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Anosmia and dysgeusia amongst COVID‐19 patients are associated with low levels of serum glucagon‐like peptide 1

Abstract Purpose Anosmia and dysgeusia (AD) are common amongst COVID‐19 patients. These symptoms are not frequently associated with rhinorrhea or nasal congestion and the underlying mechanism is unclear. Previous reports suggested that glucagon‐like peptide‐1 (GLP‐1) signalling plays a role in the modulation of olfaction and ageusia. We aimed to assess the correlation between GLP‐1 and COVID‐19‐associated AD. Methods Blood samples obtained from COVID‐19 patients with and without AD were tested for serum GLP‐1 levels using enzyme‐linked immunosorbent assay (ELISA). A second control group comprised of COVID‐19‐negative volunteers. Results Forty‐nine subjects were included in the study. Nineteen were positive for COVID‐19. Of the 19 patients, 10 had AD and 9 declined such complaints. Age and basic metabolic rate were similar amongst all study groups. Serum GLP‐1 levels were significantly lower amongst patients with AD compared with patients without AD and COVID‐19‐negative individuals (1820 pg/mL vs 3536 pg/mL vs 3014 pg/mL, respectively, P < .02). Conclusion COVID‐19 patients who reported AD had lower serum levels of GLP‐1 compared with those lacking AD symptoms and COVID‐19‐negative individuals. These results suggest that GLP‐1 may be involved in the pathogenesis of AD. However, further larger scale studies should corroborate our findings.

activity is regulated by the enzyme dipeptidyl-peptidase-4. The taste cells, particularly L cells, produce GLP-1 amongst other hormones. 6 Several reports suggest that GLP-1 functions as a neurotransmitter mediating taste and olfaction. 5,7,8 Mice lacking the GLP-1 receptor have significantly reduced taste sensitivity to sweeteners. 7 Pre-proglucagon (the precursor of GLP-1) and GLP-1 receptor mRNAs have been identified in cell layers in the olfactory bulb suggesting that GLP-1 may mediate information flow from the olfactory epithelium to the brain. 8 In view of its role in the modulation of gustatory and olfaction functions, we aimed to examine the association between serum GLP-1 levels amongst COVID-19 patients reporting AD vs patients and COVID-19-negative individuals with intact olfaction and taste.   Table 1. None of the patients with AD had rhinitis or rhinorrhea.

| RE SULTS
Age and BMI did not significantly differ between groups. The median age of patients in groups A, B and C were 52 (range 34-62), 64 (range 40-80) and 60 years (range 40-69), respectively (P = .06); with male predominance (57.1%) in all groups. Height and weight data were missing in five subjects. COVID-19 patients were more obese than COVID-19 negative controls (Table 1).
Type 2 diabetes mellitus was reported in 22.2% (2/9) of patients in group A, 40% (4/10) in group B and 3.3% (1/30) in group C (Table 1). One diabetic patient with intact olfaction and ageusia was treated with GLP-1 receptor analogue (liraglutide). Prevalence of co-morbidities aside of diabetes (including primary hypertension, hypothyroidism and hyperlipidemia) was similar amongst groups A and B (Table 1).  Abbreviations: AD, anosmia/dysosmia and dysgeusia; SD, standard deviation; T2DM, type 2 diabetes mellitus. a A significant difference was detected between groups B and C with regard to the prevalence of diabetes (P = .01).
b Other common comorbidities included hypertension, hypothyroidism and hyperlipidemia.
The mean serum GLP-1 levels amongst group A patients were significantly lower compared with GLP-1 levels in groups B and C (1820 ± 226 pg/mL vs 3536 ± 449 pg/mL and 3014 ± 161 pg/mL, P < .002, respectively) ( Figure 1). Serum GLP-1 levels amongst groups B and C were similar (P = .65). GLP-1 levels were also found significantly low amongst group A patients vs groups B and C after adjustment to age, sex, diabetes and BMI (P = .02). No correlation was found between the severity of disease and serum GLP-1 levels. Prevalence of smell and/or taste impairment is high amongst COVID-19 patients. 2,[9][10][11] A proposed mechanism for this chemosensitive dysfunction was local inflammation and cytokine release in the oral and olfactory mucosa induced by SARS-CoV-2 tissue invasion. 12 The high expression of ACE2 in the oral mucosa, especially the tongue and taste buds as well as the nasal cavity olfactory epithelium, supports this notion. 3,13 However, this theory is questionable in mild COVID-19 cases, where the inflammatory response is less robust and rhinorrhea or nasal congestion are absent. 14 Indeed, these symptoms were not commonly reported in our cohort.

| D ISCUSS I ON
Others suggested that the interaction of SARS-CoV-2 with sialic acid receptors on taste buds impairs vital components of the salivary mucin. Reduced sialic acid in the saliva may accelerate the degradation of the gustatory particles. 12,15 However, this does not explain dysosmia.
Our findings may point to another intriguing mechanism of AD, which may be related to the gut hormone GLP-1. 5 Aside from its major role as an incretin, enhancing insulin secretion and maintaining energy homeostasis, GLP-1 has been reported to carry out protective and regulatory effects in numerous tissues, including heart, adipose, muscles, bones, kidneys, liver, lungs and brain as well as the olfactory epithelium and the taste buds on the tongue. 16,17 In fact, it functions as a neurotransmitter, coordinating communication between the peripheral organs and the brain. 5,18,19 GLP-1 modulates taste sensitivity and affects taste preferences. 5,18,19 Expression of GLP-1 was reported in two populations of taste cells (Type II and   III cells), and its receptor has been identified in taste nerve fibres in mice and rodents. 18  In summary, our preliminary findings point to a possible mechanism by which decreased GLP-1 may be involved in the impairment of olfaction and ageusia amongst COVID-19 patients. Further research is required to conclude a causal association.

CO N FLI C T O F I NTE R E S T
None to declare.

CO D E AVA I L A B I LIT Y
Not applicable.

CO N S E NT TO PA RTI CI PATE
All study patients signed an informed consent permitting the collection of blood samples for research purposes.