COVID-19 may bring high risks of severe disease and death in many patients by disrupting key metabolic signals and thereby triggering hyperglycemia, according to a new study from researchers at Weill Cornell Medicine and NewYork-Presbyterian.

In the study, reported Sept. 15 in Cell Metabolism, the researchers found that hyperglycemia – high blood sugar levels – is common in hospitalized COVID-19 patients and strongly associated with worse outcomes. The researchers also found evidence suggesting that SARS-CoV-2, the coronavirus that causes COVID-19, can induce hyperglycemia by disrupting fat cells’ production of adiponectin, a hormone that helps regulate blood sugar levels.

“We normally don’t think that fat cells are very active, but in fact they synthesize many protective proteins for your body – and it appears that SARS-CoV-2 may disable that protection in many patients,” said Dr. James Lo, an associate professor of medicine in the Weill Center for Metabolic Health and Cardiovascular Research Institute at Weill Cornell Medicine and a cardiologist at NewYork-Presbyterian/Weill Cornell Medical Center.

Hyperglycemia, the core feature of diabetes, is associated with inflammation and weakened immunity against infections, and was recognized as a significant risk factor for severe COVID-19 early in the pandemic. However, doctors later began finding evidence that COVID-19 is associated with hyperglycemia in patients who have no history of diabetes.

To better understand this important but mysterious aspect of COVID-19, Lo and colleagues analyzed the records of 3,854 patients who were hospitalized with COVID-19 at NewYork-Presbyterian Hospital/Weill Cornell Medical Center and affiliated hospitals in the first few months of the pandemic in the United States.

They found that a remarkably high proportion (49.7%) of these patients presented with hyperglycemia or developed it during their hospital stays.

Hyperglycemia in these COVID-19 patients was also strikingly associated with worse outcomes. Compared to patients with normal blood sugar levels, the patients with hyperglycemia were nine times more likely to develop severe lung dysfunction (acute respiratory distress syndrome, or ARDS), 15 times more likely to be given mechanical ventilation, and three times more likely to die.

Surprisingly, the researchers found that hyperglycemia and the dire risks it brings also occur in other, non-COVID-19 forms of severe lung dysfunction: They found it in the same proportion in ARDS cases associated with COVID-19 and in ARDS cases from non-COVID-19 causes such as severe influenza or bacterial pneumonia.

However, hyperglycemia in the latter cases appeared to be caused mostly by the death or dysfunction of beta cells that produce insulin, the principal hormone that regulates blood sugar levels.

“In contrast, hyperglycemia in COVID-19 hyperglycemia is mainly caused by insulin resistance, in which insulin is present but the tissues it normally acts upon are no longer sensitive to it,” said first author Dr. Moritz Reiterer, a postdoctoral fellow in Lo’s laboratory.

Further tests revealed that the COVID-19 ARDS patients had severe declines in blood levels of adiponectin, a hormone produced by fat cells which normally has a protective effect against diabetes by enhancing insulin sensitivity.

How SARS-CoV-2 disrupts fat cells’ production of adiponectin isn’t yet clear. It may do so indirectly, by raising the general level of inflammation, which in turn disrupts fat cells. But the researchers demonstrated that SARS-CoV-2 can infect human and mouse fat cells, hinting at the possibility that the virus disrupts adiponectin production in this direct way in COVID-19 patients.

The results open up a novel perspective on COVID-19, offering, among other things, a new explanation for why some people have worse COVID-19 outcomes.

“Patients with obesity, for example, may be more vulnerable to COVID-19 because they may already have some degree of insulin resistance and fat cell dysfunction, and possibly their fat cells are more susceptible to infection,” Lo said.

The findings also suggest that a class of diabetes drugs called thiazolidinediones, which boost adiponectin production, may be useful in treating COVID-19 when it includes hyperglycemia. Further research is needed before this becomes clinically actionable.

Lo is now investigating whether COVID-19-induced hyperglycemia persists and develops into diabetes even after the recovery from COVID-19.

Lo led the study in collaboration with other investigators at Weill Cornell Medicine and NewYork-Presbyterian including Dr. Laura Alonso, chief of the Division of Endocrinology, Diabetes and Metabolism at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center and the Herbert J. and Ann L. Siegel Distinguished Professor of Medicine at Weill Cornell Medicine; Dr. Robert Schwartz, associate professor of medicine in the Division of Gastroenterology and Hepatology at Weill Cornell Medicine and a gastroenterologist at NewYork-Presbyterian/Weill Cornell Medical Center; Dr. Edward Schenck, assistant professor of clinical medicine in the Division of Pulmonary and Critical Care Medicine at Weill Cornell Medicine and a pulmonologist at NewYork-Presbyterian/Weill Cornell Medical Center; and Dr. Monika Safford, chief of the Division of General Internal Medicine at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medicine and the John J. Kuiper Professor of Medicine at Weill Cornell Medicine.

Dr. Robert E. Schwartz is a paid scientific advisory board member for Miromatrix Inc. Dr. Schwartz is a paid speaker and consultant for Alnylam Inc.

—Jim Schnabel, freelance writer for Weill Cornell Medicine