Unwrapping the action of a new diabetes drug: leptin
Researchers have unraveled the metabolic pathway of a new promising anti-diabetic agent, leptin.
Leptin effectively reduces blood glucose in diabetic mice by depleting substrates critical for energy production in the body, according to a new study by researchers at Life Sciences Institute’s Diabetes Research Group in University of British Columbia, Vancouver, Canada. The report appears on the May issue of Diabetologia.
Leptin is a hormone produced by the adipose tissue, a fat storage in the body. The hormone regulates appetite and blood sugar levels, among other physiological functions. Since its discovery in 1994, a number of studies demonstrated the anti-diabetic effects of leptin: lowering blood glucose levels and correcting metabolic imbalances in type 1 diabetes.
Individuals with type 1 diabetes lack the ability to produce insulin, which is required to remove sugars from the bloodstream. Leptin therapy is currently being clinically tested to treat this group. Despite efforts by multiple research groups, however, detailed understanding of how leptin works as an anti-diabetic agent has remained a puzzle.
In the new study, the researchers investigated the downstream metabolic pathway of leptin-induced glucose reduction in type 1 diabetic mice. “We found that leptin-treated mice have a severe depletion of…energy-yielding substrates [in the liver and bloodstream],” the researchers reported. The depletion of these substrates is closely followed by the return of blood sugars and energy-producing metabolisms to normal levels. Leptin treatment limits the availability of substrates, in particular, glycerol, a critical component in several metabolic pathways that produce energy. By dampening the energy production in the body, the blood sugar levels are kept in check.
The researchers further noticed that leptin’s anti-diabetic effects take place gradually, over the course of four days following the start of the therapy. This is in contrast to insulin, a well-known, fast-acting anti-diabetic agent. Leptin’s slow-acting property is thought as one of its positive attributes since it is less likely to cause fatal deficiency in blood sugars, or hypoglycemia.
In the study, however, leptin treatment induced severe hypoglycemia when diabetic mice underwent fasting. “…[D]iabetic patients given leptin by injection may suffer hypoglycemia, depending upon when fasting occurs in relation to leptin injection,” the researchers reported. “[The study]…highlights that additional studies are warranted to fully assess the hypoglycemic risk of leptin for type 1 diabetes treatment.”
Many research groups are investigating leptin therapy as an alternative to or combination with currently available treatments. Conventional interventions for diabetes, such as insulin injections, are undoubtedly lifesavers and allow the conditions to be more manageable – at a cost. Firstly, they do not address the root of the problem: disrupted metabolic balance. Insulin injections rapidly remove sugar from the blood, but the procedure must be repeated frequently. Also, an inappropriate application can deplete too much sugar, leading to life-threatening hypoglycemia. Secondly, some anti-diabetic drugs are accompanied by adverse side effects, including nausea and vomiting. Long-term use of the treatments, including insulin injections, can also increase risks of heart disease, blindness, kidney failure, etc.
Researchers are hoping that leptin therapy can provide safer and more effective treatment for some patients, particularly those with type 1 diabetes. Unlike insulin, leptin is slow-acting and gradually normalizes the blood sugar levels. Also, leptin does not promote accumulation of lipids in tissues and, therefore, likely would not increase the risk of heart disease and other harmful conditions.
University of British Columbia has long held a tradition of leading in diabetes research. In the 1970’s, the university’s researchers John Brown and Ray Pederson discovered a hormone that could stimulate insulin release. Soon after, a research team at the same university, led by Ray Pederson and Chris McIntosh, uncovered an enzyme that digests the hormone and a corresponding inhibitor that blocks this enzyme. These discoveries led to a new class of diabetic drugs on the market today, including exenatide (Byetta and Amylin) and liraglutide (Victoza and Novo Nordisk).
Timothy Kieffer, the project leader of the new report discussed here and a leading figure in the diabetes research, continues the tradition together with his colleagues in Diabetes Research Group. His achievement on stem-cell-based treatment for diabetes ranked within top 8 Notable Advances by Nature Medicine and top 10 Breakthroughs of the Year by Science for 2014.