**4. Discussions**

Three of our selected studies [63,65,67] were held in India, with a similar number of participants (60–120) and similarly composed groups of study, classified by periodontal status, but with the first two not mentioning their age. All the Indian studies used plasmatic measurement of vitamin C and they also had in common a finding regarding the lower plasmatic levels of ascorbic acid in periodontitis and diabetic patients than periodontitis nondiabetic patients. Four of our six eligible studies [63–65,67] excluded patients with any systemic disorder (other than the groups with type 1 or type 2 DM), those with presence of any disease that may alter the immune system (bacterial or viral infections, hypercholesterolemia, cardiovascular events), those who had been treated with any dietary supplements, antibiotics, and anti-inflammatory drugs in the previous 6 months, those with history of smoking or tobacco consumption, those with history of using any mechanical or chemical aids for plaque control (mouthwashes) and pregnan<sup>t</sup> subjects. On the other hand, two studies included smokers (for example, Gumus et al. [66] recorded patients' smoking history), one of them targeting the

smoking population to shape a conclusion (Amaliya et al. [68] included 26 heavy smokers of which the number of cigarettes per day ranged from 15 to 24 and 19 light smokers who smoked on average 8 cigarettes per day), but fulfilled the other exclusion criteria present in all the mentioned studies.

An interesting conclusion was presented in Amaliya et al.'s [68] study, referring to vitamin C as an important prophylactic and protective measure, especially in malnourished people with both DM and PD, even though they included heavy smokers with high exposure to ROS. Their results were based on the intake of about 400 mg vitamin C daily, for at least one month, by consuming approximately 30 guava fruits, a specific diet for people living in Purbasari Tea Estate in West Java, Indonesia [68]. On the contrary, Gumus et al. only supported a difference between diabetic patients regarding the evolution of PD by mentioning that subjects with type 2 DM had fewer teeth and more sites with probing depths >4 mm than patients with type 1 DM. In this study, vitamin C and the total antioxidant capacity did not appear to play a significant role in the pathogenesis of PD–DM [66].

Individuals afflicted with DM and PD may also exhibit a decrease in vitamin C concentration through a confounding factor, depression. Depression often complicates the managemen<sup>t</sup> of other conditions (cancer, diabetes, myocardial infarction, severe trauma) or can occur secondary to other diseases such as inflammatory conditions, Parkinson's disease and hypothyroidism [69].

Some articles demonstrated the association between poor vitamin C and increased depression symptoms [70,71], between DM and depression [72] and between severe PD [73] and depression. Studies have shown that depression is a consequence of inadequate levels of ascorbic acid [74]. More, vitamin C can reduce the problems associated with depression [75]. Depression prevalence is two to three times higher in patients with DM, with some cases remaining underdiagnosed [76]. Depression is also a risk factor for PD [77–79]. This is the reason some future research must be done to minimize the influence of this confounding factor and evaluate its strength using different questionnaires [80,81].

Several recent reviews analyzed the role of vitamin C in the pathophysiology of periodontal tissue damage [10,54,82,83].

Kaur et al. and Muniz et al. pointed out the beneficial effects of ascorbic acid as a dietary antioxidant on PD managemen<sup>t</sup> in the context of the established link between PD and oxidative stress. They implied that, as a complementary treatment for PD, the use of an antioxidant has the potential to improve periodontal clinical parameters [82,83].

In 2018, Varela-Lopez et al. [10] performed a systematic review of human and animal studies, and they concluded that vitamin C may be useful for prevention or improvement of PD. They also emphasized the need for more research to clarify dosages and taking frequency of ascorbic acid supplementation.

In a systematic review from 2019, Tada and Miura [54] highlighted the effects of vitamin C on the prevention of incidence and the development of PD. The authors observed proof of the association between vitamin C, PD and DM which suggests a complex mechanism of action between ascorbic acid and the two disorders that requires further study.

In our analysis, decreased levels of vitamin C were observed in PD patients with DM but data about efficacy of vitamin C administration are few and inconclusive. Perhaps larger doses administered over a longer period of time are needed, especially for periodontitis patients with uncontrolled type 2 DM.

To our knowledge, this is the first systematic review to assess and summarize the current outcomes on the correlation between ascorbic acid levels and PD–DM interaction. There are limitations to the present study because of the heterogeneity of the included studies' methodology. The findings of our review reflect different outcomes because of the different experimental designs.
