Diabetes and COVID-19, potentialities of Morus alba L . (mulberry) and Stevia r ebaudiana Bertoni (stevia). Mini-review

Diabetes mellitus is one of the main comorbidities associated with mortality and severe disease in infections with SARS-CoV-2. Extracts from the leaves of Morus alba and Stevia rebaudiana are used in traditional medicine to control diabetes. A brief review is made of the potential of these extracts to improve the conditions associated with COVID-19, not only through the control of diabetes but also for the presence of chemical compounds, particularly ﬂ avonoids, which have shown antiviral activity in pharmacological and in silico studies.


Introduction
At the beginning of 2020, the pandemic caused by the SARS-CoV-2 virus broke out. Although the pathophysiological mechanisms of its action are not yet well defi ned, it is observed that most of the cases that result in severity or death correspond to patients with associated pathologies, such as cardiovascular diseases, diabetes mellitus, chronic lung and kidney disease, hypertension and cancer, so special attention should be paid to people with underlying conditions such as those mentioned [1,2].
Diabetes is one of the leading causes of death in the world and is associated with several macros and microvascular complications, which ultimately affect the overall survival of the patient [3]. Uncontrolled blood glucose is recognized as a signifi cant predictor of severity and death in patients infected with different viruses, including pandemic infl uenza A 2009 (H1N1) [4], SARS-CoV [5] y MERS-CoV [6]. In the current SARS-CoV-2 pandemic, some studies did not fi nd a clear association between diabetes and severe disease [7]. However, other reports from China [1,2] and Italy [8] showed that older patients with chronic diseases, including diabetes, had an increased risk of severe COVID-19 and mortality.

Mulberry in COVID-19
Mulberry (Morus alba) is a plant of Asian origin whose chemical composition there are fl avonoids with known biological activity. It is recognized as an important functional food due to the presence of bioactive compounds, including fl avonoids such as anthocyanins, rutin, quercetin, and Citation: Hernández  isoquercitrin. At least 44 fl avonoids have been isolated from 91 species and varieties of mulberry, as glycosidic and acylated derivatives, in relatively large quantities, standing out for their antioxidant potential [9]. In China, the leaves are consumed as an infusion as a healthy drink, and they have also been included in food products, supplied as healthy foods to regulate blood sugar levels, useful for controlling type 2 diabetes mellitus [10].
Multiple studies indicate that mulberry leaf extract has an important postprandial hypoglycemic effect, through the inhibition of -glucosidase and glucose transport [11]. The therefore, interrupting the progression from pneumonia to ARDS is key to lowering the death rate from COVID-19 [15].
They recommended starting with Sang Ju Yin and Xie Bai San as soon as possible, especially at the beginning of dyspnea and before ARDS, considered a critical condition, that is, for mild/ moderate cases (not for severe condition), aiming to prevent patients from progressing to severe cases. Sang Ju Yin and Xie Bai San could play a protective role before the development of ARDS, although results of clinical trials are needed to confi rm that presumption [14].

Stevia in COVID -19
The consumption of foods low in sugar has become a fastgrowing trend worldwide. In this sense, Stevia rebaudiana is positioned as a source of high-potency sweetener, which produces a sweet taste without adding caloric value. More than 40,000 clinical studies have been conducted in Japan showing that steviol glycosides are safe when used as sweeteners [16].
Non-nutritive sweeteners are sugar substitutes that have zero calories and do not raise blood glucose levels. They may be the preferred option for reducing carbohydrate and calorie intake in people with diabetes [17], being the indirect way in which steviol glycosides reduce postprandial blood glucose concentrations: displacing sucrose or other carbohydrates ( [18]. However, some preclinical and clinical studies for steviol glycosides suggest a possible independent effect of reducing postprandial blood glucose concentrations, increasing insulin secretion, and improving insulin sensitivity in subjects with diabetes, with some mechanistic evidence for these effects, which appear to involve insulin secretion, signalling, and release; positive regulation of key genes and improved glucose uptake. Additional clinical studies are needed to clarify and confi rm these fi ndings [19].
For stevia extracts also are reported benefi ts as antioxidants and blood pressure reducers. In addition to steviol glycosides, this plant contains several phytochemicals, including phenols and fl avonoids [20]. The aforementioned properties allow the use of the aqueous and alcoholic extracts of this plant and the steviol glycosides in herbal medicines for diabetic patients as a pharmacological alternative, which makes them potentially valuable in order to reduce the risk of severity and death from COVID -19 [16].
Crude extracts of S. rebaudiana leaves showed a very potent radical scavenging activity towards reactive oxygen species and reactive nitrogen species. This could explain why raw leaf extracts were more effi cient in the care of type 2 diabetes, as shown by Ferreira, et al. [21].
So far there are few reports linking the use of stevia with benefi cial effects to counteract the harmful effects of COVID -19. COVID-19 is related to an imbalance of radicals and antioxidants [22], it could be successful to evaluate the effects of steviol glycosides and raw stevia extracts, which have much better radical scavenging activity than vitamin C [23,24]. The presence of steviol glucuronide in the blood has been reported after consuming stevia or steviol glycosides, a metabolite capable of capturing radicals in different organs of the human body, also taking into account that its level in the blood is suffi ciently high (± 5 μM to 20 μM) and can be increased by doubling the intake. The raw extract of stevia leaf could be even better since the antioxidant activity of the leaf extract cannot be totally related to the steviol glycosides, some different compounds such as phenols and fl avonoids present in the crude extract are effective antioxidants [22] . isorhamnetin and their derivatives, as well as epigallocatechin gallate gallocatechin-7-gallate, have also been reported in mulberry leaves [10].

Conclusions
Mulberry and stevia are plants that contain components that are used effectively for the treatment of one of the most dangerous comorbidities in COVID-19, diabetes. In addition, they contain compounds that can reduce infection with SARS-CoV-2 and potentially prevent the evolution towards the