A key enzyme in the renin angiotensin system (RAS), ACE converts angiotensin (Ang) I to the vasoconstrictor Ang II, which is thought to be responsible for most of the physiological and pathophysiological effects of the RAS. This classical view of the RAS was challenged with the discovery of the enzyme, ACE2, which not only degrades Ang II, but also leads to formation of the vasodilatory and anti-proliferative peptide, Ang 1–7 [8].

SARS-CoV infection is mediated by the binding of its spike (S) protein to a cellular receptor on its target cells, and a recent study proved that ACE2 is a functional receptor for SARS-CoV S protein [4, 5]. An investigation of ACE2 protein localization in 15 human organs found that ACE2 was abundant in the epithelia of lung and small intestine, where SARS-CoV might enter [9]. Another investigation of 72 human tissues by Harmer and his colleagues [10] confirmed ACE2 mRNA expression in bronchus, lung parenchyma, ileum, testis, and cardiovascular, renal, and gastrointestinal tissues, and pancreas.

The multi-system nature of SARS infection has been demonstrated in several autopsy studies [11–13]. These studies demonstrated atypical pathological changes, such as hydropic degeneration, fatty degeneration, and interstitial cell proliferation involving the liver, heart, kidney, and pancreas, in patients suspected of having died from SARS. In one study of alimentary tract and digestive glands from seven SARS autopsies, routine pathology, electron microscopy (EM), in situ hybridization (ISH), immunohistochemistry, and real-time polymerase chain reaction (PCR), found no evidence of direct viral infection in the liver or pancreas [14]. In another study of patients who died of SARS, immunohistochemistry and in situ hybridization (using a murine monoclonal antibody specific for SARS-CoV nucleoprotein and probes specific for a SARS-CoV RNA polymerase gene fragment, respectively) found SARS-CoV mainly in the lung and distal convoluted renal tubule, and to a much lesser extent in the pancreas and liver [15]. Interestingly, ACE2 mRNA was detectable at low levels in rat liver and increased following bile duct ligation (363-fold). And in healthy livers, ACE2 protein was confined to endothelial cells, occasional bile ducts, and perivenular hepatocytes but in human cirrhosis there was widespread parenchymal expression (97-fold) of ACE2 protein [16].

In this study, immunostaining for ACE2 protein was strong in the pancreatic islets but very weak in the exocrine tissues. Abundant ACE2 immunostaining was found in alveolar epithelial cells of the lung, parietal epithelial cells of the kidney, myocardium of the heart, but not in hepatocytes. These differences in ACE2 expression in different organs were consistent with our findings showing differences in survival associated with elevations in various parameters. Significant elevation in levels of AST, LDH, and s-Cr, and severe hypoxia were associated with higher death rate, which suggested SARS damaged several organs including heart, kidney, and lung. However, significant elevation of ALT, an indicator of liver damage, was not associated with higher mortality. Our results implied that the higher the level of expression, the greater the level of damage by SARS-CoV. Interestingly, hyperglycemia as another possible reason for higher death rate was supported by our idea that coronavirus acutely damaged the pancreatic islets leading to hyperglycemia. Consistent with our finding that pancreatic islets are strongly immunopositive for ACE2 while exocrine tissues are only weakly positive, there are almost no reports of pancreatitis in patients with SARS.

Many viruses (such as enteroviruses, Coxsackie B virus, retroviruses, rubella, mumps, cytomegalovirus, Epstein–Barr, and varicella zoster virus) have been implicated on the basis of temporal and geographical associations in the development of Type 1 diabetes in humans. Indeed, serological evidence of infection and isolation of viruses from the pancreas have been reported in a few cases of recently diagnosed diabetes [17, 18].

In our previous report, hyperglycemia was an independent predictor of death, and patients with even mild SARS (receiving no glucocorticoid medications during the course) had a higher level of FPG [1]. In our follow-up study, diabetes occurred during the hospitalization of 20 of 39 patients who received no corticosteroids during the course of SARS. But after 3 years of follow-up, only two of these patients had diabetes. Also after 3 years follow-up, FPG, PPG, and insulin levels were similar in the SARS group and their matched, healthy non-SARS siblings, which suggested that the damage of islets by SARS-CoV was transient.

A causal relation between varicella zoster virus and the onset of diabetes was suggested in two individuals presenting with acute insulin dependent diabetes mellitus for a brief period [19]. Both had been infected with chicken pox in the recent past. After good diabetic control had been established, insulin was withdrawn over a few weeks. Follow-up for the next two years did not reveal recurrence of diabetes.