Diabetes is a leading cause of death in the world and in Western countries such as Europe and the United States. According to the American Diabetes Association, the total estimated cost of diabetes diagnosed in 2016 was over $ 260 billion, including nearly $ 80 billion in productivity reductions. People with diabetes have about twice as much medical bills as those who don’t have the disease. Medical care for non-healing wounds is also estimated to cost more than $ 50 billion annually. These numbers give an example of the economic impact that diabetes has on the health system and on society. But before diabetes appears manifestly, a condition known as pre-diabetes develops several years before, during which very nuanced symptoms begin to appear, which, in the vast majority of cases, are not given much importance. Even simple alterations in blood tests or changes in biological rhythms, easy fatigue or mood swings are often treated symptomatically.
In prediabetes, blood glucose levels rise, but the level is not high enough to be diagnosed as type 2 diabetes. This condition in almost all cases becomes full-blown type 2 diabetes which can be followed by complications such as heart disease and stroke. A serious complication of diabetes are ulcers that can form from wounds. The feet are one of the most common places of injury. Small wounds that develop on the feet can eventually become ulcers. According to the American Podiatric Medical Association, on average 17% of people with diabetes who develop an ulcer end up having a lower limb amputation. Patients with type 2 diabetes also have a higher prevalence of sleep disorders including obstructive sleep apnea (OSA), shortened sleep duration, restless legs syndrome, and insomnia. In patients with type 2 diabetes, a meta-analysis of nearly 4,000 studies indicated that disruption of sleep duration and quality alters glycemic control.
The finding that sleep debt causes metabolic changes similar to those seen in type 2 diabetes is therefore an established biological fact. Impaired wound healing is a clinically relevant problem and obese and diabetic patients are at increased risk of surgical site infection. Sleep fragmentation is known to impair immune function. Wounds in diabetics are difficult to treat and the prolonged inability to promote wound healing is a major cause of amputation. A 2018 research investigated the impact of sleep fragmentation on wound healing in diabetic animals. The scientists compared obese mice with characteristics of type 2 diabetes to normal-weight mice without diabetes. The team anesthetized 34 adult male mice and created small surgical wounds on their backs. Then, they measured the time it took to heal those wounds in two conditions: one group of rodents followed a regular sleep schedule, while the other group was forced to wake up multiple times each night.
The disrupted sleep pattern caused a significant delay in wound healing in rodents with diabetes. The sleeping animals needed about 13 days to achieve 50% healing, compared to the group without interrupted sleep, which took about 10 days. Sleep fragmentation caused a significant increase in wound levels of TNF-alpha only in obese mice and an increase in cortisol only in normal mice. Normal weight mice achieved 50% wound healing in less than 1 week and completed healing in just 2 weeks. Researchers noted that type 2 diabetes could lead to inflammation, poor blood circulation and neuropathy. Because of these complications, the body is more likely to get infected. First, sleep deprivation and sleep fragmentation are different but they can share similar traits. Sleep deprivation is a physiological stress, as evidenced by increases in cortisol.
Sleep fragmentation in humans has also been associated with increases in cortisol. Sleep quality affects the immune system and weakens the healing process, so it’s easy to see the connection between sleep and wound healing. Indeed, too much cortisol suppresses normal immune responses, which in turn affect wound healing. Studies have shown that sleep is crucial for the immune response. A lack of sleep can weaken the immune response, exposing the body to infections; for example, shorter sleep durations are linked to a higher risk of developing the common cold. The inflammatory response is equally useful in the wound healing process and in the modulation of pain. There is now strong evidence that giving painkillers to reduce any manifestation of pain can predispose to the paradoxical appearance of a chronic pain syndrome.
The diabetic patient has its typical painful manifestation in neuropathy. Past studies have shown that diabetic neuropathy has a precise molecular basis dictated by the constant hyperglycemia that causes damage to the structural proteins of the tissues, in this case to the nerve structures. In addition to nerve conduction damage, the inflammation that always accompanies the diabetic patient tends to accentuate the pain and raise the pain threshold. Therefore, diabetic patients feel the need to periodically take analgesics since neuropathy is very painful and can affect not only the quality of life, but also that of sleep. And here the circle closes: in the event of sleep fragmentation, cortisol levels rise and one might think that they counterbalance the inflammation, thus reducing pain. But, as mentioned before, it is not only the underlying inflammation that determines the neuropathy, but there are other underlying metabolic and biochemical changes.
On the contrary, the rise in cortisol hinders the immune function that serves to heal wounds. If cortisol (and testosterone in men) is prevented from rising as a result of sleep deprivation or poor sleep quality, insulin resistance is improved and therefore the possibility that insulin therapy contrasts the onset of complications. Potential mechanisms underlying the development of insulin resistance from sleep restriction include chronic inflammation, changes in metabolically active hormones secreted by gastrointestinal and adipose tissues, and alterations in testosterone and cortisol. Epidemiological studies have shown that increased plasma C-reactive protein (CRP) and interleukin-6 (IL-6) predict future cardiovascular events, hypertension, obesity and diabetes. Some epidemiological studies have also linked shorter sleep duration with higher plasma levels of CRP and inflammatory cytokines such as IL-6 and TNFα (inflammatory biomarkers).
Therefore, the first line of treatment against diabetic complications, neuropathy and peripheral ulcers remains, it is true, the disciplined control of daily blood glucose. But from the above, it is clear how complicated the biology of this disease is; and how important a pathogenetic root such as poor sleep quality can be in its evolution. Unfortunately, today’s lifestyles and habits compromise good sleep hygiene: the increasing use of media tools even among the older population, as well as in children and adolescents, has involved the older age groups. How much their technological involvement affects their sleep quality is not the subject of this discussion. On the contrary, it is central to the fact that adults or elderly people with diabetes and other risk factors that could lead to complications have a quality of sleep that does not expose them to the problem.
Whether it is pain that does not make them fall asleep, or the inability to fall asleep due to other factors, sleep hygiene is a rule that is perhaps as important as daytime medicines.
Antza C et al. J Endocrinol. 2021 Dec 13; 252(2):125-141.
Liu PY et al. J Clin Endocrinol Metab 2021; 106(9):3436-3448.
Huynh P et al. BMJ Open Diab Res Care. 2020; 8(1):e000982.
McLain JM et al. Sleep. 2018 Nov 1; 41(11):zsy156.
Ogilvie RP, Patel SR. Curr Diab Rep. 2018; 18(10):82.
Dott. Gianfrancesco Cormaci
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