Getting to the root of Type II diabetes... with liquorice?

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Metabolism is a balancing act that gets harder with age
(Picture of Philippe Petit on high wire, Notre-Dame
Cathedral, Paris, 1971. picture: Cordisere)

The liquorice root is full of surprises. Chewed as a breath freshener in Italy and a sweet in Sweden (and the north of England), this little brown stick has also been used as a remedy for mouth ulcers for thousands of years.

New research has identified a natural chemical extracted from the liquorice root that could be used to treat Type II diabetes.

Our metabolism is a delicate balance. Insulin, a hormone secreted by the pancreas, regulates levels of glucose and fatty acids in the blood by storing them out of the way in fat and muscle tissue. Some stored compounds can be converted back into glucose when the body needs energy.

Wear and tear on this balance,  as our cells age or through diet or stress, can overload our tissues with fatty acids. Fat and muscle cells become unable to soak up excess glucose and in some cases build a resistance to insulin, a hallmark of Type II diabetes.

Recent drug-based therapies aimed to restore the metabolic balance by targeting the wiring of PPAR-gamma, a receptor protein in the nuclei of many fat cells.  PPAR-gamma responds to fatty acids in digested food by activating genes to boost metabolism. The hope was to manipulate PPAR-gamma to lower the level of fatty acids and improve the cells' sensitivity to insulin.

But there was a problem. The synthetic drug rosiglitazone triggers PPAR-gamma very strongly, successfully lowering blood glucose levels but also firing many other genes at the same time. Out of context, some of these genes were linked to unforeseen side-effects such as weight gain, fluid retention and heart disease.

The liquorice root.
Amorfruitins found at low levels inside
might be extracted to treat Type II diabetes.
(Picture: Ryan Opaz)

In a recent study in PNAS, Christopher Weidner and colleagues investigated a natural alternative. Amorfruitins, extracted from the edible roots of Amorpha fruticosa (the indigo bush) and  Glycyrrhiza foetida (a species of liquorice) are natural activators of PPAR-gamma. Amorfruitins were shown to influence glucose and fatty acid metabolism similarly to rosiglitazone but with more selective targeting of PPAR-gamma,  respectful of its powerful role in controlling different sets of genes.

The team, led by Sascha Sauer from Max Planck Institute for Molecular Genetics in Berlin  showed that amorfruitins decreased insulin resistance in the fat cells of diabetic mice without any observed weight gain. Amorfruitins also reversed some of the genetic changes brought about by a high-fat diet.

Dr Sauer said. “In view of the rapid spread of metabolic diseases like diabetes, it is intended to develop these substances further so that they can be used on humans in the future.”

Sauer's team have begun to investigate how amorfruitins steer the wiring of PPAR-gamma so effectively. They found differences between the genes expressed by PPAR-gamma in response to rosiglitazone or amorfruitins. This is something of a smoking gun: a first step towards understanding what it is about liquorice, a legume, that gives amorfruitins their remarkable ability to correct wiring inside mammalian cells.

What does this mean for me?

It’s estimated that 190 million people are affected by Type II diabetes worldwide and that this figure will double over the next 20 years. This study shows not only a direct health benefit of a natural plant extract on metabolic diseases, but also suggests the mechanisms for how it might work inside mammalian cells. Sauer's team hope the edible nature of the liquorice root, will make it easier to obtain approval for the use of amorfruitins in humans.

What does this mean for science?

This study highlights the importance of "basic" cell biology research to support medicine: only after investigating how a drug works can we confidently predict what (side) effects it may have on the wiring inside our cells. The differences in gene expression patterns between natural and synthtic PPAR-gamma activators suggest clear differences in how they act inside the cell. This raises questions for future drug design approaches - what makes amorfruitins so subtle and selective? Can their mechanism be copied synthetically, maybe to target other important transcription factors?


Reference:

Weidner, C., de Groot, J., Prasad, A., Freiwald, A., Quedenau, C., Kliem, M., Witzke, A., Kodelja, V., Han, C., Giegold, S., Baumann, M., Klebl, B., Siems, K., Muller-Kuhrt, L., Schurmann, A., Schuler, R., Pfeiffer, A., Schroeder, F., Bussow, K., & Sauer, S. (2012). From the Cover: Amorfrutins are potent antidiabetic dietary natural products Proceedings of the National Academy of Sciences, 109 (19), 7257-7262 DOI: 10.1073/pnas.1116971109