Reversing Diabetes: It Must be Understood and Addressed Early
By: Mikaeel Valli
Type 2 diabetes (T2D) is a chronic metabolic disorder marked by insulin resistance and high blood glucose levels (hyperglycemia). If not managed carefully, chronic hyperglycemia may lead to cardiovascular disease, stroke, retinopathy, and kidney failure. With upwards of 60,000 new cases each year in Canada, current methods to manage diabetes (such as lifestyle changes and medication) only provide satisfactory results, as they fail to stop disease progression. Thus, clinicians and researchers are focused on developing novel interventions to treat diabetes. One promising strategy involves reversing diabetic symptoms early in its course. Dr. Ravi Retnakaran is an endocrinologist, clinician-scientist, and a leader in this field. For these reasons, in addition to many more, the IMS Magazine was pleased to interview Dr. Ravi Retnakaran.
Reviewing his career trajectory, Dr. Retnakaran recalled the pivotal decision he made regarding the subspecialty to pursue in internal medicine. “When I did clinical research in diabetes during my residency, the significant scope and breadth of diabetes caught my attention” he explained. “It became clear that endocrinology is what I wanted to do. Motivated by the significant impact of T2D on his patients, Dr. Retnakaran established his research laboratory at the Lunenfeld-Tanenbaum Research Institute in Mount Sinai Hospital. Since 2006, his research group has been focused on understanding the early pathophysiology of T2D and using this knowledge to develop novel therapies for clinical trials.
A major cause of T2D is the declining ability for pancreatic beta (β)-cells to produce insulin. While in vivo and in vitro experiments have made strides in preserving β-cell function, these results have not been replicated in humans. This led Dr. Retnakaran to emphasize, “[that in order] to intervene in a rational way, we need to understand the biology of diabetes early in its course.” In hopes of addressing this question, Dr. Retnakaran leads randomized control trials at Mount Sinai Hospital to test novel interventions on patients with T2D. Evidence suggests that early in the course of T2D, there is a window of opportunity in which β-cell dysfunction is reversible. Currently, the best therapy to achieve this reversal effect is short-term intensive insulin therapy (IIT) for two to five weeks immediately after T2D onset. Although this intervention has been known for over 20 years, it is not popular in clinics, as the effects are temporary. At 12 months following IIT, approximately 46% of patients remained in remission. “This effect is a good thing. However, we need to figure how we can maintain the initial benefit”, explained Dr. Retnakaran.
Taking a modern spin on this intervention, Dr. Retnakaran incorporates concepts from oncology and rheumatology to design new strategies for improving β-cell function and maintaining the protective effect. Results from the first clinical trial, called “BEST”, showed that a dipeptidyl peptidase-4 inhibitor, Sitagliptin, failed to preserve β-cell function achieved by IIT therapy. However, results from a subsequent trial, called “LIBRA”, were more promising. Following IIT, the injectable anti-diabetic medication, Liraglutide, maintained β-cell function. However, when patients were taken off Liraglutide, the effect was lost. When analyzing these results, Dr. Retnakran commented, “This suggests that maintenance therapy of Liraglutide was not changing the underlying biology. Otherwise, we wouldn’t expect to see the effect completely lost.” Insights from BEST and LIBRA have led to two current clinical trials funded by CIHR, called “RESET-IT” and “PREVAIL.” In explaining the rationale of RESET-IT, Dr. Retnakaran says, “Insulin is the only therapy that has [demonstrated a] persistent and sustained effect. Therefore, we are testing intermittent insulin therapy as both, induction and maintenance therapy, in the RESET-IT trial.” This trial is currently underway with the goal of measuring β-cell function after 2 years. PREVAIL is another induction-maintenance trial that combines the use of Exenatide, a drug shown to be effective in glycemic control of diabetes, with insulin early in the course of diabetes.
Current approaches for treating diabetes are focused on controlling blood glucose levels and improving insulin sensitivity. However, with this strategy, pancreatic β-cell function continues to deteriorate to a point of irreversibility and prompts the need for permanent insulin therapy in late stages of diabetes. Hence, treatment paradigms used in PREVAIL and RESET-IT are novel, as insulin is used as an early therapy to rescue β-cell function. Based on growing evidence, Dr. Retnakaran can see a new treatment model for diabetic patients. At diagnosis, patients will be referred to an endocrinologist to start induction therapy to reverse the β-cell dysfunction. Subsequently, patients will return to their family doctor for maintenance therapy.
Another aspect of Dr. Retnakaran’s work has been to longitudinally monitor young pregnant women, tracking their physiological changes. “Pregnancy is a natural physiological stress test for pancreatic β-cells”, he explained. Pregnant women may develop temporary diabetes termed gestational diabetes mellitus, which is also characterized by hyperglycemia. Gestational diabetes mellitus increases the risk of developing T2D in following years. Thus, as part of two large longitudinal cohort studies at Mount Sinai Hospital and in Liuyang (China), Dr. Retnakaran’s team has been carrying out various cardiometabolic tests on pregnant women with healthy, moderately abnormal, or gestational diabetic glucose levels. His team has observed that the abnormalities in glucose homeostasis during pregnancy are directly proportional to the underlying degree of β-cell dysfunction. “[This means that] you can use what happens with glucose in pregnancy and predict the future risk of diabetes,” he explained. Together, this study provides beneficial insight into the early pathophysiology of women at risk of T2D prior to the clinical manifestations of outcomes. Additionally, Dr. Retnakaran collaborates with teams at the Hospital for Sick Children to assess likelihood of diabetes in children born from mothers with gestational diabetes. With these cohort studies, Dr. Retnakaran found that “not only can we positively impact young pregnant women’s health early on, but we can potentially reduce the developmental issues and positively impact the next generation”.
Through both aspects of his research, Dr. Retnakaran hopes to develop strategies aimed at early intervention to capitalize on the narrow window of opportunity in reversing β-cell function. He wishes to enhance the understanding of T2D and positively change the outcomes faced by patients with T2D.