COVID-19 trigger hyperglycemia – disrupts fat cells and causes decreased production of the hormone Adiponectin


A new study by researchers from Weill Cornell Medicine-New York, USA has shown that COVID-19 not only is able to trigger hyperglycemia but it also disrupts fat cells and causes decreased production of the hormone Adiponectin especially in stages of disease severity.
Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a protein hormone and adipokine, which is involved in regulating glucose levels as well as fatty acid breakdown. In humans it is encoded by the ADIPOQ gene and it is produced in primarily in adipose tissue, but also in muscle, and even in the brain.

To date it has been observed that individuals infected with SARS-CoV-2 coronavirus who also display hyperglycemia, suffer from longer hospital stays, have a higher risk of developing acute respiratory distress syndrome (ARDS) and have and increased mortality.

The study team showed that hyperglycemia is similarly prevalent among patients with ARDS independent of COVID-19 status.

Yet, among patients with ARDS and COVID-19, insulin resistance is the prevalent cause of hyperglycemia, independent of glucocorticoid treatment, which is unlike patients with ARDS but without COVID-19, where pancreatic beta cell failure predominates.

Furthermore a screen of glucoregulatory hormones revealed lower levels of adiponectin in patients with COVID-19.

Hamsters infected with SARS-CoV-2 demonstrated a strong antiviral gene expression program in the adipose tissue and diminished expression of adiponectin.

The research team also demonstrated that SARS-CoV-2 can infect adipocytes.

The study findings were published in the peer reviewed journal: Cell Metabolism.

going into the specifics of the research ….

The deadly coronavirus disease 2019 (COVID-19) pandemic is underscored by high morbidity and mortality rates seen in certain vulnerable populations, including individuals with diabetes mellitus (DM), obesity, cardiovascular disease, and advanced age, with the latter associated with many chronic cardiometabolic diseases (Drucker, 2021; Holman et al., 2020; McGurnaghan et al., 2021; Yang et al., 2021; Zhou et al., 2020).

Hyperglycemia with or without a history of DM is a strong predictor of in-hospital adverse outcomes, portending a 7-fold higher mortality compared with patients with well-controlled blood glucose levels (Zhu et al., 2020). Thus, hyperglycemia may be seen as a biomarker that predicts poor prognosis.

A retrospective study that compared patients with hyperglycemia who were treated with insulin against those who were not showed increased mortality in those receiving insulin (Yu et al., 2021). However, it remains unclear whether insulin treatment is a surrogate for severity of hyperglycemia and overall morbidity or whether it is an actual causative factor for death. There is, thus, uncertainty regarding specific treatments for hyperglycemia in acute COVID-19 (Lim et al., 2021).

Despite our early recognition of the association between hyperglycemia and perilous outcomes, the pathophysiological mechanisms that underlie hyperglycemia in COVID-19 remain undefined (Accili, 2021; Lockhart and O’Rahilly, 2020). Hypotheses have included a broad range of pathologies, such as direct infection of islets leading to beta cell failure (BCF) and systemic inflammation leading to insulin resistance (IR).

Dexamethasone substantially reduces mortality in patients with severe COVID-19 infection requiring oxygen or invasive mechanical ventilation (Horby et al., 2021). Glucocorticoids can also provoke hyperglycemia by inducing IR and beta cell dysfunction.

The widespread usage of dexamethasone in severe SARS-CoV-2 infection is expected to exacerbate both the incidence and severity of hyperglycemia in COVID-19. However, the contribution of glucocorticoids to hyperglycemia in acute COVID-19 has not been defined.

Although COVID-19 is primarily marked by a respiratory tract infection, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to infect other cell types and often leads to extrapulmonary consequences (Gupta et al., 2020; Puelles et al., 2020). For example, ACE2 and other entry receptors for SARS-CoV-2 can be expressed on pancreatic islet cells, and endocrine cells differentiated from human pluripotent stem cells are permissive to infection (Tang et al., 2021; Wu et al., 2021; Yang et al., 2020).

Early reports of unexpected diabetic ketoacidosis (DKA) in COVID-19 patients fueled concerns for a novel form of acute onset BCF. For example, one case described a patient with new-onset DKA who was found to be autoantibody negative for type 1 DM (T1DM) but showed evidence of prior SARS-CoV-2 infection based on serology results, suggesting the possibility of pancreatic beta cell dysfunction or destruction as a result of COVID-19 (Hollstein et al., 2020).

However, given the high rates of COVID-19 during this pandemic coupled with low background rates of new onset T1DM, the connection between these two events in this case could be “true, true, and unrelated.”

Recent studies disagree on whether ACE2 is expressed on pancreatic beta cells or whether the SARS-CoV-2 virus is found in pancreatic beta cells of deceased individuals with COVID-19 (Coate et al., 2020; Kusmartseva et al., 2020; Müller et al., 2021; Tang et al., 2021; Wu et al., 2021).

Conversely, the well-known connection between obesity and IR might lead to impaired immunity and more severe SARS-CoV-2 infection (Goyal et al., 2020a). In fact, population-level studies have reported a higher risk of complications in patients with obesity and COVID-19 (Barron et al., 2020; Docherty et al., 2020; Williamson et al., 2020). Viral infection may lead to systemic IR and worsened hyperglycemia. In sum, despite much attention, the pathophysiology of hyperglycemia observed in acute COVID-19 remains unknown.

In this study, we assessed the pathophysiological mechanism of hyperglycemia in acute and severe COVID-19 and analyzed protein hormones regulating glucose homeostasis.

We compared patients with COVID-19 with critically ill control patient groups (those with acute respiratory distress syndrome [ARDS] and hyperglycemia but without COVID-19) and found striking differences in the characteristics associated with hyperglycemia, further highlighting the metabolic dysfunction seen in this disease.


Here, we found that hyperglycemia is a clear and strong poor prognostic factor in COVID-19 that is associated with progression to ARDS, need for mechanical ventilation, and death. In our center, the vast majority (86%) of critically ill patients with COVID-19 and with ARDS experienced hyperglycemia.

Although this number is strikingly high, we observed an equal proportion of patients with ARDS without COVID-19 who also exhibited hyperglycemia, demonstrating the importance of a comparison group. These findings have also been borne out in other studies, although control groups were often not included, thus making it difficult to ascertain the specific effect of COVID-19 (Carrasco-Sánchez et al., 2021; Smith et al., 2021; Wang et al., 2020).

The molecular underpinnings of hyperglycemia in acute SARS-CoV-2 infection remain unclear. To address this gap, we studied patients with hyperglycemia and afflicted with severe SARS-CoV-2 infection as this group is expected to show the most dramatic metabolic effects from acute viral infection. IR is the predominant mechanism of hyperglycemia in severe COVID-19, even after accounting for glucocorticoid use.

Notably, the mechanism of hyperglycemia is different in COVID-19 compared with our two ICU control groups without COVID-19 where BCF was more common. While we did observe BCF in a minority of patients, many of them had pre-existing advanced diabetes marked by the use of two or more anti-hyperglycemic medications or insulin, or an elevated percent hemoglobin A1c (%HbA1c), signifying prior poor blood glucose control.

We also note that hyperglycemia is associated with an increased risk of mortality in both control patient groups without COVID. In contrast, the presence of hyperglycemia in patients with COVID-19 and ARDS did not portend a higher risk of death, further supporting a fundamental difference in the mechanism of hyperglycemia in COVID-19. Perhaps classifying the mechanism of hyperglycemia as IR or BCF in an individual infected with SARS-CoV-2 by insulin, C-peptide, and glucose measurements may guide glucose lowering therapy.

Insulin is the accepted treatment for hyperglycemia in hospitalized patients. Our study raises the question for patients with hyperglycemia and severe COVID-19 who display an IR phenotype, whether adding an insu

lin sensitizing medication, such as a thiazolidinedione or metformin, may increase glucose metabolism and spare insulin usage. This would need to be tested for safety and efficacy before clinical recommendations are made. Conversely, patients with COVID-19 and hyperglycemia with BCF would be treated with insulin as the mainstay, avoiding insulin sensitizing agents due to the potential for adverse effects.

Our data suggest that adipose dysfunction is a feature of COVID-19 that may drive hyperglycemia. Adiponectin and adiponectin/leptin ratios are markedly reduced in patients with severe COVID-19. There may be other hormones affecting IR and insulin secretion dysregulated in COVID-19 that were not assayed in this study. Hamsters infected with SARS-CoV-2 show the presence of SARS-CoV-2 viral RNA in the AT along with substantial decreases in Adipoq expression.

The decrease in adiponectin protein but not mRNA in the visceral fat of hamsters infected with SARS-CoV-2 suggests that there may be post-transcriptional mechanisms at play. While circulating adiponectin is decreased in both patients with COVID-19 and hamsters infected with SARS-CoV-2, circulating leptin levels are higher in patients with COVID-19 whereas Lep is decreased in the hamsters.

The hamster model may capture some but not all features of the human disease. Of note, the hamster model used in this study is comparatively mild as hamsters do not need to undergo mechanical ventilation unlike the patients with COVID-19 and ARDS. In the future, the hamster is a promising model that can be used to dissect the pathophysiological mechanisms of acute and long COVID pertaining to glucose homeostasis and diabetes.

Strikingly, both human and mouse adipocytes have relatively higher expression of TFRC, NRP1, and FURIN than ACE2 and TMPRSS2, the latter two being the better studied viral entry factors. Future studies will be needed to determine which receptor(s) SARS-CoV-2 uses to infect adipocytes.

We also find that Adipoq is decreased in mouse adipocytes following in vitro infection with SARS-CoV-2, but ADIPOQ in human breast adipocytes is not. This may be due to the fat depot origin of the cells, specific donors, or participation of other factors in vivo.

Collectively our results implicate direct viral infection of ATs as one potential mechanism for AT dysfunction and IR. While we show that adipocytes are capable of being directly infected by SARS-CoV-2, it is possible that other cell types within the adipose, such as endothelial cells and preadipocytes, may be susceptible.

Systemic inflammation in acute COVID-19 may also contribute to adipose dysfunction and IR. Diagnosing adipose dysfunction in COVID-19 by assessing circulating adipokine levels has the potential to be clinically actionable in the future as medications such as thiazolidinediones decrease AT inflammation and improve adipose function and insulin sensitivity in part through adiponectin. Whether thiazolidinediones decrease viral replication and impact future metabolic complications in survivors with COVID-19 remains an area for future research.

This study is not powered to detect rare events, nor does it rule out potential SARS-CoV-2 infection of pancreatic islet cells, but it suggests that it is not a major etiology of hyperglycemia in the majority of patients with COVID-19. Recent studies using pancreatic tissues from deceased individuals who had COVID-19 have shown that in some individuals a small minority of beta cells show signs of active viral infection (Müller et al., 2021; Tang et al., 2021; Wu et al., 2021).

Even when human islet cells are infected in vitro with SARS-CoV-2 and a higher infection rate was observed, there was only a mild (Wu et al., 2021) or no effect (Tang et al., 2021) seen in glucose-stimulated insulin secretion. Thus, viral infection of beta cells in patients may be uncommon or often subclinical.

Notwithstanding, follow-up studies on COVID survivors and those with “long COVID” are needed to monitor for future IR and BCF. Early data suggest that there may be persistent IR post-COVID-19 (Montefusco et al., 2021). It remains to be determined if patients who recovered from hyperglycemia prior to discharge will have an increased future risk of developing diabetes.


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