A drug initially discovered to treat fungal infections may be the key to treating and managing metabolic disorders.
Rapamycin is a drug discovered from soil bacteria on Easter Island. Named for Easter Island’s original name, Rapa Nui, rapamycin has been extensively studied and approved to be an immunosuppressant drug for organ transplant recipients.
Animal model studies have also shown that this drug might effectively treat Alzheimer’s disease and potentially prolong life for as long as possible. Since it promotes longevity, this drug might also treat metabolic disorders.Â
What are metabolic disorders?
Metabolic disorders are defined as inborn errors of metabolism involving deficiencies of enzymes important in the metabolism of proteins, lipids and carbohydrates [1]. Common metabolic diseases include the following:
- ObesityÂ
- Cardiovascular diseases
- Type 2 diabetes/prediabetes
- Type 1 diabetes
- Non-alcoholic steatohepatitis
- Kidney diseases
The increasing incidence and prevalence of metabolic disorders remain a significant public health concern and burden.
Evidence from published studies consistently indicates that one or more metabolic disorders increases the risk of developing another metabolic disease.Â
Rapamycin and metabolic disorders
To understand the relationship between rapamycin and metabolic disorders, it is essential to understand what mTOR is and its role in the metabolism and development of metabolic disorders.Â
The mammalian target of rapamycin (mTOR) is a protein critical in controlling several functions of the cells, such as cell survival and cell division [2].
This protein binds to rapamycin and other drugs. In patients with cancer, mTOR may be more active when present in specific cancer cells but not in normal cells.
Hence, certain medications target mTOR deactivation to kill cancer cells. Apart from being called mTOR, this protein is likewise called the mechanistic target of rapamycin.
In recent years, significant progress has been made in elucidating the functions of mTOR and its roles in disease. This protein is recognized as a signal integrator and responds to different signals from the following:
- Nutrients
- Growth factors
- Oxygen status
- Energy status
After responding to these signals, mTOR proteins are involved in cell proliferation and growth, including:
- Synthesizing proteins
- Nucleotides
- Lipids
- mRNA
It is also involved in the metabolism of energy and autophagy (cell death).
The mTOR pathway
Several genetic disorders and cancer would reveal improper regulation of the mTOR pathway. mTOR signaling is a critical regulator of cellular metabolism, which balances catabolic and anabolic processes.
During fasting, glycogen stored in the liver is broken down to produce glucose, while adipose tissues are broken down to generate fatty acids.
Upon feeding, glycogen is stored in the liver and the muscles, and lipids are stored in fatty tissues. When mTOR signaling is dysregulated, this is linked to the development of obesity and diabetes.Â
The mTOR pathway is inhibited during treatment with rapamycin. However, there are conflicting results when undergoing rapamycin treatment.
For example, short-term therapy with rapamycin leads to an improvement in insulin sensitivity. In addition, treatment with rapamycin protects against obesity.
However, some studies showed that rapamycin treatment leads to harmful metabolic effects. For instance, rapamycin treatment leads to worsened hyperglycemia and exacerbates glucose intolerance.
It is currently unclear why rapamycin produces both positive and negative effects.
Rapamycin and type 2 diabetes mellitus
Although there are some conflicting results on the effects of rapamycin on type 2 diabetes, many studies have shown that rapamycin treatment slows down the progression of this disease and prevents the development of complications.Â
An animal model study [3] published in the Aging journal revealed that the physiology of the rats’ pancreas might help explain why rapamycin treatment in pre-diabetic and diabetic rats leads to different results.
The study authors, led by Peter Reifsnyder from the Jackson Laboratory, Bar Harbor, in the US, concluded that the rats’ pancreatic insulin content (PIC) dictated their responses to rapamycin.
Those with low PIC exhibited positive responses towards rapamycin, with the rat models showing increased insulin sensitivity and weight loss following treatment with rapamycin. In contrast, animal models with high PIC exhibited the opposite effects.
Although this was the study’s general finding, the authors observed that short-term treatment with rapamycin led to reduced weight gain and increased sensitivity to insulin in more than half of the animal model studies they investigated.Â
In another animal model study [4] published in the Cellular Biology International journal, treatment with rapamycin reduced insulin resistance, relieved lipid and glucose metabolism disorders, inhibited mTOR, reduced inflammatory levels and promoted autophagy (or cell death).
The authors concluded that activation of autophagy or cellular death reduced hepatic steatosis (hepatic or liver fats) and insulin resistance.
Overall, rapamycin was shown to:
- Diminish insulin resistance
- Prevents insulin resistance
- Normalizes glucose metabolism in rats that were induced to be diabetics
In animal model studies where the rats were fed with high-fat diets, rapamycin was shown to:
- Decrease insulin levels
- Improve insulin sensitivity
From these findings, more studies showed the positive effects of rapamycin, whether administered intermittently or in the short term, in improving insulin sensitivity and reducing body weight in diabetic rats.Â
Rapamycin and cardiovascular disease
There is evidence from recently published studies that rapamycin may treat cardiovascular diseases. For example, an animal model study [5] published in the Aging Cell journal revealed that rapamycin treatment improved cardiac function in both male and female rats, even after treatment was stopped.
In the study, the authors from the Department of Pathology at the University of Washington used aging but healthy mice. They explained that even in healthy aging, humans and animals experience increasing cardiac morbidity and mortality with age.
Some of these cardiac effects include left ventricular hypertrophy (enlargement of the left side of the heart), alterations in cardiac proteins, a decline in diastolic function and changes in the metabolic substrates of the heart.Â
Investigators treated mice in the study with ten weeks of rapamycin and found that this led to improvement in the following:
- Diastolic function
- Decreased stiffness
- Enlargement of the left muscles of the heart
Interestingly, the effects persisted for another eight weeks, showing that treatment with rapamycin improves heart function over time.
Although the findings of these studies need to be verified in more extensive trials and human studies, initial results suggested that rapamycin can potentially treat and improve cardiac function related to functional decline due to aging.
Rapamycin and kidney disease
Rapamycin has also been shown to manage or treat kidney disease potentially. In an animal model study [6] published in the Journal of the American Society of Nephrology, findings indicated that in mice with diabetic nephropathy and progressive kidney disease, treatment with rapamycin resulted in improvements in glomerular filtration rate (GFR) of the kidneys of these animals.
Before treatment with rapamycin, these animals exhibited inflammation of the kidneys, glomerular hypertrophy, and interstitial fibrosis or increased tissue fibers in the kidneys.
However, treatment with rapamycin slowed down all these negative processes in the kidneys of the mice. This suggested that rapamycin could mediate kidney disease and increase the survival rate of the mice.
Although this was an animal study, the initial findings provide additional evidence that rapamycin might be a potential drug against kidney disease in the future. More research studies and clinical trials in humans are still needed to verify the findings of these animal model studies.Â
Summary
In summary, rapamycin is a promising drug that has been approved for the treatment of fungal infections and for suppressing the immune system to prevent organ rejection in organ recipients.
However, the effects of this drug have now extended to its ability to prolong life and delay the aging process and as a treatment for Alzheimer’s disease, at least in animal model studies. It is also believed that this drug can potentially treat metabolic disorders.
However, there is still a need to verify findings from animal model studies in human clinical trials.
[1] https://www.nih.gov/research-training/accelerating-medicines-partnership-amp/common-metabolic-diseases
[2] https://www.cancer.gov/publications/dictionaries/cancer-terms/def/mtor
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5191889/
[4] https://pubmed.ncbi.nlm.nih.gov/29908010/
[5] https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13086
[6] https://journals.lww.com/jasn/Fulltext/2009/12000/The_Role_of_the_Mammalian_Target_Of_Rapamycin.7.aspx
