system. The influx of immune cells are very active metabolically and therefore produce an excess of oxidants that attack proteins in the pancreas. In addition, stressed beta cells themselves play a role in their own demise by making and accumulating modified proteins that the immune system recognizes as foreign, leading to their elimination by the immune system. Over production of oxidants by immune cells and stressed beta cells results in insulin oxidation that is also released in the blood. Indeed, our studies have shown that insulin modified by oxidants is a target of immune responses in patients with type 1 diabetes. The proposed project is geared towards generating a novel molecule (antibody) to specifically study and measure oxidized insulin, so that we can specifically address the following fundamental questions: 1) can oxidized insulin, measured in blood, alert doctors that beta cells are stressed, and perhaps reflect the ongoing immune attack on them? If so, we would have identified a novel marker of beta cell stress and damage, which is an unmet need, as we struggle to fully determine the extent to which the disease has advanced in individuals at risk of future type 1 diabetes; such a new marker will help better design (faster, shorter, and with fewer subjects) clinical trials to test novel therapies to prevent, reverse and cure the disease; 2) can oxidized insulin impair sugar metabolism by interfering with the action of normal insulin? If so, this would identify a novel disease mechanism and at the same time a new therapeutic target; 3) Is oxidized insulin found in the pancreas affected by type 1 diabetes, especially in stressed beta cells? This demonstration would support new therapeutic strategies that rely on novel molecules that can specifically recognize stressed beta cells making oxidized insulin and at the same deliver therapeutic signals, selectively to stressed beta cells, and possibly fend off the immune cells that attack them. Given that insulin is solely and abundantly produced in beta cells, oxidized insulin represents an ideal target for localized and selective delivery of therapies, which would allow for increased safety and efficacy.
Anticipated Outcome
We expect that this research will demonstrate that oxidized insulin is of critical importance in type 1 diabetes, at multiple levels: 1) it can be exploited as a marker of disease progression in blood; 2) it can represent a contributor to the disease causes if it is found to interfere with the action of normal insulin, and hence a therapeutic target; 3) it can provide evidence that oxidized can be exploited as a tool to guide precise delivery of novel therapies to beta cells that are stressed and under attack by the immune system; such therapies can both provide help to protect the beta cells, sustain their function, and fend off the immune cells that attack them. Thus, this research may open a new avenue for a new class of therapeutic agents to be developed and specifically designed for type 1 diabetes.
Relevance to T1D
This project is directly relevant to type 1 diabetes. The research is focused on a modified insulin produced by beta cells, that is targeted by the immune system in patients. This modified insulin, or oxidized insulin, can serve as a marker of disease progression, helping us stage the disease, and ultimately represents a disease-specific target for therapeutic intervention. In fact, oxidized insulin may represent an ideal target for the precise delivery of novel therapies to beta cells that are stressed and under attack by the immune system, and such therapies can both provide help to protect the beta cells, sustain their function, and fend off the immune cells that attack them. Thus, this research may open a new avenue for a new class of therapeutic agents to be developed and specifically designed for type 1 diabetes.