Metformin & Metabolism: Beyond Diabetes
by Martin Hornshaw, Ph.D.
Diabetes is the 21st century plague
You don’t want to get diabetes; you really don’t. Despite the fact that this disease is generally manageable, the consequences of losing the ability to regulate your blood sugar are potentially debilitating and even fatal. Complications of type 2 diabetes are many, and they can be extreme.
Obesity and diabetes, without attempting hyperbole, are almost at ‘plague’ proportions in some countries such as the US and the UK. There are estimated to be approximately 4.5 million people in the UK living with diabetes, of which approximately 1.1 million are undiagnosed. As of 2012, 29.1 million Americans were living with diabetes (of which 8.1 million were undiagnosed and therefore untreated), and 86 million people older than age 20 had prediabetes. Diabetes is the 7th leading cause of death in the US, although it is likely that the contribution of diabetes is underestimated. These huge numbers primarily relate to type 2 diabetes and have been increasing year on year.
How do you treat type 2 diabetes?
Type 1 diabetes is treated with insulin. However, treatment for type 2 diabetes is quite different. While there are a number of drugs, metformin is the front-line drug for diabetes treatment if a healthy diet and physical activity alone are insufficient to control blood sugar (glucose) levels. Metformin works in two basic ways to lower blood sugar levels. Primarily, it reduces the amount of sugar produced by cells in the liver. Secondly, it increases the sensitivity of muscle cells to insulin so that glucose can be absorbed.
Understanding the mode of action
Metformin reduces insulin resistance and improves the uptake of glucose in muscle. You might be surprised to learn that it also reduces the risk of cancer and lowers the values of LDL cholesterol (Adam et al, 20161). Quite a busy and useful drug. However, the mode of action of metformin in type 2 diabetes is not completely understood. Perhaps if we understood perfectly how metformin works we could better treat diabetic patients and find additional therapeutic uses.
We must take a dive into metabolism to understand what metformin is doing. Metabolomics, the quantitative study of the metabolites present and how they change, in an organism, cell or tissue, is a powerful tool to understand the mode of action of drugs. Adam and co-workers recently published the first study that used a global metabolomics approach to investigate the effect of metformin on metabolite profiles in both diabetic patients and mouse models. They looked at serum metabolites associated with metformin treatment in a human population and several tissue types in mice using Metabolon’s technology. The purpose of the mouse study was to not only corroborate the human findings, but also extend the study to other relevant tissues without taking tissue from diabetic patients.
In the authors’ own words “In summary, we observed that serum values of citrulline were reduced under metformin treatment in human patients with T2D and, in a translational approach, also in plasma, skeletal muscle, and epididymal adipose tissue of diabetic mice. The underlying mechanism is most likely the metformin-induced activation of AMPK and its consequent increase of eNOS activity, which is linked to citrulline by the NO cycle.”
I will offer a little explanation around these abbreviations and why they are significant. AMPK is 5' AMP-activated protein kinase, which is an enzyme involved in cellular energy homeostasis. Citrulline is an amino acid not found in proteins and can be metabolized from arginine, one of the essential amino acids. It is also produced from ornithine in the urea cycle. Ornithine, urea and arginine were all lowered in human serum in this study, which you would expect in order to produce citrulline. AMPK activation results in many effects including ketogenesis (breakdown of fatty acids and ketogenic amino acids to produce ketone bodies), stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis and triglyceride synthesis, modulation of insulin secretion and more. In other words, AMPK lies at the heart of a lot of important metabolism. eNOS is endothelial nitric oxide synthase and, as the name suggests, is an enzyme that synthesizes nitric oxide (NO). eNOS is essential for a functioning cardiovascular system and generates NO in the vascular endothelium lining the interior surface of blood vessels. NO can have beneficial cardiovascular effects, for example, it relaxes smooth muscle. It’s not unexpected then that metformin is used to treat patients with type 2 diabetes who also have cardiovascular disease. It is often the case that diabetes is accompanied by other diseases.
Metformin has been in the news quite a lot lately. In addition to being a front-line oral treatment for diabetes, metformin has been finding new uses, for example, in head and neck cancer.
A recent paper (Curry et al, 20172) demonstrated that a low-dose treatment (and, therefore, likely to have fewer side effects) with metformin in non-diabetic cancer patients’ cells resulted in an increase in cancer cell death by apoptosis. They also observed that fibroblasts, the cells supporting and surrounding cancer, exhibited signs of deterioration, which lessened their capacity to help cancer cells grow and metastasize.
Good news! Maybe metformin affects the metabolic pathways that cancer cells rely on for energy to grow and at the same time changes the cancer’s micro-environment. Quite possibly, metformin plus a traditional cancer therapeutic could work successfully as a combination therapy. This study was performed in a small number of people however, so this is early in the development of metformin as a potential treatment.
One aspect of the paper that I might criticize slightly was that it did not explore thoroughly the metabolic changes induced by metformin in the cancer patients. While they looked at the lactate level in three patients, using mass spectrometry imaging pre- and post-treatment with metformin, and found it altered, I would suggest a more global analysis of metabolism would also have had merit in case metformin has unexpected metabolic effects in this cancer. This could have given critical understanding to the mechanism of action of metformin when applied as a potential cancer treatment.
In short, the lowered values of citrulline observed in patients with type 2 diabetes treated with metformin “most likely resulted from the pleiotropic effect of metformin on the interlocked urea and nitric oxide cycle” pathways of metabolism1. Global metabolomics, as opposed to a targeted metabolomics approach, uncovered this. It is unlikely that a targeted metabolomics approach studying the levels of a small number of metabolites could have provided the necessary evidence to draw this conclusion.
To further the possibility of utilizing metformin in cancer treatment will require more study. The next step would be to go to Phase 2 clinical trials, and I would further suggest using a global metabolomics approach to study in more depth the metabolic changes induced by metformin in cancer patients.
- Adam J et al., Metformin Effect on Nontargeted Metabolite Profiles in Patients with Type 2 Diabetes and in Multiple Murine Tissues. Diabetes. 2016 Dec;65(12):3776-3785.
- Curry J et al., Metformin effects on head and neck cancer squamous carcinoma microenvironment: Window of opportunity trial. The Laryngoscope 2017 Feb 10. doi: 10.1002/lary.26489. [Epub ahead of print]