**2. Pathophysiology of T2D and COVID-19**

There has been some insight into the pathophysiological mechanisms of COVID-19 infection and diabetes, but much remains to be investigated. The SARS-CoV2 utilizes angiotensin converting enzyme 2 (ACE2) to gain entry into infected cells and reduces expression of ACE2, and over activation of renin angiotensin aldosterone system (RAAS) is proposed to contribute to adverse effects in patients with diabetes (PWD) and COVID-19 infection [3].

Mechanisms accentuated in PWD include increased inflammatory cytokines, increased lipopolysaccharides, and increased RAAS (angiotensin 2) which results in vascular endothelial damage, increased ROS and IL-6 in increased insulin resistance (due to exaggerated angiotensin 2 activity) which results in hyperglycaemia [4]. There is increased blood viscosity due to increased fibrinogen and d-dimer [4].

The S1 spike protein of SARS-Cov2 is predicted to bind to DPP4 which may facilitate epithelial infection [1, 5].

It has been noted that infection with SARS-Cov-2 virus results in damage to pancreatic beta-cells [6]. Apart from COVID-19 related impaired insulin production [7], COVID-19 can cause insulin resistance due to activation of integrated stress response (ISR) initiating serine/threonine kinases which can induce IRS-1 serine phosphorylation. Hence, patients with COVID-19 infection can present with hyperglycaemia for the first time and may require insulin for insulin naïve patients or the one on insulin may have increased requirements [8].

Patients with type 2 diabetes (T2D) have a dysregulated immune response with higher ratio of lymphopenia, and increased levels of neutrophils, CRP and IL-6 have been noted in PWD with COVID-19 infections. T2D is associated with activation of the RAAS in different tissues [3]. In PWD pulmonary dysfunction has been reported involving changes in lung volume, lung diffusing capacity, ventilation, bronchomotor tone and neuroadrenergic bronchial innervation [3].

Increased metabolic rate, dysregulation of glucose metabolism, aggravation of inflammation and immune modulation result in increased oxidative stress, cytokine production, endothelial damage, increased glucotoxicity which ultimately can result in increased severity of COVID-19 and rapid progression of cardiorespiratory failure [4].

#### **3. Clinical manifestations**

The most common symptoms of COVID-19 infection are fever, cough [9], fatigue and shortness of breath [10]. Other symptoms such as sore throat, rhinorrhoea, ageusia, anosmia, vomiting and diarrhea have also been reported [11]. An observational study noted that male patients were more vulnerable than female patients to COVID-19 infection [9]. Common comorbidities include diabetes mellitus, hypertension obesity and cardiovascular disease [10].

Multiple comorbidities are associated with more severe disease and higher mortality [9]. Patients with T2D are more likely to develop severe COVID-19 infection as compared with patients without diabetes [12]. An increased prevalence of chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD) has been noted in patients with T2D and COVID-19 infection [11]. COVID-19 infection may result in severe insulin resistance and insulin deficiency precipitating diabetic ketoacidosis (DKA) in patients with T1DM and not commonly but still possible in T2DM, result in new onset diabetes, or in PWD result in new or increased insulin therapy at times with very high dose requirements. Dexamethasone therapy which has been found to be beneficial in COVID-19 infection, can result in further hyperglycaemia and has the potential of precipitating Hyperosmolar hyperglycaemic state (HHS) and DKA [7]. Regular monitoring of capillary blood glucose (CBGs) is warranted for inpatients. As hyperglycaemia with ketosis may occur in COVID-19 infection, ketones should be checked in all patients with diabetes initially or if CBG > 12 mmol/L [13].

Laboratory findings include lymphopenia, thrombocytopenia, raised CRP, raised ALT and other markers of inflammation such as ferritin [10]. Compared with patients without diabetes, patients with T2DM were found to have a higher ESR, CRP, IL-6, TNF-α and procalcitonin but lower lymphocyte and T lymphocyte subsets [12]. HbA1C, IL-6 and lymphocyte count have been proposed as risk factors for the severity of COVID-19 infection and T2DM [12]. CT scan changes are common and include ground glass abnormalities, lung lesions and enlargement of lymph nodes [10].
