COVID-19 increase hyperglycemia after infection

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Researchers are observing a new long-term health concern in patients hospitalized with COVID-19 – an increase in new-onset hyperglycemia lasting months after infection.

An Italian study found that about half of the patients admitted to the hospital for COVID-19 during the start of the pandemic had new cases of hyperglycemia, or high levels of blood sugar. They also had poorer outcomes.

“These people were not diabetic before,” says lead author Paolo Fiorina, MD, Ph.D., who is affiliated with the Division of Nephrology at Boston Children’s Hospital.

“But during admission, about 46 percent of the patients were found to have new hyperglycemia.” While most cases resolved, about 35 percent of the newly hyperglycemic patients remained so at least six months after the infection.

Hyperglycemia persisted beyond infection

The study assessed the health of 551 people admitted to the hospital in Italy from March through May 2020. A follow-up period included six months after hospital admission.

Compared with patients with no signs of glucose abnormalities, the hyperglycemic patients also had worse clinical concerns:

  • longer hospitalizations
  • worse clinical symptoms
  • a higher need of oxygen
  • a higher need of ventilation
  • more need of intensive care treatment

“We wanted to understand the mechanism why these patients did poorly compared to those who did not have hyperglycemia,” says Fiorina, who published an earlier paper showing COVID-19 worsened glucometabolic control in diabetics. The current study was published in Nature Metabolism.

Hormones also out of balance

To learn more, all patients were fitted with a glucose sensor at admission. Over the course of time, the researchers detected many abnormalities in glucose metabolic control in the hyperglycemic patients.

They also found that hyperglycemic patients had abnormal hormonal levels. “We discovered they were severely hyperinsulinemic; they produced too much insulin,” says Fiorina. They also had abnormal levels of pro-insulin, a precursor of insulin, and markers of impaired islet beta cell function. Islet beta cells make and secrete insulin.

“Basically, the hormonal profile suggests that the endocrine pancreatic function is abnormal in those patients with COVID-19 and it persists long after recovery,” he says.

Inflammation from excess cytokines

Hyperglycemic patients also had severe abnormalities in the amount of inflammatory cytokines, including IL-6 and others.

“We thought that blocking IL-6, and potentially even other cytokines, would be a benefit for beta cell function,” adds Fiorina, whose theory was proven true. Patients treated with anti-IL-6 therapy (tocilizumab), had greater improvement in glycemic control higher compared with those who did not receive the medication.

A coming wave of diabetic patients?

While glucometabolic abnormalities declined over time in some patients – particularly after COVID-19 infection – other issued remained. Many patients had higher post-prandial (after eating) glucose levels and abnormal pancreatic hormones in the post-COVID-19 period.

“This study is one of the first to show that COVID-19 has a direct effect on the pancreas,” says Fiorina. “It indicates that the pancreas is another target of the virus affecting not only the acute phase during hospitalization but potentially also the long-term health of these patients.”

The study points to the importance of evaluating pancreatic function in patients hospitalized for COVID-19 – while in the hospital and over the long term. “This goes beyond fasting glucose testing because we observed glucose metabolic abnormalities during the day which were not always present in a normal fasting test,” says Fiorina.

In terms of treatment, questions remain about how to care for patients with COVID-19-related glucose abnormalities. Should patients be treated just with an anti-diabetic drug like an insulin sensitizer, or should anti-inflammatory drugs like tocilizumab and other drugs be used?

“If you keep targeting and blocking insulin, but you have a strong and chronic inflammation, it may lead to chronic damage,” says Fiorina, who suggests larger studies need to be done to test anti-diabetic and anti-inflammatory treatment. “When you consider how many patients have been hospitalized with COVID-19, and continue to be worldwide, we may see a huge increase in the diabetic population.”

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Diabetes is one of the most relevant co-morbidity in worsening the prognosis of COVID-19 [1]. Data is also showing that hyperglycemia, in both people with or without diabetes, is an important risk factor for death in COVID-19 [2], [3], [4], [5]. A. Sing is reporting some important aspects of this finding [2]. In summary, evidence shows:

  1. That hyperglycemia in people with diabetes at the time of hospital admission is more relevant as risk factor than the previous glycemic control evaluated by HbA1c [2]. This evidence emerges particularly from the CORONADO Study (Coronavirus SARS-CoV-2 and Diabetes Outcomes), a French nationwide multicentre observational study, aiming to identify the clinical and biological features associated with disease severity and mortality risk in people with diabetes, hospitalised for COVID-19 [3].
  2. That hyperglycemia at the admission in hospital seems worsening the prognosis of COVID-19 more in people without diabetes than in people with diabetes [2].

However, it is worth to mention that glucose variability during the hospitalization, in both diabetes and non-diabetes, also emerged as independent risk factor for a worse prognosis in COVID-19 [4], [5].

According to this evidence, it is clear that acute hyperglycemia has a key role as independent risk factor in COVID-19. This evidence has raised a great interest, being considered somehow a new finding. However, how much new is it?

Already, during the previous SARS epidemic, diabetes and hyperglycemia emerged as risk factors for a worse prognosis of the disease [6].

The specific and more relevant role of acute hyperglycemia in diabetes, more than the previous HbA1c, is well known in the Intensive Care Units (ICU), where an increased gap between admission glucose and HbA1 has been found as predictor of mortality in critically ill patients with diabetes [7], [8]. The impact of acute (stress) hyperglycemia and glucose variability in critically ill patients is very well known [9]. Moreover, it is also well known that acute hyperglycemia in the ICU is more dangerous for people without diabetes than for people with diabetes [10].

Acute hyperglycemia induces inflammation, endothelial dysfunction and thrombosis, through the generation of oxidative stress [11]. In diabetes chronic hyperglycemia, through oxidative stress, is inducing an increase of antioxidant defences in the cells therefore, during an acute spike of hyperglycemia the tissues are somehow protected [12]. This is not the case in absence of diabetes, exposing the tissues to more damage. In vitro experiments were able to demonstrate the key role of some miRNAs in this phenomenon [13].

According to what described above, the question is not why hyperglycemia worsens the prognosis of COVID-19, but why it is so frequent. For example, it has been reported that acute hyperglycemia occurs in about 50% of patients hospitalised for COVID-19, while the prevalence of diabetes in the same population was about 7% [14]. A possible hypothesis is that the “Severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2)” may affect the pancreatic β-cells producing a reduction of insulin secretion [15]. At the same time, the infection is also accompanied by a huge production of cytokines, which may induce insulin resistance [15]. Both, reduced insulin secretion and insulin resistance, may hesitate in hyperglycemia [15].

In conclusion, the effect of acute hyperglycemia during COVID-19 is not so much surprising and it should be treated according to the already existing guidelines [16], [17], [18].

Reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445137/

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More information: Laura Montefusco et al, Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection, Nature Metabolism (2021). DOI: 10.1038/s42255-021-00407-6

Sebastiano Bruno Solerte et al, Sitagliptin Treatment at the Time of Hospitalization Was Associated With Reduced Mortality in Patients With Type 2 Diabetes and COVID-19: A Multicenter, Case-Control, Retrospective, Observational Study, Diabetes Care (2020). DOI: 10.2337/dc20-1521

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