Obstructive sleep apnoea as a result of environmental, hormonal and psychological factors in non-obese Individuals

Without a doubt, we are living in a time of a global health crisis. Chronic disease, anxiety, and obesity are at an all-time high. The medical world has come a long way. However, big pharma’s primary focus is on prolonging the lives of sick individuals rather than getting to the root cause of such diseases. For the past nine years, I have worked as a clinical scientist specialising in respiratory and sleep. Evidentially and more noticeable, there is a significant increase in Obstructive sleep apnoea (OSA) in non-obese individuals living a career-driven and high-stress lifestyle. I have come across many executive directors and business owners who see no value in more than five hours of sleep and barely make time for their health. Over the years, staying up to date with relevant literature, I’ve developed a hypothesis as to why such individuals are susceptible to OSA despite not having the typical risk factors such as big round necks and large bellies. It’s sometimes challenging to compile thoughts into scientific theories, as creative freedom disappears when required to do your day-to-day duties as a clinician. However, I’m currently in a hospital bed and therefore thought it would be an excellent opportunity to use my brain to put together the evidence. Before we get there, let us discuss where it originated because that gives insight into why the curious excitement.

Roughly nine years ago, I enrolled on the National School of Healthcare Scientists training program in the NHS, UK. It was a training program designed to handpick some of the UK’s top health science students and train them to become highly skilled practitioners, researchers, and clinical leaders. The recruitment process was competitive, and out of thousands of applicants, I was one of the very few to get a placement in the respiratory and sleep specialism. During the program, we had to produce a thesis and a scientific paper for our research studies. I’d already experienced research in respiratory physiology in previous years when completing my research masters under Dr Michael Johnson and Professor Graham Sharpe at Nottingham Trent University. Therefore I felt that investigating in sleep would broaden my knowledge and make me a more rounded healthcare scientist. Dr Milind Sovani and I at Nottingham University Hospitals decided to examine the prevalence of sleep-disordered breathing (SDB) in Adults with Type 1 diabetes.

SDB is an umbrella term for OSA, Central Sleep Apnoea, and Obesity Hypoventilation. We screened the patients for any cardiac pathology or other issues that may cause nocturnal hypoxia and used overnight pulse oximetry to measure blood oxygen to screen for SDB. As an additional measurement, we decided to monitor nocturnal blood glucose to see any relational changes in those who have evidence of SDB. One particular case study sparked an interest. As a result, I have come up with a theory that I feel may contribute to solving the OSA crisis, or at least in part spur research or other means to treat sleep apnoea. In this case study, the individual was a well-controlled non-obese male with type 1 diabetes with an athletic background. He used insulin sparingly as he rarely consumed carbohydrates, mentioning that he prefers to use ketosis as a means to support his cycling performance. As a result, he only injected insulin after a meal in the evenings before bed to ensure blood sugars remained stable during sleep. We superimposed his overnight oxygen with his blood glucose data and found that following his acute insulin injection, he had a rapid drop in blood glucose as expected. The blood glucose continued to fall for roughly an hour, where it remained stable at a healthy level for the remainder of the night.

Interestingly and unexpectedly, during the period where his blood glucose dropped, he also had corresponding falls in oxygen saturation. Since we had ruled out other causes of hypoxia, we suspected this resulted from sleep-disordered breathing. For the remainder of the night, where his blood glucose remained stable, so did his oxygen. It was this phenomenon that generated my curiosity to delve further into science.

I went back to my study and took some time to review the literature regarding insulin and glucose thoroughly and their relation to SDB. I sat thinking, what am I missing? What’s different between an individual with type 1 diabetes and a healthy individual regarding blood glucose regulation? It’s well known that T1D patients do not produce insulin but were there any other physiological modulators involved in this hormone pathway that may also contribute to ventilatory control. It took me a while to delve into many research articles but eventually found that exogenous insulin injections do not give the same acute leptin response as chronic insulin secretion ^[1]. I wondered whether in T1D the normal endogenous response differed. When food is consumed, the digestive process increases both an insulin and leptin response; correspondingly, this leads to a feeling of satiety. Having majored in performance nutrition, I was aware that Leptin played a role in glucose metabolism and appetite. I was surprised to discover that Leptin also plays a role in ventilation ^[2]. The deeper I delved into the literature, the more interested I became and found that a few research groups had discussed the notion that Leptin plays a role in ventilation stimulation back in the ’80s. At that time, there was only one study that looked at the role of Leptin in OSA. However, recently leptin deficiency has decreased chemosensitivity to CO2, leading to hypoventilation ^[3], which was normalised following Leptin replacement ^[4]. Therefore, I speculated that low levels of circulating in a ketogenic diabetic might contribute to hypoventilation at night, especially during metabolic disturbances from insulin injections.   Following this insightful discovery, I lost my curiosity due to being marked down on my final paper submission to make such significant statements in my conclusion with very little observational evidence. However, recently, due to trends in my clinics and the increase in the atypical diagnosis of OSA, this theory has been on my mind, and today, I’ve mapped out an idea of multifactorial issues that may be contributing to the increased prevalence of sleep apneoa in the non-obese individuals.

We live in a society that devalues sleep. For millions of years through evolution, sleep has been a vital part of the animal kingdom. Not just essential for survival, but wellbeing, emotion regulation and high performance. However, over the last 100 years, since the invention of the light bulb by Thomas Edison, sleep quality has significantly decreased. As a species, due to our 24/7 economy and an exteroceptive culture our ability to recognise and manage stress is insufficient. We are addicted to coffee and other stimulants to maintain wakefulness. Our diets consist of highly palatable foods with an excess of calories due to added sugar and fats. There is an obesity crisis and the prevalence of OSA is increasing at a significant enough rate to warrant a sleep health crisis. The reason society lives in such a manner I shall save for a future post. Nonetheless, we are sleeping less, eating more and incompetently managing our stress, which is detrimental to our health. We have to stop being narrow minded and to start looking at the growing situation as a multifactorial cause rather than through the lens of an individual specialist often a case in western medicine.

Overconsumption of sugary and fatty foods, causing a calorie surplus, is the main contributor to obesity. However, biologically when looking at the nervous, metabolic and hormonal pathways related to our health, it is evident that stress and poor sleep also play a significant role ^[5][6]. The consumption of food causes an increase in blood glucose and insulin. The part of insulin is to direct blood glucose into either the liver or skeletal muscle for storage; however, excess blood glucose and insulin leads to metabolic syndrome and type 2 diabetes over time. Insulin also mediates the release of Leptin. Eating stimulates an increase in Leptin, and that signals to our brains that we are full, and therefore we feel less need to continue consuming food. Leptin also plays a role in glucose metabolism. Following a meal, blood glucose increases, and insulin rises; this signals the uptake of glucose into cells and activates Leptin that increases glucose metabolism. Thus, we use more glucose as fuel. Physiologically it makes sense that when we consume energy, we need to use energy. However, a by-product of glucose metabolism and the creation of ATP is Carbon Dioxide (CO2). It is well established that CO2 is a ventilatory stimulant and the primary regulator of breathing. With Leptin playing a role in chemosensitivity to CO2, this whole metabolic process can be associated with breathing. But what would happen if leptin regulation perturbed in any way? First, we need to discuss the role of stress and low sleep duration.

Both physical and psychological stress increases stress hormones such as adrenalin and Cortisol by stimulating the hypothalamic-pituitary-adrenal axis (HPA axis), a part of the autonomic nervous system. Chronic sleep deprivation (<6 hours per night) and poor sleep quality also contribute to the increased stimulation of the HPA axis and thus increases in Cortisol through sympathetic activation ^[7]. The problem here is that Cortisol and Leptin have an inverse circadian rhythm ^[8]. Throughout the day, when Cortisol is higher, Leptin maintains relatively low through a feedback loop maintaining homeostasis (hormonal balance). Leptin tends to peak at night to suppress our appetite. Still, I believe it also plays a role in preserving ventilation during sleep by regulating the carotid chemoreceptors to more sensitive changes in CO2 and pH. Furthermore, Cortisol stimulates the release of Leptin via the HPA axis ^[8], therefore in individuals with poorly managed physical, mentally or emotionally stresses, excessive caffeine consumption and less than adequate sleep as typical those seen in high-stress careers, this system may become blunted or overexpressed. As a result of sympathetic overactivity, prolonged cortisol overtime may deplete leptin concentrations or lead to leptin resistance, similar to what we see in insulin in type 2 diabetes. Not only will this impair skeletal muscle protein uptake and increase blood glucose through gluconeogenesis, both detrimental to our health. Over time, it may result in leptin dysregulation impacting breathing during sleep resulting in hypoventilation and central sleep apnoea. The effects may not be significant enough to notice through day-to-day observations because people are more active. Therefore, ventilation is higher due to more production of CO2 with daily activity. Still, it’s possible to suggest looking for evidence of hypoventilation — shallow laboured breathing while when metabolism is low — for example, during sleep or at rest. In highly stressed individual, we often observe a physiological sigh which could be due to a response to a momentary lap of breathing, plausible speculation. Also, in those who have a poor diet, are obese and show signs of metabolic impairment, both insulin and leptin resistance may occur, resulting in obesity hypoventilation, a dangerous sleep breathing disorder that, if left untreated, can result in hypercapnia and unconsciousness. However, that’s a central issue, and OSA is a peripheral issue, so how does this relate to OSA?

OSA is characterized by cyclical airway collapses that cause a reduction in oxygen saturation and micro-arousals from sleep, significantly impairing sleep quality. In patients with OSA, it is documented that pharyngeal muscles lose their muscle tone and collapse of the upper airway ^[9]. A study conducted at Harvard medical school in 2002 suggested a positive association between epiglottic pressure and genioglossus activation. The genioglossus is the muscular area that does not activate properly and causes airflow obstruction in OSA. Genioglossus activity, therefore, appears to be tightly regulated by intrapharyngeal pressure on a moment-by-moment basis within inspiration ^[10]. In lay terms, the force generated during breathing correlated with the activity of the airway muscles, acting almost like strengthening exercises for the airways. In conclusion, it’s possible to suspect that an impairment in the leptin regulation of breathing leading to night-time hypoventilation will reduce the airway muscles’ activation.  The decreased peripheral nerve input as observed in skeletal muscle could lead to pharyngeal and glottal muscle atrophy and weakness, increasing the risk of collapsing, therefore contributing to obstructive sleep apnoea.

It would be interesting to see what would happen in such patients with OSA if they improved stress management. By reducing work hours, performing relaxation techniques that down-regulate the sympathetic nervous system, such as combining Breath Control, Yoga Nidra, and Meditation, increased the amount of time spent outdoors with nature, all of which decreased cortisol levels. As a recommendation, I would suggest increasing sleep duration to more than 6 hours per night and improving sleep quality through excellent sleep hygiene practice (with or without CPAP) and having a diet grounded in whole foods, reducing sugar intake. I hypothesize that we would most likely see improvements in leptin and cortisol regulation that, over time, may reverse obstructive sleep apnoea in lean (BMI < 35). These lifestyle changes shall result in fat loss in obese individuals as all three changes shall reduce calorie consumption and improve metabolism. Over time there may be improvements significant enough to warrant discontinuation of CPAP, removing what can be perceived as a burden, therefore improving the individual’s quality of lives. While I have not obtained any anecdotal evidence for this theory, there has been a case study of particular interest in the media. Dr Jordan Peterson, Professor of Psychology at Toronto University and his daughter only eat beef. They are partakers in a beef only diet and have seen significant health improvements, where it looks to have cured both depression and rheumatoid arthritis. While I am not advocating this diet, it was of particular interest that he mentioned in an interview with Joe Rogan (2017) that within a space of a week of removing sugar from his diet, he stopped snoring. Snoring is symptoms of and a precursor to obstructive sleep apnoea. When the pharyngeal muscles relax enough so that airflow causes vibration in the airway, it creates an annoying snore sound. I wonder whether the removal of sugar improved leptin regulation of breathing and, therefore, improved his pharyngeal muscles’ function and improved airway patency. The observation of his health helped reignite the spark of curiosity on a theory that was of interest nearly four years ago, and today I feel I’ve made progress on that. I hope that this writing serves my purpose to educate and inspire individuals to live healthier and happier lives.

In addition to this, in 2021, Jordan Peterson announced that he had been diagnosed with central sleep apnoea, a form of SDB – hypoventilation. Whilst I do not have a complete medical history, the information I do know of Dr Peterson is that he has many health concerns, including anxiety. His diet consists of meat only. He is a very lean individual with limited adipose tissue – this is a combination of leptin deficiency. Given the hypothesis above, it would be interesting to get this information to him and his family to review the literature himself.

In summary, despite the obesity crisis, we still see an increase in obstructive sleep apnoea. Here I propose a hypothesis that the development of OSA in non-obese individuals is due to environmental issues related to stress. This multifaceted issue would present a challenge to research investigating uni variable contributors to OSA. Furthermore, I suggest that sleep apnoea is a physiological dysfunction related to hormonal changes, leading to dysregulation of breathing via insufficient leptin signalling to peripheral chemoreceptors: airway muscle atrophy and a mechanical default of the upper airway. A knock-on effect as our species becomes externally driven by reward and medication and lacking awareness of the ability to monitor and regular their internal physiology – something I suspect will only worsen the further we move into this technological age.

References

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