By: Yan Mardian
Every 18 April the National Diabetes Day (or Hari Diabetes Nasional) is celebrated in Indonesia. This campaign is led by the Indonesian Ministry of Health and is intended to increase the awareness of diabetes mellitus. Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin or when the body can not effectively use the insulin it produces. Insulin is a hormone that regulates blood sugar. Hyperglycaemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body’s systems, especially the nerves and blood vessels. In 2014, 8.5% of adults aged 18 years and older had diabetes. In 2019, diabetes was the direct cause of 1.5 million deaths, and 48% of all deaths due to diabetes occurred before the age of 70 years (1).
Data reveal an increased risk of diabetes in the months after acute COVID-19 infection – which could have implications for stretched public health systems. A few reports have raised the possibility that COVID-19 could increase the risk of type 2 diabetes. In The Lancet Diabetes & Endocrinology, Xie and Al-Aly offer further evidence for the increased risk of diabetes beyond the first 30 days of infection (post-acute phase) by analyzing the US Department of Veterans Affairs national health-care records of those who survived the first 30 days after a positive COVID-19 test. These data raise important questions about the relationship between COVID-19 and diabetes concerning causality, biological mechanisms, and implications for clinical care and public health (2).
Incidence of diabetes and antihyperglycemic medication use was compared between 181,280 COVID-19 survivors, 4,118,441 contemporary controls without COVID-19 infection from the same year, and 4,286,911 historical controls from 2017. Diabetes was defined by the International Classification of Diseases-10 diagnosis codes or an HbA1c of more than 6·4% (46 mmol/mol). The authors used in-verse probability-weighted survival analyses, including predefined and algorithmically selected high dimensional variables, and reported two measures of risk; hazard ratio (HR) and burden per 1000 people at 12 months.
The study revealed that COVID-19 infection appears to significantly raise the risk for diabetes by about 40% at 1 year. Significantly increased diabetes risks compared to those not infected ranging from 31% to more than double were found in a subgroup analysis based on diabetes risk score, body mass index, age, race, prediabetes status, and deprivation level, and even after adjusting for confounding factors. Risks and burdens of post-acute outcomes increased in a graded fashion according to the severity of the acute phase of COVID-19 (whether patients were non-hospitalized, hospitalized, or admitted to intensive care), but a significant excess diabetes burden was seen even among those with “mild” COVID-19. All the results were consistent in analyses using the historical control as the reference category.
Given the extraordinary number of COVID-19 cases globally — 480 million confirmed cases and counting — the modest increase in diabetes risk could correspond to a drastic rise in the number of people diagnosed with the disease worldwide. But the findings of the aforementioned study might not translate to other groups of people. The US veterans in the study were mostly older, white men, many of whom had elevated blood pressure and were overweight, putting them at high risk of developing diabetes. And it’s possible that some people in the control group had undetected mild or asymptomatic COVID-19 but were never tested, potentially skewing the data. Other factors might also be contributing to the apparent rise in diabetes among people who recovered from COVID-19. Existing cases of diabetes might have gone undetected until people sought medical care for COVID-19.
Another study, recently published in Diabetologia, also suggested that people who recover from a mild case of COVID-19 appear to have an increased risk for subsequent new-onset type 2 diabetes but not other types of diabetes. The findings were based on a nationwide primary care database in Germany. The retrospective cohort analysis was performed using data from the Disease Analyzer, a representative panel of 1171 physician practices in Germany, from March 2020 to January 2021, with follow-up through July 2021. Individuals with a history of COVID-19 or diabetes and those taking corticosteroids within 30 days after the index dates were excluded (3).
A total of 35,865 patients with confirmed SARS-CoV-2 infection were propensity score-matched on a one-to-one basis for sex, age, health insurance, and comorbidities with those who had acute respiratory tract infections (controls) but were COVID-19 negative. Median follow-up was 119 days for the COVID-19 group and 161 days for controls. There was a 28% increased risk of type 2 diabetes for those who had COVID-19 versus controls (15.8 per 1000 person-years vs 12.3 per 1000 person-years, respectively, which was significantly different, and an incidence rate ratio [IRR] of 1.28). The incidence of other types of diabetes or unspecified diabetes for the COVID-19 and control groups did not differ significantly (4.3 per 1000 person-years vs 3.7 per 1000 person-years; IRR, 1.17).
There are many plausible theories about how COVID might cause diabetes, but none have been proven (4). One possibility is that inflammation caused by the virus could bring about insulin resistance, which is a feature of type 2 diabetes. Early in the pandemic, researchers raised concerns based on anecdotal reports in young people and children that SARS-CoV-2, like other viruses, might damage cells in the pancreas that produce insulin, triggering type 1 diabetes. But data on a link between SARS-CoV-2 infection and newly diagnosed cases of type 1 diabetes remain mixed. Several studies have found no evidence that the disease is causing the uptick in cases of type 1 diabetes in younger adults or children. And a laboratory study published in February also challenged the idea that SARS-COV-2 destroys insulin-producing pancreatic cells. In that study, leveraging comprehensive single-cell analyses of in vitro SARS-CoV-2-infected human pancreatic islets, they demonstrate that productive infection strictly depends on the SARS-CoV-2 entry receptor ACE2 and targets practically all pancreatic cancer cell types. Notably, the infection remains highly circumscribed and largely non-cytopathic and, despite a high viral burden in infected subsets, promotes only modest cellular perturbations and inflammatory responses. Similar experimental outcomes are also observed after islet infection with en-demic coronaviruses. Thus, the limits of pancreatic SARS-CoV-2 infection, even under in vitro conditions of enhanced virus exposure, challenge the proposition that in vivo targeting of β cells by SARS-CoV-2 precipitates new-onset diabetes. Whether restricted pancreatic damage and immunological alterations accrued by COVID-19 increase cumulative diabetes risk, however, remains to be evaluated (5).
In COVID-19 patients, insulin resistance seems to be ab-normal when compared to patients with other critical conditions. This could be a factor affecting the process of new-onset hyperglycemia or diabetes in COVID-19. Montefusco and colleagues demonstrated hyperglycemia and insulin resistance in COVID-19 patients without diabetes. The persistence of hyperglycemia and insulin resistance was documented six months after acute COVID-19 infections. Furthermore, regarding glucose homeostasis in patients with coronavirus infection, the gut is less focused than the pancreas, liver, skeletal muscle, and adipose tissue. However, increased intestinal glucose absorption via the sodium-dependent glucose transporter (SGLT1) in the intestinal epithelium, which is mediated by the downregulation of ACE2 with a SARS-CoV-2 infection, might also be involved in hyperglycemia in COVID-19 patients (6).
Assessing the diabetogenic and ketosis-prone potential of SARS-CoV-2 variants is an additional challenge. The pandemic variants of SARS-CoV-2 have been reported to change the viral characteristics, including the transmissibility and antigenicity. However, most of the currently available data were based on studies conducted before the major variants of SARS-CoV-2 were circulated. The Omicron variant is associated with a more attenuated disease severity compared to previous circulating variants. Its cellular entry is reported to be less dependent on TMPRSS2. Replication is reduced in the lower respiratory tract that highly expresses TMPRSS2, whereas the infectivity of the Omicron variant is not affected in non–expressing cells in the upper respiratory tract. Moreover, the Omicron variant is characterized by a higher ACE2 binding affinity and increased immune evasion. The expression of ACE2 and TMPRSS2 under steady-state conditions have different distributions. The tissue tropism of variants and their impact on glycometabolism might be affected (6).
We are amidst dual pandemics of COVID-19 and diabetes and face the threat of the emergence of SARS-CoV-2 variants, including the Omicron variant. These are intricately interrelated, and it is particularly important to reveal the precise mechanism underlying the association between COVID-19 and diabetes as well as to dissolve the vicious circle of hyper inflammation and hyperglycemia. The incidence and etiology of new-onset diabetes remain to be fully elucidated, and the diabetogenic properties of SARS-CoV-2 depending on the variants is a subject for future investigation. A lingering question is also whether the metabolic changes observed in people who had COVID-19 persist after one year. More research is needed to clarify long-term trends in new-onset diabetes at a population level and to tease apart what might be causing them.
- World Health Organization. Diabetes [Internet]. 2021 [cited 2022 Apr 13]. Available from: https://www.who.int/news -room/fact-sheets/detail/diabetes#:~:text=In 2014%2C 8.5%25 of adults,age of 70) from diabetes.
- Xie Y, Al-Aly Z. Risks and burdens of incident diabetes in long COVID: a cohort study. lancet Diabetes Endo-crinol. 2022 Mar;
- Rathmann W, Kuss O, Kostev K. Incidence of newly diagnosed diabetes after Covid-19. Diabetologia. 2022 Mar;1–6.
- Watson C. Diabetes risk rises after COVID, massive study finds. Nature. England; 2022.
- van der Heide V, Jangra S, Cohen P, Rathnasinghe R, Aslam S, Aydillo T, et al. Limited extent and conse-quences of pancreatic SARS-CoV-2 infection. Cell Rep. 2022 Mar;38(11):110508.
- Yonekawa A, Shimono N. Clinical Significance of COVID-19 and Diabetes: In the Pandemic Situation of SARS-CoV-2 Variants including Omicron (B.1.1.529). Biology (Basel). 2022 Mar;11(3).