Health & Science
Diabetes in the COVID-19 Era: How Deadly Is It?
How diabetes exacerbates COVID-19 on a biological level.
Diabetes is one of the top 10 leading causes of death worldwide, owing to its myriad complications. This chronic metabolic disease has become a cause for concern due to its rapid surge in prevalence over the past few decades. In 2019, its global prevalence is just shy of half a billion people (which is responsible for at least 1.6 million deaths). This number is predicted to rise by an additional 25% in 2030, surpassing half a billion of the world’s population.
Broadly, diabetes is divided into two categories: type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), with the latter being more common. T1DM occurs when one’s pancreas is unable to produce sufficient or any insulin (a hormone that promotes the absorption of glucose from the blood to be stored in the liver, adipose tissues and skeletal muscles). T2DM occurs when one becomes resistant to the effects of insulin, causing the individual’s pancreatic cells (specifically beta cells) to overproduce insulin in order to mitigate resistance. Over time, prolonged insulin resistance causes beta cell dysfunction, which cripples insulin production.
What makes diabetes so deadly (even before the pandemic), are its adverse complications. Excess glucose in the blood, known as hyperglycemia, induces inflammation that damages blood vessels and nerves in every body part imaginable: the eyes (diabetic retinopathy), heart (coronary heart disease, diabetic cardiomyopathy), brain (stroke), kidneys (diabetic nephropathy), hands and feet (diabetic neuropathy, ischemia, ulceration); it may also increase one’s susceptibility to skin, gum and bladder infections. Not only do these complications substantially impact one’s quality of life, but they also take a toll on one’s physiologic reserve, which in turn increases mortality.
The Impact of Diabetes on COVID-19 Morbidity and Mortality 👥
Based on a nationwide retrospective study conducted in China, which analyzed over a thousand laboratory-confirmed COVID-19 cases, it was observed that patients with a single comorbidity (i.e., hypertension, diabetes, chronic kidney disease, COPD, malignancy, etc) had poorer clinical outcomes than those with none. Notably, diabetic patients with COVID-19 are predisposed to more severe disease presentation (34.6% versus 14.3%), admission to Intensive Care Unit (14.6% versus 5.5%), requiring invasive ventilation (8.5% versus 2.7%), and higher mortality (10.0% versus 2.5%), when compared to non-diabetic patients without underlying comorbidities.
Another study in 2020 with similar results conducted a meta-analysis that included 16,000 COVID-19 patients from America, China and France discovered that diabetic patients with COVID-19 are twice as likely to develop severe disease presentations (e.g., acute respiratory distress syndrome requiring ventilation and ICU care), with twice the mortality rate (two times more likely to die from COVID-19).
As these studies have highlighted associations between diabetes and COVID-19 severity and mortality, making it a strong indicator of poor clinical outcomes, it raises an important question: What are the exact pathogeneses (processes by which a disorder / disease develops) in diabetes that make it so deadly?
Diabetic pathogeneses that exacerbate COVID-19 disease severity🍬
Diabetes is a multisystemic disorder, where a state of persistent hyperglycemia affects multiple organ systems in the human body (hence the list of complications), by constantly inducing oxidative stress and inflammation. This happens via complex mechanisms, often affecting multiple regulatory agents.
Here, I would like to highlight specific pathogeneses that predispose people with diabetes to a higher risk of adverse outcomes from COVID-19.
1. Hyperglycemia-induced Endothelial Dysfunction 🏥
The endothelium is a single layer of endothelial cells that line the inner walls of blood vessels. In the presence of hyperglycemia, various endothelial metabolic pathways are affected.
To offer you some perspective, imagine your blood vessels are made of pipes filled with running water. When acid is dumped into the water, it gets contaminated. The acid then irritates the walls of the pipes, gradually wearing them down. As the pipes react with acid, by-products are released that further contaminate the water, which continue to react with other pipes along the way.
Similarly, on a cellular level, high glucose levels activate unfavorable pathways within endothelial cells resulting in the production of ROS (reactive oxygen species), AGEs (advanced glycation end products) and reactive dicarbonyl compounds, contributing to oxidative stress and inflammation.
At the beginning of the pandemic, there were numerous reports of COVID-19 patients suffering from thrombosis (i.e., blood clots) in various locations (e.g., lungs, brain, legs, toes). Though it has been postulated that direct injury to vascular structures could be the main cause of blood clots, predominantly due to SARS-CoV-2 targeting ACE2 receptors, which are present on the surface of endothelial cells. Damaged endothelium activates the host’s innate immune system to recruit platelets, which form clots at damaged sites. Despite its protective intentions of wound repair, when frequent, this increases risks of thrombosis (occlusion) and embolism (where the blood clot breaks apart, gets carried within the bloodstream, occluding a smaller blood vessel).
Aside from direct causes of blood clots, there have also been postulations of indirect causes. The diabetic endothelium produces ROI (reactive oxygen intermediates, which is a type of ROS). ROI has been observed to interrupt the functions of eNOS (endothelial nitric oxide synthase), which is an enzyme that synthesizes NO (nitric oxide).
NO is an essential cellular signaling molecule that maintains vascular tone via vasodilation (which in turn keeps blood pressure at a safe level); it is also an immunomodulatory agent that reduces the release of pro-inflammatory cytokines by macrophages and inhibiting platelet aggregation. Without sufficient NO, the aforementioned processes become dysregulated: absent vasodilation leads to vasoconstriction and hypertension, uncontrolled immune cells would worsen inflammation, and platelets would inappropriately aggregate, placing the individual in a hypercoagulable state (an increased tendency to develop blood clots), with higher risks of developing coagulopathies when infected by COVID-19.
2. Hyperglycemia induces Immune System Dysfunction 🐛
Aside from the vascular complications manifested in diabetes, infections are a particular concern to this population group, due to their immune system’s inability to effectively fight off pathogens. There are two broad categories which explain these immune dysfunctions; they are mainly: suppression of cytokine production and defective immune cells.
Several studies have observed that in individuals with diabetes, their immune cells produced significantly lower cytokines compared to healthy individuals. Interestingly, when white blood cells from healthy individuals were exposed to a high glucose medium, they produced less cytokines (IL-2, IL-6 and IL-10) when stimulated by antibodies. Another study exposed healthy individuals to a solution of glucose and octreotide (a hormone drug that suppresses insulin secretion, inducing a state of hyperglycemia), revealed reduced expressions in IL-6 and IL-17A by certain immune cells. In order to understand the significance of cytokines, we have to first look at the sequence of events when an infection occurs.
In the early stages of infection, pathogens and inflammation processes that damage host tissues would emanate signals that activate the innate immune response. This triggers a group of specialized white blood cells known as granulocytes, as well as NK cells (Natural Killer cells) — the latter mainly produce interferons (a type of cytokine) in order to activate other white blood cells, notably macrophages. Activated macrophages then synthesize other cytokines such as pro-inflammatory interleukins (IL-1, IL-6, IL-8, IL-12) and TNFs (tumor necrosis factors) in an attempt to fight off invading pathogens as an acute response, simultaneously mounting the body’s adaptive immune system.
Based on the aforementioned events, reduced cytokine release in the presence of hyperglycemia may attenuate the body’s immune response against invading pathogens. Interestingly, this observation has been made in France, where a study looked at the interferon responses in different COVID-19 patients. Apparently, patients with more severe forms of the disease had lower interferons compared to patients with milder symptoms. Furthermore, studies using mice models infected with SARS-CoV and MERS-CoV viruses have shown that a strong innate immune response is crucial in resolving infections, whereas a delayed or inadequate response would result in an adverse inflammatory immune reaction, known as a cytokine storm, which has been well-documented in patients with COVID-19.
Aside from a blunted initial response to pathogens, hyperglycemia also causes immune cell dysfunction. In one study, diabetic mice models that were infected with pneumonia bacteria mounted a less aggressive immune response to the infection, which was evident from the presence of fewer granulocytes observed in their lung tissues and reduced cytokine production, compared to healthy mice models. In other studies, hyperglycemia has been shown to impair phagocytosis by specialized white blood cells known as macrophages (observed in diabetic mice models) due to defects in their complement receptors. Additionally, a state of chronic hyperglycemia was observed to increase the polarization of M2 macrophages in mice models — this type of macrophage contributes to immunosuppression, which is hypothesized to weaken one’s immune system against invading pathogens.
The impact of hyperglycemia on immune cells has been studied extensively; although some of its mechanisms still remain elusive, numerous preliminary findings have pointed at its adverse effects on the immune system. By having a better understanding on these mechanisms, novel treatment modalities could be developed to better manage infections in patients with diabetes; thus, improving prognosis.
3. Hyperglycemia disrupts RAAS 🔍
In an animal study that looks at ACE2 expression in mice organs, a group of non-obese diabetic (NOD) mice was observed to have increased expression in the pancreas, liver and kidney. Although this finding may not accurately translate to humans, a study that investigated the relationship of risk factors and ACE2 expression in human lungs discovered that diabetes is causally associated with increased ACE2 levels. This indicated that people with diabetes may have more ACE2 receptors, making them more susceptible to COVID-19 infection.
Prior to the pandemic, I was only familiar with the concept of ACE2 being a protein that makes up RAAS (Renin-Angiotensin-Aldosterone System), an endocrine system for pharmacotherapeutic agents (i.e., ACE inhibitors, ARB, etc) to manage hypertension. However, to viruses such as SARS-CoV-2, ACE2 is a gateway for cell entry and infection. As the virus locks onto an ACE2 receptor, they enter the cell together, causing a down-regulation (depletion) of ACE2. With more cells infected, the amount of ACE2 receptors decrease, resulting in a dysregulated RAAS.
The above figure represents a part of RAAS, the Renin-Angiotensin-Aldosterone System. Note that ACE is abundant in the lungs. There are two pathways leading to completely opposite outcomes. In COVID-19 patients, down-regulated ACE2 would mean the ACE2/Ang-1(1–7) pathway (in blue) has been attenuated, and is less likely to produce protective effects. The system then shifts to the ACE/Ang II pathway (in red), which further causes vascular permeability contributing to pulmonary edema, and aggravates inflammation in the lungs, due to the nature of Ang II and AT1 receptors mediating inflammatory cells (e.g., macrophages).
With this adverse outcome in mind, imagine how disastrous it would be if compounded in diabetic patients who supposedly have more ACE2 receptors.
With the recent surge of COVID-19 cases in South Asia countries, I couldn’t help but wonder if ethnicity might have contributed to disease severity. Interestingly, several studies revealed that South and East Asians are prone to developing diabetes due to several biological factors such as genetics (eight novel alleles have been identified in East Asians with T2DM), reduced insulin secretory function, and smaller pancreatic beta-cell mass. When compounded with external factors like lifestyle changes, economic development and the impact of industrialization, these further fuel the rise of this chronic metabolic disease.
It is no surprise that India has been dubbed as “the world’s capital of diabetes”, whereby every one in six people with diabetes is from India. Unfortunately, India also has the most number of COVID-19 deaths among Asia countries, ranking third highest in the world with a death toll of 418,511, just behind Brazil (544,302) and America (625,363), at the time of writing this article.
Despite the contagious delta variant (B.1.617.2) first detected in India, which has since ravaged the country, it raises a possibility that the impact of this variant could be more devastating when combined with a baseline of diabetes. Nevertheless, other variables such as demographics, presence of comorbidities, socioeconomic status, blood glucose management, etc., should be taken into consideration if this hypothesis were to be investigated.
Amidst the grim reports of diabetes and COVID-19 mortality, a preexisting anti-diabetic medication has been making headlines: Metformin. This medication reportedly reduces mortality in COVID-19 patients, and may have properties beyond glycemic control (even capable of modifying the gut microbiome), which is definitely worth exploring. If this is right up your alley, stick around for the next update!
As always, stay safe.❤️
Love, Alice
