**1. Introduction**

Diabetes mellitus (DM) is a chronic metabolic and degenerative disorder that is characterized by chronic hyperglycemia and causes long-term complications like retinopathy, neuropathy, and nephropathy, generally accelerating macro- and micro-vascular changes. It is becoming one of the largest emerging threats to public health in the 21st century [1,2]. Several immune alterations have been described in diabetes with cellular immunity being more compromised and with changes in polymorphonuclear cells, monocytes, and lymphocytes [3]. DM individuals have higher glucose serum concentrations than healthy individuals (between 4.0 to 5.4 mmol/L or 72 to 99 mg/dL when fasting and up to 7.8 mmol/L or 140 mg/dL two hours after eating [4]; hemoglobin A1c (glycohemoglobin) ≤5.7%). In type 1 DM, the pathogenesis is multifactorial because of antibody-mediated autoimmunity, environmental toxins exposure, and major histocompatibility complex (MHC) Class II histocompatibility complex HLA-DR/DQ genetic polymorphisms. These features create an increased susceptibility to disease onset due to a continuous loss of insulin-producing β-cells in the pancreas, which is due to the T-cells' infiltration through mitochondrial-driven apoptosis [5]. On the other hand, in type 2 DM, there is an insulin resistance that is associated with changes in the mitochondrial metabolism with reduced mitochondrial density, ATP production, and mitochondrial RNA (mtRNA) levels, as well as increased markers for oxidative stress. The chronic

exposure of the circular mtDNA to these effects might trigger significant tissue modifications found in the pancreas and endothelial cells, leading to secondary vascular disease and causing cardiac, renal, ophthalmic, and neurological complications [5–7] (Figure 1).

**Figure 1.** Main diseases related to *Candida* sp. occurring with higher incidence in patients with diabetes mellitus type 1 or type 2 (adapted image from GraphicsRF on stock.adobe.com).

In 2017, the worldwide prevalence of adult-onset diabetes (20–79 years) was nearly 425 million, and the World Health Organization and the International Diabetes Federation predicted that the number of adults in the world with diabetes will rise near 629 million by the year 2045 [8,9] (Figure 2). A higher prevalence of DM, cardiac, and pulmonary diseases can be found in senior patients with candidemia [10–13]. The relationship between diabetes and candidiasis has been widely studied [13–16], particularly due to the increased susceptibility of diabetic patients to fungal infections compared to those without DM [14,15,17,18].

Several mechanisms are attributed to higher *Candida* sp. predisposition among DM patients depending on the local or systemic infection. Among the recognized host conditions for candidal colonization and subsequent infection are yeas<sup>t</sup> adhesion to epithelial cell surfaces [19], higher salivary glucose levels [15,20], reduced salivary flow [21], microvascular degeneration, and impaired candidacidal activity of neutrophils. These conditions are particularly serious in the presence of glucose [22,23], secretion of several degradative enzymes [24–26], or even a generalized immunosuppression state of the patient [8,27–31]. These factors have a major influence on the balance between host and yeasts, favoring the transition of *Candida* sp. from commensal to pathogen and causing infection. In fact, in a very recent study, Gürsoy et al. [32] suggested that there is a higher presence of intestinal *Candida albicans* colonization in diabetic patients. In fact, there may be a tendency of type 1 DM in patients with a high prevalence of intestinal *C. albicans*. *C. albicans* is also known to wait for a change in some aspect of the host physiology that normally suppress growth and invasiveness through a phenomenon called phenotypic switch system or white-opaque transition, described in 1987.

**Figure 2.** The estimated number of people with diabetes worldwide and per region in 2045 between 20–79 years in age, with a total of 629 million (source: International Diabetes Federation) (adapted image from GraphicsRF on stock.adobe.com).

This involves reversible and heritable switching between alternative cellular phenotypes. It occurs at sites of infection and recurrently in episodes of infection in certain cases in diabetic patients [33].

Yeasts are part of the normal gu<sup>t</sup> microflora, but cell counts do not normally surpass 10 colony forming units (CFU)/g feces [34,35]. Nevertheless, it has been described that *Candida* sp. is more widespread in the feces of patients with type 1 and type 2 DM with poor glycemic control as opposed to healthy subjects [36]. The main reasons for this colonization seem to be altered functions of the immune system in diabetic patients with poor glycemic control or a direct effect of elevated blood glucose levels, creating specific conditions for intensive fungal colonization [36]. In fact, another report [37] showed that in patients with type 1 DM, the total gu<sup>t</sup> CFUs significantly rise up to 40% in *C. albicans* colonization compared to 14.3% in healthy individuals. This may be related to the decrease in commensal bacteria-probably the result of yeast-bacterial competition. Also, this higher growth may disrupt the ecological balance of intestinal flora, which occurs in type 1 DM [37]. Regarding the gastrointestinal colonization, Kowalewska et al. [38] studied the serum levels of interleukin-12 (IL12) in relation to the percentage of yeast-like fungi colonies residing in the gastrointestinal tract in children and adolescents with DM type 1. Results showed that high IL12 levels can inhibit infection with yeast-like fungal colonizing the gastrointestinal tract in children and adolescents with type 1 DM. However, further studies are needed to confirm the antifungal activity of IL12 [38].

The development of drug resistance among *Candida* sp. isolates allied to epidemiologic variations in *Candida* sp. natural flora has significant implications for morbidity and mortality [39–42]. The extensive use of medications, especially azoles, has promoted the selection of resistant species by shifting colonization to more naturally resistant *Candida* sp., such as *C*. *glabrata*, *C. dubliniensis*, and *C. krusei* [43–46]. Presently, the world distribution of *Candida* sp. is a feature of the epidemiology in the area, but it indicates a predominance of *C. albicans*, *C. glabrata*, *C. tropicalis*, *C. parapsilosis*, and *C. krusei* [45,47]. It has been confirmed that 90% of fungemia cases are attributed to *Candida* sp. [39,40], and the mortality has ranged from 40% to 80% in immunocompromised hosts [39,40,48]. Furthermore, a high mortality rate was also detected among non-immunocompromised patients (60%) [49] and those with diabetes (67%) [41].

The main pathophysiologic and nutritionally relevant sugars in diabetic patients are glucose and fructose, but other simple carbon sources also play an important part in the growth of *Candida* sp. in DM patients. Man et al. [50] evaluated the growth rate of *C. albicans* in the presence of different concentrations of glucose and fructose to obtain a better understanding of the nutrient acquisition strategy and its possible relation to the hyperglycemic status of diabetic patients. The authors determined that the glucose concentration is directly related to *C. albicans* growth, which may be linked to the frequent yeas<sup>t</sup> infections that occur in non-controlled diabetic patients. Interestingly, fructose showed *C. albicans* inhibition capacities. This implies fructose-containing food may prevent the development of candidiasis. This is an important outcome in oral *Candida* sp. biofilms, especially for patients who use prosthesis [50]. In fact, other carbon compounds such as sucrose, maltose, and lactose increase the fungal population density [43,51,52] and decrease the activity of antifungal agents. A recent report explored the effects of glucose in diabetic mice on the susceptibility of *Candida* sp. to antifungal agents [53]. In that work, Mandal et al. [53] revealed that voriconazole (Vcz) has the greatest reduction in antifungal drug efficacy followed by amphotericin B (AmB). Glucose displayed a higher affinity to bind to Vcz through hydrogen bonding, decreasing the susceptibility of antifungal agents during chemotherapy. Additionally, Mandal et al. [53] confirmed that Vcz presented three important hydrogen bonds and AmB presented two hydrogen bonds that stabilized the glucose. In vivo results of the same study proposed that the physiologically relevant higher glucose level in the bloodstream of mice with DM might interact with the available selective agents during antifungal therapy, decreasing glucose activity by complex formation. Vcz-glucose and AmB-glucose complexes seem to present less effectiveness as their pure molecule. Accordingly, a proper selection of drugs for DM patients is important if we are to control infectious diseases [53]. Similarly, Rodaki et al. [54] studied the impact of glucose on *C. albicans* transcriptome for the modulation of carbon assimilatory pathways during pathogenesis. The elevated resistance to oxidative and cationic stresses and resistance to miconazole uncovered that glucose concentrations in the bloodstream have a significant impact upon *C. albicans* gene regulation. No significant susceptibility level was perceived for anidulafungin, while Vcz and AmB became less effective [54]. In another study, Rodrigues et al. [52] demonstrated that *C. glabrata* decreases its susceptibility to fluconazole when cultured in a medium enriched with glucose [52].

Accordingly, the aim of this review is to analyze the literature related to the occurrence of candidiasis in diabetic patients by discussing specific features of *Candida* sp. that relate directly to the occurrence of candidiasis in DM patients and related diseases, as well as by reviewing recent and relevant studies on the topic.

#### **2. Particular Features of** *Candida* **sp. that Increase the Incidence of Candidiasis in Diabetic Patients**
