Goat’s Rue Plant, Metformin, and Medication Action in the Body
Goat's Rue and the Metformin Medication
The goat’s rue or French lilac (Galega officinalis) is an interesting plant that has been used in several ways. It contains a biologically-active chemical called galegine. The plant was once valued in folk medicine, though today it's known to have toxic characteristics. Modern studies of galegine led to the creation of metformin, which is a useful medication for treating type 2 diabetes.
In science, the word "medication" is interchangeable with the word drug. This article explores the fate and behaviour of the metformin drug in the body. There is much that still needs to be learned about the substance, even though it has been used to treat diabetes for over sixty years. It's believed to affect the body in multiple ways and by multiple mechanisms. It's an intriguing chemical that is being explored as a treatment for other disorders in addition to diabetes.
The Goat's Rue or French Lilac Plant
Galega officinalis belongs to the pea family, or the Fabaceae. The family is also known as the Leguminosae. "Rue" means regret, so perhaps the plant was given the name goat's rue because it was toxic for animals. It's also known as French lilac and as professor weed. The plant is native to the Middle East but has spread to Western Asia and Europe.
Goat's rue is a perennial and herbaceous plant. Its pea-like flowers are white, blue, purple, and occasionally pink. They are borne on a structure called a raceme. This structure consists of flowers arranged in vertical rows along a tall stem. The most mature flowers are at the bottom of the raceme and the youngest ones at the top. Though the flowers of goat's rue are attractive, the plant itself can become unruly. The fruits are small pods.
The plant's leaves are pinnately compound. A row of narrow leaflets is present on either side of the rachis, which is an extension of the leaf's stem. The plant grows from a taproot. A taproot is a thick root that grows downwards. It has relatively thin lateral roots. Carrots and parsnips are taproots of their species.
The name "goat's rue" is also used for a North American plant with the scientific name Tephrosia virginiana. This might be confused with G. officinalis. The latter plant is found in the United States and Canada, though it's not given much respect due to its toxicity to livestock. It's classified as a noxious weed in the United States. Strangely, it was once used as a forage crop until its toxic effects were discovered. The plant has killed grazing animals.
History of Galegine Use and Metformin
Goat's rue was used as a folk medicine as long ago as the medieval period. It was prescribed for people who were experiencing frequent urination. This is a symptom that might indicate the existence of diabetes. Though the plant may have been at least somewhat effective as a medicine, as time progressed people became dissatisfied with its mild benefits. In addition, they disliked its potentially toxic effects.
As science and technology advanced, scientists were able to explore some of the chemicals in goat's rue. In the late 1800s, they discovered that the plant was rich in a substance called guanidine. This substance lowered the blood glucose level, but at the same time it was obviously too toxic to use as a medicine. Researchers then turned their attention to a related chemical in the plant called galegine, or isoamylene guanidine. This also lowered the glucose level and was less toxic than guanadine. For a short while, galegine was used as a medicine.
Scientists created chemicals related to galegine that were more effective medicines, but they were unable to create a nontoxic drug that was sufficiently helpful in lowering the blood glucose level. Some effective chemicals, such as phenformin and buformin, had an unacceptable risk of increasing the concentration of lactic acid in the blood to a dangerous level. The acid produced a very serious condition called lactic acidosis. Thankfully, the situation eventually changed.
Jean Sterne (1909–1997) was a French physician. He investigated the effects of dimethylbiguanide (metformin) on a high blood glucose level and discovered that it had an excellent combination of effectiveness and safety. Sterne called the medication glucophage, a designation that is used as a trade name today. The name means "glucose eater". Metformin is the generic name of the medication.
Metformin has two nitrogen-containing units that are quite similar, as can be seen in the illustration of the molecule's skeletal formula below. Each unit is known as a guanidine ring. Metformin's full chemical name is N, N-dimethylbiguanide.
In a skeletal formula for an organic compound, carbon atoms aren't shown. They are understood to be at the vertices where lines representing the bonds join. The existence of the hydrogen atoms attached to the carbon atoms is implied. Each carbon atom can form four bonds in total. If a carbon atom is joined to a nitrogen atom (for example), the other three atoms joined to the carbon are assumed to be hydrogen ones.
The illustrations below show that half of the galegine molecule is identical to half of the metformin one. The metformin molecule is said to be a structural analog of the galegine one. Structural analogues are similar to each other with respect to their molecular structure but have a section that is different. The difference may be important with respect to a molecule's properties. Galegine is said to be at least somewhat toxic. Metformin is considered to be much safer.
Blood Sugar Regulation and Type 2 Diabetes
Normal Regulation of Blood Sugar
Glucose is the primary energy source for our cells. In order for it to be absorbed through the cell membrane, insulin must be attached to a receptor on the membrane. The glucose then enters the cell and is used as an energy source. Insulin is a hormone made by the pancreas. It travels to the body's cells via the bloodstream.
The circulatory system also transports glucose to the cells. Glucose in the blood is sometimes known as blood sugar. When glucose from foods and drinks enters our bloodstream, some of it is sent to the liver. Here it's stored in the form of a molecule called glycogen.
If our blood sugar level falls too slow, glucose is released from the glycogen and enters our blood stream. The liver can also make glucose from amino acids and other molecules. This process is known as gluconeogenesis. A healthy body is able to keep the blood sugar level fairly constant by balancing the blood sugar level and the glucose requirements of cells.
Type 2 Diabetes
In type 2 diabetes, cells become partially resistant to the presence of insulin. The blood sugar level rises because glucose can't leave the blood and get into the cells. In addition, the pancreas may be unable to release enough insulin to overcome the resistance. The disorder is sometimes a combination of insulin resistance and pancreatic insufficiency. A continuously high blood sugar level can cause harmful effects in various parts of the body.
This article focuses on metformin's origin and mechanism of action rather than a detailed description of diabetes. Anyone who has symptoms of ill health that don't disappear quickly, are severe, or frequently recur should visit a doctor.
Metformin is said to be the most commonly prescribed medication for type 2 diabetes. It lowers the blood glucose level, generally without causing it to fall too low, provided it's taken according to a doctor's recommendations. Metformin also has other effects, at least in lab experiments. Evidence suggests that it may be helpful in protecting the heart and in treating some types of cancer.
Despite the fact that it seems to be involved in multiple processes in the body, metformin has a good safety record when used according to a physician's instructions. "Good" doesn't mean perfect, however. A physician's knowledge and care is essential because in very rare cases the drug has caused lactic acidosis. It may cause less serious side effects in some people.
If a patient needs treatment for type 2 diabetes, their doctor will prescribe a suitable medication for their particular situation. This medication may or may not be metformin. The purpose of this article is to describe the history and behaviour of metformin, not to recommend treatment for diabetes.
Absorption of Metformin in the Intestine
Foods and drinks that we ingest are digested in the small intestine. Nutrients are then absorbed through the lining of the intestine. Metformin must be transported through the lining via a carrier protein, except perhaps when it's present at a very high concentration. In this case, it may move by diffusion. Carrier proteins are also required on or in membranes in other parts of the body in order for metformin to be absorbed.
Some of the carriers needed for metformin absorption are present on the enterocytes that line the inner surface of the small intestine. Appropriate carrier proteins are also present on the cell membrane of the hepatocytes, or liver cells, and on the cells of the kidneys. Metformin is transported between organs in the bloodstream.
Researchers are investigating how structural alterations in carrier proteins affect the activity of metformin. Defects in the genes coding for the proteins might contribute to the fact that although in general the medication is very useful, it's less effective in some people than in others. Major carrier proteins are listed below.
- PMAT (plasma membrane monoamine transporter) on the enterocytes, which enables absorption from the lumen (cavity) of the intestine
- OCT1 (organic cation transporter one) on the basolateral membrane of the enterocytes, which enables metformin to reach the bloodstream.
- OCT1 and perhaps OCT3 on the hepatocytes
- OCT2 on renal epithelial cells in the kidneys
- MATE1 and MATE2 (multidrug and toxin extruder 1 and 2) for transporting metformin into the urine
Metformin has a high absorption rate in the liver compared to its absorption in other areas. This organ seems to be a major location of the drug's beneficial activities in treating diabetes.
Evidence obtained so far indicates that the metformin molecule isn't metabolized. The molecule stays intact as it exerts its effects and is eventually excreted in the urine. It does undergo a minor alteration in the body to become a positive ion, or a cation, but other than this it doesn't change.
Many proteins in the body seem to be involved in the activity of metformin. Genes contain the "instructions" for making the proteins. The instructions are encoded in the structure of a gene. If a gene's structure is incorrect or altered, a defective protein may be made.
Some Effects After Absorption
Based on discoveries made so far, metformin appears to help type 2 diabetes by four methods, particularly the first one in the list below.
- Inhibition of gluconeogenesis in the liver
- To a lesser extent, increasing the sensitivity of tissues to insulin
- Also to a lesser extent, inhibition of glucose absorption in the intestine
- Possibly, by stimulating glucose absorption by other tissues
Identifying all of the chemical reactions that metformin affects is proving to be difficult. A huge number of reactions occur in the human body. Human biochemistry is a fascinating but complex subject.
Despite the difficulties involved, researchers have made two discoveries that appear to be significant.
- Metformin inhibits a complex of proteins in the mitochondria known as respiratory-chain complex 1.
- Metformin stimulates the activity of an enzyme known as AMPK (AMP-activated protein kinase), especially in the liver. AMP stands for adenosine monophosphate.
Pharmacological activation of AMPK promotes glucose uptake, fatty acid oxidation, mitochondrial biogenesis, and insulin sensitivity; processes that are reduced in obesity and contribute to the development of insulin resistance.— Hayley M. O'Neill, Diabetes and Metabolism Jourbnal
Effects on the Mitochondria and Beyond
Metformin is thought to produce many (but not all) of its effects by influencing the mitochondria of cells. These organelles produce most of the ATP (adenosine triphosphate) needed by a cell. ATP molecules provide the energy that a cell needs. Some of our cells contain hundreds of mitochondria.
ATP is made when ADP (adenosine diphosphate) joins to phosphate. Energy is absorbed during this process. AMP (adensosine monophosphate) contains only one phosphate and is used to make both ADP and ATP.
Experimental evidence from multiple experiments suggests that metformin inhibits respiratory-chain complex 1 in the mitochondria.
- The inhibition of respiratory-chain complex 1 causes the concentration of ATP to decrease, since ATP is made in the mitochondria.
- The decrease in ATP causes a decrease in gluconeogenesis, since several steps in the process require ATP as an energy source.
- The relative amounts of ADP and AMP increase compared to the amount of ATP because the first two chemicals are no longer being used for ATP production (or are being used to a lesser extent).
- The increase in AMP availability causes an increase in the concentration of AMPK.
- AMPK triggers many processes, some of which are believed to be helpful with respect to type 2 diabetes. The substance is often referred to as an "energy-sensing protein".
- AMPK-triggered activities that may be useful in type 2 diabetes include absorption of glucose by cells other than intestinal ones (thereby lowering its concentration in the blood) and increased sensitivity of cells to insulin.
More research is needed to clarify all of the details involved in the processes described above. If the mitochondria are inhibited by metformin, as the evidence suggests, it would be interesting to know if a cell is adversely affected by a decrease in ATP production.
Further Studies Are Required
The information obtained so far in relation to metformin is interesting, but further studies are needed. The substance seems to have widespread effects in the body. Its therapeutic reach might be wider than realized. It's possible that the beliefs about the drug's behaviour in the body that are described above will be modified as more discoveries are made. I will be watching the research reports with interest.
Though the creation of new medications is important, learning about the behaviour of old ones could be very helpful in the treatment of disease. This could be the case with respect to metformin. It's an intriguing drug.
- Goat's rue plant facts from CABI (Centre for Agriculture and Biosciences International) Invasive Species Compendium
- Information about type 2 diabetes from the Mayo Clinic
- Facts about the liver and blood sugar from the University of California, San Francisco Medical Center
- The botanical background of metformin from Practical Diabetes and the Wiley Online Library
- Metformin: From Mechanisms of Action to Therapies from Cell Metabolism and Science Direct
- AMPK and Exercise: Glucose Uptake and Insulin Sensitivity from Diabetes and Metabolism Journal
- Goat's rue information and concerns from WebMD
This content is accurate and true to the best of the author’s knowledge and does not substitute for diagnosis, prognosis, treatment, prescription, and/or dietary advice from a licensed health professional. Drugs, supplements, and natural remedies may have dangerous side effects. If pregnant or nursing, consult with a qualified provider on an individual basis. Seek immediate help if you are experiencing a medical emergency.
© 2020 Linda Crampton