COVID-19-associated new-onset hyperglycaemia: a reversible entity or persistent risk?

Abstract

Newonset hyperglycaemia (NOH) in COVID-19 is a clinically and biochemically heterogeneous entity. While the clinical variations range from a predominant pattern of insulin resistance (IR) and β-cell overstimulation to a depleted β-cell reserve phenotype, differences in working definition make NOH biochemically diverse. The American diabetes association (ADA) defines NOH as fasting plasma glucose (FPG) values 100–125 mg/ dL and/or glycated hemoglobin (HbA1c) 5.7%–6.4%, without prior evidence of dysglycaemia. However, studies have used FPG≥126 mg/dL or two FPG 100–125 mg/dL and/or single plasma glucose 100–199 mg/dL. Over half a dozen viruses are known to be diabetogenic, including enteroviruses, Coxsackie virus, rubella, cytomegalovirus (CMV) and hepatitis C virus (HCV). The basis of this dysglycaemia is either cytolysis or molecular mimicry, resulting in insulinopenic diabetes. Interestingly, certain infections (CMV, HCV) portend a higher risk of T2DM, by exaggerating IR. In the previous SARS epidemic, NOH was identified as an independent risk factor for mortality, even prior to steroids with the persistence of overt diabetes in 10% of patients at 3 years followup. Genetic similarity and common receptor (ACE2) between SARSCoV-1 and SARSCoV-2 suggest that a proportion of patients with NOH in COVID-19 will have persistent hyperglycaemia. IR has been suggested as the central pathogenic mechanism of NOH, backed by observations of reduced adiponectin and improved glycaemic profile with the use of tocilizumab. Higher levels of insulin and Cpeptide in NOH during COVID-19 as compared with NOH preCOVID, also indirectly favours this hypothesis. In a study, the biochemical signature of β-cell hyperstimulation (high insulin, Cpeptide, proinsulin, homeostatic model assessment (HOMA-β, HOMAIR)) was observed, with a good correlation of HOMAIR with inflammatory scores. This suggests a synergistic IR on a background of already high IR in patients predisposed to severe COVID19. High inhospital insulin requirements (>2 units/kg/day) lend further credence to the role of IR. A cytokinemediated IR rather than stress hyperglycaemia (due to counterregulatory hormones including cortisol) is also suggested by our observation of a relative hypocortisolism in severe COVID-19. Direct viral infiltration of the islets is reported using immunofluorescence and electron microscopy techniques. Interestingly, ACE2 expression is more common in the endothelial vasculature than in β-cells. In cells that did not express ACE2, dipeptidyl peptidase type 4 was found to mediate viral entry. The role of depleted β-cell reserve is suggested by reports of autoantibodynegative, fulminant diabetes after COVID-19. Pancreatitis due to exocrine ACE2 expression has been suggested, but the real risk of this complication is, in fact, minimal (<1%). Interestingly, a high glycaemic variability (GV) has been documented in patients with COVID-19 using continuous glucose monitoring. GV is a marker of depleted β-cell reserve akin to an insulinopenic milieu in patients with T1DM as the physiological cascade requires sensing of the delta fall in insulin by the α-cells to release glucagon. Further, it can also be envisaged that the β-cell hyperstimulation seen in acute stages in response to a high IR, will ultimately result in exhaustion of reserves and persistent hyperglycaemia. Dysregulated immune response in COVID-19 may lead to the formation of antiinsulin autoantibodies, suggested by reports of type 1 diabetes mellitus (T1DM) following COVID-19 and molecular mimicry (figure 1). Oxidative stress mediates hyperglycaemiainduced endothelial injury, thrombosis and inflammation, especially in acute hyperglycaemia. Its contribution has also been suggested in COVID-19 induced NOH. Stress hyperglycaemia is an integrated neuroendocrine response, mediated by catecholamines,