Fenugreek may ease side effects 
of diabetes treatment

Fenugreek is cultivated worldwide and may enhance GLP-1 potency.

We hear it at the end of every drug commercial. Taking a particular medication will aid one problem while causing a whole slew of other issues. This is certainly true for the treatment of type 2 diabetes. Currently, glucagon-like peptide 1, or GLP-1, analogs are approved to treat type 2 diabetics and are undergoing clinical trials for other disorders including neurodegenerative diseases. But alongside their therapeutic properties, these analogs initiate a global activation of their target receptor, GLP-1R, and that activation ultimately leads to side effects that include nausea, vomiting and gastrointestinal distress.

In an attempt to avoid the adverse effects associated with current GLP-1 analog treatments, labs led by Rong-Jie Chein and Klim King, both of Academia Sinica in Taipei, Taiwan, sought to characterize molecules that set off the signaling pathway of GLP-1R without directly interacting with GLP-1R.

The researchers screened extracts from edible plants for these positive modulators and, in a recent issue of the Journal of Biological Chemistry, report finding a novel compound in fenugreek. According to Chein and King, the plant, cultivated worldwide as an herb, spice and vegetable and sometimes recommended to breastfeeding mothers to stimulate milk production, contains a compound that binds to and enhances GLP-1 potency.

GLP-1 is a peptide hormone that enhances insulin secretion. GLP-1 binds the receptor GLP-1R, which is expressed in various tissues throughout the body, including but not limited to the lungs, heart, kidney, blood vessels, neurons and white blood cells. GLP-1 signaling has been an ideal candidate for drug discovery and development and is a target for many therapies including treatments for psoriasis, heart disease and neurodegenerative disorders.

Therapeutic treatment of type 2 diabetes aims to enhance activation of the GLP-1R receptor. The GLP-1 analogs that this strategy uses are maintained at a chronically high plasma level. It is an artificial, systemic approach that leads to the disrupted regulation of GLP-1R signaling, which — along with the aforementioned side effects — could ultimately lead to the development of pancreatitis and pancreatic malignancies. To be able to circumvent these adverse effects, a modulator that activates the receptor based purely on physiological needs has been sought.

In a previous investigation of GLP-1 regulation, Cheng and colleagues at Academia Sinica discovered that some endocannabinoids, like lipids, can positively modulate GLP-1R by enhancing the activity of GLP-1. They also established a feasible detection to screen such activity from plant extracts. These prior study results are what prompted the researchers to screen active compounds from edible herbs including fenugreek.

Using positive modulators of GLP-1R signaling differs from the current analog therapy, as the modulators themselves do not activate the GLP-1R. This allows for control over the degree of activation of these receptors and is less likely to lead to chronic activation of GLP-1R.

Using a combination of two assays, the paper's authors found the active compound N55 from fenugreek seeds that affected GLP-1R signaling. The first assay measured intracellular cAMP levels — cAMP is needed for proper insulin secretion essential for treatment of type 2 diabetes. The second assay the investigators used looked at GLP-1R endocytosis, or the uptake of GLP-1R into the cell. Endocytosis of GLP-1R is a measure of receptor activation and stimulation of the cAMP pathway. Using these two assays, the investigators showed that N55 promoted GLP-1-dependent cAMP production and GLP-1R endocytosis. Unlike the current analogs, which bind GLP-1R and permanently turn on the receptor, N55 binds to GLP-1 and stimulates the cAMP pathway according to the physiological level of GLP-1. This leads to proper insulin release.

N55 is highlighted as the first compound of a new class of modulators that enhance GLP-1R signaling. Chein and King’s research also outlines the concept that GLP-1 may be a novel target for type 2 diabetes and other conditions. Additionally, the screens used to detect N55 may be crucial for future plant compound discovery efforts related to other receptors and ligands. Future studies assessing the effects of N55 in vivo will be needed before its use as a therapeutic treatment.

Natalie Wheeler Natalie Wheeler is a neuroscience Ph.D. candidate in her final year at Virginia Commonwealth University.