Diabetes mellitus, more commonly known as simply “diabetes,” involves the dysfunction of insulin, a hormone produced by pancreatic beta cells which controls sugar levels in the body. Historically, there were two classifications of Diabetes mellitus: Type 1, an autoimmune disorder which attacks pancreatic beta cells and thereby prevents the normal production of insulin, and Type 2, a progressive disease that reduces the ability of the body to utilize insulin properly. More recently, a third type has emerged in the literature: Type 3c, insulin dysfunction resulting from pancreatic disease states. Because the therapeutic approaches for each of these distinct types varies greatly, this discussion will focus solely on Diabetes mellitus, Type 2.
Because 90% of all diabetes patients over the age of 40 are diagnosed with Type 2, this subtype has become increasingly visible within the world of public health and for good reason. While elevated blood sugar may seem relatively inconsequential, in reality, diabetes affects every system of the body. Rampant sugar molecules damage the endothelial lining of blood vessels and prevent the formation of new, healthy blood vessels (angiogenesis), setting up ideal conditions for diffuse vascular disease. Without ample blood supply, each organ system deteriorates, leading to cardiac disease, renal disorders, compromised immune function, liver dysfunction, stroke, psychiatric disorders, visual impairments, and neuropathy.
Not only are the ramifications of uncontrolled diabetes greatly underestimated, the number of diagnosed cases of the disorder is staggering, and continues to grow. According to the World Health Organization (WHO), the number of people with diabetes has risen from 108 million in 1980 to 422 million in 2014. In the United States alone, 29 million people have been diagnosed with the disease, and the epidemic continues to grow. Indeed, diabetes has become a global health crisis.
Unfortunately, the care provided by conventional medical practitioners typically emphasizes prescriptive medications to reduce blood glucose levels, and while this is a necessary aspect of disease management, it does not truly address the root of the pathology. Diet and lifestyle changes play a tremendous part in reducing risk factors in pre-diabetics and in gaining sugar control in diagnosed patients, but even with following the strictest of protocols, there are a significant number of patients who do not find improvement. It is clear that a more creative approach to studying the etiology of diabetes is necessary to developing more effective treatment options.
The Endocrine System
Cellular endocrinology “deals with all the related aspects of biochemical mechanisms, synthesis and production of extracellular signal transductions, and other mechanisms in hormonal control,” including hormonal gene expression and regulation. In other words, it investigates how the endocrine system both affects and is affected by intracellular activity. Through this lens, researchers can investigate diabetes as the result of dysfunction within the organelles of individual cells, addressing dysfunction within these organelles at every step of the metabolic process. This very targeted approach allows investigators and clinicians to develop individually-tailored treatment options that may address very nuanced causes of sugar dysregulation, thereby bringing about more successful outcomes in the management of this disease.
Metabolic Inflammation
In a study designed to investigate the effects of diabetes on the human brain, researchers found that diabetes-related intracellular stress to the mitochondria and endoplasmic reticulum created what they termed “metabolic inflammation,” which in turn, caused cell death within the brain. This manifested as cerebral dysfunction, or “diabetes-associated cognitive decline”.
This concept of diabetes-associated cellular trauma is not limited to the brain, it can happen all over the body. A study performed in 2014 by a team in France found that hyperglycemia is a huge culprit in the creation of reactive oxygen species or damaging free radicals within the diabetic body, and when combined with a reduced antioxidant ability creates a state of chronic inflammation. Despite aggressive antioxidant vitamin administration, no real evidence to the reduction of harmful inflammation was shown. While the findings of this particular study may be disheartening to some, the researchers’ proposal for further investigation provides even greater insight into the importance of antioxidant support in diabetic therapies.
For instance, it is unclear how far the pathology of the participants had progressed before they had enrolled in this study. Is there a threshold at which oxidative damage is irreversible in relation to diabetic neuropathy, insulin sensitivity, and cognitive decline? Perhaps the methods of administration, the forms of, or the dosages of the vitamins used in this study could be altered, with more favorable results. Would bolstering antioxidant precursors (as opposed to poorly-absorbed whole antioxidant formulations) within the body elicit the proper utilization of the antioxidant vitamins? This study leaves many opportunities for further investigation.
Anatomy & Physiology of a Cell
Before diving more deeply into cellular endocrinology, perhaps it would be beneficial to review the anatomy and physiology of a cell. As you may remember from biology classes gone by, human cells are eukaryotic, meaning that each cell contains a membrane-bound nucleus, genetic material, a plasma membrane, ribosomes, and cytoplasm. Human cells also contain membrane-bound structures called organelles, including mitochondria, the Golgi apparatus, lysosomes, the endoplasmic reticulum, and ribosomes.
- The nucleus is the largest organelle in a cell, and contains genetic information called chromosomes. It’s widely known as the “control center” of every cell.
- Mitochondria are tube-like structures that have highly-folded inner membranes. They utilize cellular food (glucose) to create useable energy for the cell (ATP) in a process called respiration. Depending on the energy needs of a particular cell, the number of mitochondria inside can vary greatly. You may remember these as the “powerhouses” of a cell.
- Ribosomes are tiny structures residing in the cytoplasm and alongside parts of the endoplasmic reticulum. They produce proteins, and therefore are the “protein factories” within a cell.
- Proteins manufactured by the ribosomes and other lipids within a cell are shunted to the Golgi apparatus for packaging and transit preparation, which has given rise to this organelle’s nickname: the cellular “post office.” This organelle also produces lysosomes, tiny envelopes of digestive enzymes, that become useful in the case of autophagy and apoptosis.
- Proteins and other materials are shuttled in and out of the cell via a network of fluid-filled membranous tubes called the endoplasmic reticulum, which has given rise to its apt nickname, the “transport system” of each cell.
Each of these organelles fill important roles in the normal and health metabolism of each cell, and can be compromised significantly in disease processes like diabetes, leading to dysfunction in necessary processes like glucose metabolism, energy production, autophagy, and apoptosis.
The Energy of Producing Mitochondria
Mitochondria are the energy producing organelles found in virtually all human cells. Mitochondria contain an outer membrane which allows small molecules to pass through selectively and an inner membrane, or matrix, where metabolic processes occur. DNA and enzymes can also be found in the inner matrix.
One of the main duties of mitochondria is to metabolize and breakdown carbohydrates and fatty acids in order to generate energy. Beta oxidation is a process in which fatty acids are broken down and metabolized into Acetyl-CoA. Acetyl-CoA is then utilized in the Krebs Cycle, which produces carbon dioxide, NADH and FADH2. These molecules are involved in the electron transport chain, or ETC, where oxidative phosphorylation occurs, leading to the formation of adenosine triphosphate, better known as ATP, the major energy source for most cellular processes.
The process of the ETC creates reactive oxygen species, or ROS. ROS function as secondary messengers and can directly kill bacteria or cause pro-inflammatory responses to signal other inflammatory markers to attack viruses and bacteria. On the downside, they can also cause direct damage to a cell, inducing apoptosis, or cell death, via oxidative stress. Because of their complex involvement in many cellular processes, mitochondria dysfunction has been a widely researched topic as it pertains to disease development and progression. This is particularly true in the case of Diabetes.
Any alteration in mitochondria function would negatively affect insulin secretion from beta cells of the pancreas. It is believed that the production of ROS from the mitochondria may interfere with insulin signaling in muscle cells, leading to insulin resistance, a defining feature of Type 2 Diabetes. In healthy individuals, insulin is released from the pancreas in response to elevated glucose levels and helps to push glucose back into the cells. In individuals with insulin resistance, cells are not responsive to the effects of insulin leading to elevated blood glucose levels. Lowered production of ATP would affect glucoses ability to trigger insulin. Persons with diabetes typically produce more ROS, leading to mitochondrial and cellular oxidative damage, thus leading to further worsening of diabetic complications.
Biopsies of skeletal and cardiac muscle of persons suffering from Type 2 Diabetes revealed mitochondria tend to be smaller in size than healthy individuals, further contributing to insulin sensitivity. Reduced metabolic process is also observed in mitochondria of diabetic individuals, leading to less energy and DNA production overall.
Antioxidants play an important role in the management and reduction of cellularly damaging oxidative species. Coenzyme Q10, is an antioxidant that is mobilized in the ETC. In its ubiquinone forms has been show to help reduce free radical damage and help support mitochondrial integrity. Other important antioxidants include Vitamin E, Vitamin C and glutathione and have been shown to improve mitochondrial function.
Putting It All Together
While oxidative stress and inflammation are two serious sequelae of poorly-controlled diabetes, they are unfortunately not often included in the discussion around diabetic treatment approaches. Recent research clearly presents a strong argument for investigating the effects of the disease, and of its treatment, on the cellular level, as there is much more to be uncovered in the world of cellular endocrinology.
A significant way to improve the impact of diabetes education is to include these concepts in discussions with family members, your own healthcare practitioners, and if applicable, your patients, too. When people have a basic understanding of how blood sugar affects every aspect of their bodies, they can formulate better questions for those who help manage their health, and make much more well-informed decisions about the medications they take, the food they eat, and the activities with which they involve themselves. We need to educate ourselves with information (sometimes, down to the most microscopic detail) in order to help empower those around us battling this disease. With diabetes predicted to become the 7th leading cause of death by the year 2030, it is incredibly important to explore prevention and long term care avenues now.
With that said, the reality of how to move forward after reading this primer in cellular endocrinology is quite simple. Until advanced pharmaceutical interventions that directly address the metabolic pathways discussed here are developed, we turn to current medications and interventions that have mounting evidence in support of their use. As the research shows, Metformin, often considered first line therapy for newly diagnosed diabetes and pre-diabetics, is not only a moderate glucose lowering agent, but also has the ability to inhibit mTOR, which promotes proper cell apoptosis and autophagy. The drug also has positive effects on the SIRT1 pathway, restoring insulin sensitivity in podocytes, which is critical to healthy kidney function.
For the more naturopathically inclined, natural sources of mTOR-inhibiting, SIRT1-promoting, ceramide flow-freeing substances are abundant. In his paper entitled, “Inhibition of PI3K/Akt/mTOR Signaling by Natural Products,” Dr. Shile Huang compiles an excellent resource list for natural ways to reduce oxidative stress from glucolipotoxicity. Perhaps the most surprising endorsement his writings provide is for non-GMO soy, a rich source of isoflavones. Oft the victim of much nutritional scrutiny, perhaps more investigation and consideration is needed before we as a society can write off an entire food source of nutrition and beneficial antioxidants.
All things considered, cellular endocrinology is an extremely nuanced field with vast opportunities for diagnostic and clinical investigation. With each discovery of pathways influenced by sugar dysregulation, we find more and more validation of the overarching benefits of complete nutrition and healthy lifestyles. This can only be seen as a growing body of evidence in favor of natural medicine integrated with conventional healthcare, and should ultimately promote changes to the education of medical professionals in the management of chronic diseases like Diabetes mellitus. Deeper understanding of human anatomy and physiology, combined with the use of integrative methods to address dysfunctional cellular metabolism, may just be the 1-2 punch we need to knock out this public health crisis.
Dr. Andrea Colon and Dr. Lauren Young are naturopathic physicians at Collaborative Natural Health Partners in Manchester, CT. Dr. Colon is accepting new patients and accepts insurance. She loves working closely with patients of all ages to tailor customized treatment plans. For an appointment call (860)533-0179 or visit: ctnaturalhealth.com.