Alongside lifestyle interventions, many people with diabetes take medications to keep their blood sugar in check. While these can be helpful, some have negative side effects and others become less effective after being taken for long periods of time. This is what pushes clinicians to adopt insulin therapy as the final form of treatment for patients with type 2 diabetes. Very often this also depends on the body weight of the interested parties: a good portion of patients are decidedly overweight or frankly obese, the which leads to the phenomenon of insulin resistance. This condition is often determined by the chronic inflammatory component of the disease, behind which lies the excess fat tissue and the cytokines it produces. Insulin resistance also appears in other pathologies; among these is rheumatoid arthritis (RA). Rheumatoid arthritis is an autoimmune and degenerative joint condition that causes joint swelling, pain and stiffness. This chronic condition affects around 50 million people around the world.
Interestingly, drugs used to treat rheumatoid arthritis for many years could be useful for people with type 2 diabetes. Metformin, the most famous antidiabetic drug, has also been proven to improve insulin resistance and inflammation in a good percentage of RA patients. This might seem surprising as the two conditions are worlds apart, but some links and interactions between the two have been noted over the years. For example, people with rheumatoid arthritis are more likely to develop diabetes, and conversely, people with diabetes have a greater risk of developing rheumatoid arthritis. Additionally, people with rheumatoid arthritis who develop type 2 diabetes tend to have a harder time controlling blood sugar levels. Leflunomide (Arava) is an anti-inflammatory drug approved for use in arthritis in 1998 that manages the condition well in the majority of patients.
Over the years it was increasingly noted that leflunomide lowered blood sugar and, in obese people, led to weight loss. But it wasn’t clear how or why these interactions occurred. More than twenty years ago it was discovered by chance that leflunomide interfered with some enzymes of cellular glycolysis, the major metabolic flow that uses the energy of glucose. Studies conducted a few years ago have shown that the drug has another additional target: the protein kinase S6K1, which has the function of activating cellular protein synthesis, turning off the function of the insulin receptor but also making the cell pick up glucose. through its transporters (GLUT4). This explains the reason for the hypoglycemic effect. For this reason, experts think that this molecule can find space in the management of diabetes mellitus. However, using it in the type 2 form may not be the best choice: leflunomide is basically an immunosuppressant, as well as an anti-inflammatory.
It would make much more sense to use it in the type 1 form, where there is an autoimmune component similar to that of rheumatoid arthritis. Nowadays, patients with genetic diabetes are not subjected to immunoregulatory treatment or any form of therapy that affects the immune system. They are simply labeled as “definitive diabetic patients”, for whom the only therapeutic option is the daily administration of insulin. As early as 1998, experiments were published that proved how leflunomide could block the onset of autoimmune diabetes in genetically predisposed mice. Subsequent studies have shown that the drug interferes with the infiltration of immune cells (T lymphocytes) in the pancreatic islets, which then destroy them with an inflammatory reaction (insulitis). But how does this information relate to the context of rheumatoid arthritis? It all depends on the biological root of the two conditions: chronic inflammation and the production of cytokines mediated by the autoimmune nature itself.
The first evidence that metformin could buffer inflammation in experimental arthritis dates back to 2013 and then confirmed in 2015 and 2018. During these years, the mechanisms by which the drug could act on the basis of the disease have been investigated. There is evidence that the drug acts as an antidiabetic: it limits the energy resources of immune cells, which would make them “fatigued” in their responses. Other data indicate, in addition, that the cellular pathways activated by metformin can counteract the classical inflammatory pathways dependent on cytokines. The effects of metformin on patients with RA and diabetes were reported a few years ago and there is evidence in population studies that adopting a therapy that includes metformin reduces the future risk of developing RA, especially in women. Just a few months ago, the results of a pilot clinical trial were published that tested the effects of adding metformin to the classic therapy (methotrexate) in RA patients.
Researchers assessed serum levels of inflammatory cytokines such as TNF-α, IL-1β, IL-6, IL-10, IL-17 and TGF-β1 before and after therapy, which lasted a total of 12 weeks. Clinicians found statistically significant improvements in DAS28-3 after 4 and 8 weeks for the METF group compared to placebo and were maintained after 12 weeks. The METF group showed a statistically significant increase in the percentage of patients who achieved DAS remission after 12 weeks of treatment. The results of this study were reproduced by another team of researchers, who published their results last month. The treatment lasted 6 months, but the results mimicked those of the previous study. As early as three months, most patients had noticeable subjective improvements with less C-reactive protein and adiponectin (biomarkers) in their blood and a better DAS28 test score than controls not taking metformin. The improvements were highlighted and maintained at the final timepoint of 6 months.
Metformin, therefore, exerted an anti-inflammatory effect on the disease. Considering that the daily dose used (1 gram) caused no notable side effects, the experts concluded that metformin may become a therapeutic complement for rheumatoid arthritis, which could allow for the reduction of doses of other added drugs: This it would result in fewer side effects and a better quality of life.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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