Objective
We hypothesize that T1D onset can be reduced with a combination therapy of early anti-inflammatory intervention followed by a regimen that amplifies the resolving phase. Our objective will be to identify the regimen combination that targets these two phases, that is most effective in reducing T1D incidence and can be moved forward to clinical trials. Our approach will exploit currently available agents that are select, potent, well-tolerated and are in or in consideration for clinical trials targeting non-T1D inflammatory disorders, and repurpose them to counter T1D. We will compare three different combination regimens that will target early inflammatory signaling and enhance later resolving capacity. Our analyses will include monitoring blood sugar levels, the ability of the body to remove sugar from the blood (reflects sugar tolerance), assessment of beta-cell insulin content, quantifying damage to the islet, and determining the abundances of inflammatory and resolving lipids in the plasma. We will compare these outcomes in an autoimmune rodent model of T1D treated with vehicle (no drug) or with agents targeting the select lipids. The most effective regimen will then be studied in greater detail, with the intention of moving it forward to clinical trials. Our chosen lipid candidates are novel to the field and can be feasibly targeted in normoglycemic subjects at high risk for developing diabetes.
Background Rationale
Type 1 diabetes (T1D) results from a loss in the ability of human pancreatic islets to generate enough insulin to control blood glucose levels. More specifically, the beta-cells in the islets, which synthesize and secrete insulin into the blood, are destroyed over time. Humans prone to developing T1D generate autoantibodies that can be detected in the blood. There are four major antibodies and when 2 or more are detected, these individuals are considered to be at high risk for developing T1D at some point in their lives. The triggers to start this process are many and not well-understood. However, they recruit similar pathways that eventually lead to same end, death of the beta-cells.
Currently, the only effective T1D therapy is replacing the missing insulin with daily insulin administrations. Other strategies include islet transplantation, successful but not a permanent solution; and immunotherapies or stem-cell derived beta-cell transplantation, promising but limited at this time by immuno-rejection and with issues of recovering optimal function. A common feature of these approaches is that they are initiated after the subject has been diagnosed with T1D.
Our pre-clinical studies in a T1D model, in which a progression to T1D development can be feasibly monitored, identify previously unrecognized sequential events that occur prior to the onset of T1D. A basic concept addressed in our proposal is that an inflammatory insult phase is followed by a resolution phase. When the latter phase is insufficient, the inflammatory processes predominate and lead to disease, as in T1D. We find that production of certain fats (or lipids) is increased prior to the onset of T1D. Interestingly, different inflammatory lipids increased at different ages and detection of resolving lipids was more evident near and at T1D onset. We have identified an enzyme that can generate these lipids and when we reduce its function, the lipid production is reversed and there is a decrease in the incidence of T1D. When samples from children at high risk for developing T1D, but not yet diabetic, were analyzed we find that they express more of the enzyme and also have higher abundances of some of the same lipids. Together, these observations suggest that select lipids generated by this enzyme contribute to the onset of T1D. In support, when signaling of these lipids in T1D-relevant cell preparations is modulated, mitigation of the inflammatory profile of the cells is evident. This raises the intriguing possibility that targeting these lipids during the pre-diabetic phase (before T1D onset) could be a feasible approach to prevent or preempt T1D development in humans.
To address this possibility, we have assembled a team of experts in beta-cell biology/lipid signaling, development of lipid chemical mediators/intervention studies, and lipid analyses in cells and blood. Together, we propose to assess the ability of three combination (involving two different agents) regimens aimed at (a) reducing inflammatory lipid signaling and (b) amplifying resolving lipid signaling to reduce T1D incidence. By targeting these two phases, we expect to identify an optimal regimen combination that can be moved forward towards clinical trials. Salient features of our proposal include (a) novelty, in that it targets lipid signaling, which has previously not been considered, (b) feasibility, since the chosen agents are readily available, tested in non-T1D scenarios, and demonstrated to be select, potent, and well-tolerated, and most importantly (c) focus on the pre-diabetic phase, which could alter the paradigm of T1D therapy in human.
Description of Project
Type 1 diabetes (T1D), also known as insulin-dependent or juvenile diabetes, is a consequence of beta-cell death. The beta-cells, located in pancreatic islets, synthesize and store insulin. When blood sugar levels increase (e.g., after a meal), the beta-cells are stimulated and secrete insulin, which increases sugar uptake, utilization, and storage by various organs, and blood sugar levels return to normal levels. In T1D, destruction of beta-cells leads to a loss in the source of insulin. Thus, a meal is not followed by increases in insulin secretion and this leads to elevations in the levels of blood sugar, and subsequent accumulation of sugar in organs. Progressive increases in organ levels of sugar can lead to abnormal heart function, kidney failure, blindness, and nerve damage in the feet.
Currently, insulin therapy is the only effective means to treat and control complications associated with T1D. Other approaches include islet transplantation, which can require several donors per transplantation and need for multiple procedures over a lifetime. Developing immunotherapy or stem-cell derived beta-cell replacement protocols has been challenging and fraught with rejection issues. For these reasons, there is continued need to explore new avenues to manage T1D. Additionally, the current therapies apply to those who have already been diagnosed with T1D.
Many factors (e.g., genetic, environmental, lifestyles) can trigger T1D onset. In all cases, they induce an autoimmune attack of the beta-cells, where specialized cells in one’s own body kill the beta-cells. Our lab focus is on understanding how lipid (or fat) signals impact beta-cell function and survival. The Principal Investigator of this proposal started on this journey with a JDRFI award in 1994 that led to the identification of an enzyme, which generates these lipids. We find that these select lipids are elevated prior to the onset of T1D. These lipids have profound inflammatory effects which ramp up immune responses leading to beta-cell death. Surprisingly, with inhibition or genetic-reduction of the enzyme, the pre-diabetic rise in these lipids is mitigated and is accompanied by a reduction in the incidence of T1D in an animal model. These observations are intriguing, as they identify lipids elevated prior to the onset of T1D, that have a negative impact on the health and survival of beta-cells. This raises the possibility that targeting these lipids prior to the onset of T1D may be an effective means to delay or prevent T1D onset.
Our recent work led to the identification of select lipids which we have deduced as having key roles in the onset of T1D. Of particular interest is that the increases in multiple inflammatory lipids occur early and in a sequential manner. At later ages, there is an increase in the production of a different class of lipids to affect resolution of inflammation. However, the abundances of these resolving lipids does not rise to sufficient levels to counter T1D onset. The goal of our proposed work is to identify optimum combination regimen that will mitigate the early inflammatory phase and amplify the latter resolving phase. We propose to re-purpose readily available select and potent agents that target the relevant lipids to counter T1D onset. Crucial to our mission, these agents are well-tolerated with no adverse effects and are in or under consideration for clinical trials.
While current approaches target T1D complications, none are available to prevent T1D onset. The advantage of our novel perspective is that targeting lipid signaling may be a means to achieve this goal. Successful completion of our studies will offer novel strategies to alter or prevent the course of T1D onset in the human population, and lead to a paradigm shift in T1D therapy.
Anticipated Outcome
We propose to test the 1st combination regimen during Yr01 of the award, 2nd between Yr01-Yr02, and the 3rd in Yr02. Each protocol will include cohorts that are treated with only the vehicle that the agents are prepared in or with the combination regimen. Administration of anti-inflammatory agents will begin at 4 weeks of age, when the inflammatory process begins, and resolving agents will be co-administered starting at 4 weeks, 8 weeks (more profound inflammation), or 14 weeks (nearing T1D onset age) of age.
We predict that the combination of early mitigation of inflammatory phase followed by enhancement of the resolution phase will be extremely beneficial in mitigating beta-cell death, improving glucose tolerance, and reducing T1D incidence. Beneficial positive impact evidenced with any of the regimens should be viewed as paradigm shifting in the field of T1D therapy and provide motivation to examine in greater detail the extent of lipid signaling contribution to T1D onset. It would also provide strong rationale to translate the combination regimen to clinical trials.
Relevance to T1D
Current therapeutic strategies against T1D encompass approaches to treat subjects diagnosed with diabetes with agents to reduce the progression or severity of complications associated with the disease. As such, treatment regimens are initiated following a diagnosis of T1D. Our goal here is to target events prior to the onset of T1D, those that lead to T1D onset, so that the onset of T1D is delayed or prevented. If our approach is successful, it would preempt the need to develop or employ protocols to reduce autoimmune responses that are triggered by transplantation of preparations donated by foreign sources. Importantly, it would highlight the potential for modulating novel targets during the pre-diabetic phase with classes of agents, that are already available and are constantly being improved, as a means to circumvent the development of diabetes. As such, our work could have a significant impact in the T1D field and contribute critical insights into preventing T1D development.