Objective
LAY ABSTRACT - OBJECTIVES
This study will test the safety and efficacy of the FDA-approved osteoporosis medicine, Denosumab (trade names Prolia, Xgeva), to improve beta cell function and glucose levels in individuals with early T1D.
This is a blinded one-year study. Individuals with early T1D (1-5 years since diagnosis) who are C-peptide positive, an indicator of insulin-producing beta cells, will be randomized to receive either (i) Denosumab (four times a year), or (ii) placebo (four times a year), at a 2:1 ratio, through subcutaneous injection, every 3 months for one year. All participants will continue their standard of care treatment for diabetes. The study will be conducted at three locations - City of Hope, University of Alabama and Indiana University.
The objectives of the study are to assess the safety of Denosumab and determine the efficacy of Denosumab to improve beta cell function and glucose balance in individuals with T1D. This will be determined by metabolic tests and blood level of hormones and other markers.
Background Rationale
LAY ABSTRACT - RATIONALE
Type 1 diabetes (T1D) is progressive and has no known cures. Central to the disease is immune cell mediated injury and loss of beta cells that produce the natural hormone insulin. Individuals with T1D have insufficient insulin to maintain healthy levels of glucose. However, in the early stages of T1D many beta cells are alive and functioning. If, during this time, one could protect the beta cells against further injury and enhance their replication the progression of the disease and the need for artificial insulin would be delayed and decreased.
We discovered that a protein pathway known to cause bone loss was also detrimental to beta cell health. It blocked beta cells from replicating and propagated injury in beta cells. We found that blocking this pathway improved beta cell health. In mice, blocking this pathway not only delayed but also reversed early onset T1D. Importantly, a safe and widely used medicine for osteoporosis, Denosumab (trade names Prolia, Xgeva), blocks this pathway. We found that Denosumab improved the health of human beta cells in culture and protected them against diabetes-related injuries, including the cytotoxicity from serum from individuals with T1D. Denosumab also altered immune cells and decreased inflammation. This is important since immune cells and inflammation contribute to T1D.
The advantages of Denosumab are: 1) its established safety profile; 2) its long half-life, reducing administration frequency to months rather than hours or days; and 3) it is one of the few agents that directly improves beta cell health.
In this study we will test the safety and efficacy of Denosumab to improve beta cell function and glucose levels in individuals with early T1D.
Description of Project
LAY ABSTRACT
Type 1 diabetes (T1D) is progressive and has no known cures. Central to the disease is immune cell-mediated injury and loss of beta cells that produce the natural hormone insulin. A common finding in individuals with T1D is insufficient insulin to maintain healthy levels of glucose. However, in the early stages of disease, many beta cells are alive and functioning. If one could support and protect the beta cells against injury at this time the progression of the disease and the need for artificial insulin would be delayed and decreased. We discovered that beta cells are injured by a pathway that is also known to cause bone loss. We found that blocking this pathway not only delayed but also reversed T1D in animals. Importantly, a safe and widely used medicine for osteoporosis, Denosumab (trade names Prolia, Xgeva), that blocks this pathway, improved the health of human beta cells and protected them against injuries that are relevant to the disease. Other advantages of Denosumab include its safety and its long half-life requiring taking this drug every few months. In this study, we will explore if Denosumab, given four times a year, is safe for and improves beta cell function and glucose balance in people with early T1D. If successful, the proposed study will identify a new T1D treatment that could be administered infrequently (every few months) to preserve and boost beta cell health, thus lowering the requirement for insulin.
Anticipated Outcome
LAY ABSTRACT - OUTCOMES
Individuals with T1D will receive either placebo or denosumab every 3 months (4X/year). This study will determine the safety of giving Denosumab to individuals with early T1D, through examination of their health parameters and occurrence of adverse events. Due to the wide use of denosumab for other indications we expect it to be well tolerated in individuals with T1D as well. The study will assess the efficacy of Denosumab to improve glucose balance in T1D patients. Several parameters including levels of C-peptide secretion, islet hormones, HbA1c, and percent time in glycemic range will be determined. All these tests provide insight into beta cell function. Due to the strong preliminary and pre-clinical data supporting our hypothesis, we expect denosumab to improve beta cell health, and thus enhance beta cell function.
Relevance to T1D
LAY ABSTRACT-RELEVANCE TO T1D
Type 1 diabetes (T1D) arises from abnormal immune cell injury to beta cells. The injured beta cells can then no longer make the needed amount of insulin to stay healthy. However, in the early stages of T1D many beta cells are still alive and functioning. If one could protect the beta cells against injury at this time and increase their numbers through proliferation, the progression of the disease and the need for extra insulin would be delayed and decreased.
Out team tested a widely used medicine for osteoporosis, Denosumab (trade names Prolia, Xgeva). We found that Denosumab increased replication of human beta cells and protected them from injury. Other advantages of Denosumab are that it is safe and because its effects are long-lasting can be taken only a few times each year. This study will test whether Denosumab improves beta cell function and if it is safe in people with early T1D.
If successful, the proposed study will identify a new T1D treatment that could be administered infrequently (every few months) to preserve and boost beta cell health, thus lowering the requirement for insulin.