Edited by: Ioan Andrei Veresiu, Iuliu Haţieganu University of Medicine and Pharmacy, Romania
Reviewed by: Federico Biscetti, Catholic University of Sacred Heart, Italy; Mohd Ashraf Ganie, Sher-I-Kashmir Institute of Medical Sciences, India
This article was submitted to Diabetes, a section of the journal Frontiers in Endocrinology
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Diabetes mellitus (DM) is associated with several microvascular and macrovascular complications, such as retinopathy, nephropathy, neuropathy, and cardiovascular diseases. The pathogenesis of these complications is complex, and involves metabolic and hemodynamic disturbances, including hyperglycemia, insulin resistance, dyslipidemia, hypertension, and immune dysfunction. These disturbances initiate several damaging processes, such as increased reactive oxygen species (ROS) production, inflammation, and ischemia. These processes mainly exert their damaging effect on endothelial and nerve cells, hence the susceptibility of densely vascularized and innervated sites, such as the eyes, kidneys, and nerves. Since the oral cavity is also highly vascularized and innervated, oral complications can be expected as well. The relationship between DM and oral diseases has received considerable attention in the past few decades. However, most studies only focus on periodontitis, and still approach DM from the limited perspective of elevated blood glucose levels only. In this review, we will assess other potential oral complications as well, including: dental caries, dry mouth, oral mucosal lesions, oral cancer, taste disturbances, temporomandibular disorders, burning mouth syndrome, apical periodontitis, and peri-implant diseases. Each oral complication will be briefly introduced, followed by an assessment of the literature studying epidemiological associations with DM. We will also elaborate on pathogenic mechanisms that might explain associations between DM and oral complications. To do so, we aim to expand our perspective of DM by not only considering elevated blood glucose levels, but also including literature about the other important pathogenic mechanisms, such as insulin resistance, dyslipidemia, hypertension, and immune dysfunction.
Diabetes mellitus (DM) is defined as a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both (
Complications of DM can be divided into acute and chronic complications (
Hyperglycemia is the clinical characteristic that is used to define a patient with DM. However, several other—often intertwined—pathogenic mechanisms that characterize DM are also recognized:
Pathogenesis of diabetic complications. The figure presents the pathogenic mechanisms of diabetes mellitus (DM; red block, section Pathogenic Mechanisms of Diabetic Complications of main text) that cause microvascular complications (blue block) and macrovascular complications (yellow block). Destruction of pancreatic B cells in T1DM and insulin resistance in T2DM result in hyperglycemia. The resulting increase of intracellular glucose in microvascular target cells, such as capillary endothelial cells, causes ROS production in the mitochondria, activating four pathogenic downstream pathways: polyol pathway, AGEs & RAGE pathway, PKC pathway, hexosamine pathway (section Hyperglycemia of main text). Especially in T2DM, insulin resistance and the abundance of (visceral) adipose tissue result in an excess flux of free fatty acids (FFAs), which are oxidized in the mitochondria of macrovascular endothelial cells. This causes activation of the same pathogenic pathways, and downregulation of protective enzymes such as eNOS and prostacyclin synthase. Pathway-selective insulin resistance also contributes to microvascular complications (section Insulin Resistance of main text). Moreover, insulin resistance and circulating FFAs result in dyslipidemia, contributing to both micro- and macrovascular complications (section Dyslipidemia of main text). Hypertension contributes to the harmful processes by activating endothelial cells, inducing a cellular inflammatory response and reducing the availability of nitric oxide, causing vasoconstriction (section Hypertension of main text). All these processes mainly exert their harmful effects by upregulation of a pro-inflammatory state at vulnerable sites. Together with an impaired immune response and consequently higher susceptibility for infections, this immune dysfunction plays a pivotal role in the development of diabetic complications (section Immune Dysfunction of main text). Possible oral complications that are discussed in this review are listed in the green block at the bottom of the figure (section Potential Oral Complications of Diabetes Mellitus of main text). eNOS, endothelial Nitric Oxide Synthase; FFAs, Free Fatty Acids; GAPDH, Glyceraldehyde 3-phosphate Dehydrogenase; GBM, Glomerular Basement Membrane; PKC, Protein Kinase C; (R)AGEs, (Receptor for) Advanced Glycation End products; ROS, Reactive Oxygen Species.
Hyperglycemia is a key determinant for the development of complications in patients with T1DM or T2DM (
Despite the fact that each cell in the body is exposed to hyperglycemia, the damaging consequences mainly concern the endothelial cells and peripheral nerve cells (
Normally, the
The non-enzymatic formation of
Intracellular hyperglycemia also causes activation of
In the healthy situation, intracellular glucose is mainly metabolized through glycolysis. However, in a state of hyperglycemia, part of that glucose is diverted into another pathway known as the
Throughout this report, we will refer to these processes as
The second mechanism that is involved in chronic diabetic complications is insulin resistance. As its name already implies, insulin resistance is characterized by a reduced sensitivity of body cells to the actions of insulin. Since insulin resistance is closely related to obesity, it is more common in patients with T2DM, where it is an important cause for hyperglycemia. Besides its effect on blood glucose levels, insulin resistance also causes an excess flux of free fatty acids (FFAs) from adipose tissue into the bloodstream. This in turn increases the production and release of very low-density lipoprotein (VLDL) in the liver, resulting in a dyslipidemia (
In contrast to the macrovascular endothelial cells, FFA oxidation is not increased in microvascular endothelial cells in case of insulin resistance (
Already announced in the insulin resistance section, dyslipidemia is the third pathogenic mechanism that plays a role in the development of diabetic complications. Dyslipidemia is more common in T2DM than in T1DM, and is typically characterized by high levels of triglycerides and small dense low density lipoprotein (sdLDL) cholesterol particles, in combination with low levels of high density lipoprotein (HDL) cholesterol (i.e., the “lipid triad”) (
Hypertension, the fourth mechanism contributing to diabetic complications, is more common in patients with DM compared to the general population (
As we have shown in
The immune dysfunction characterizing DM also manifests itself as a chronic pro-inflammatory state (
Finally, immune dysfunction itself can be one of the causes of DM as well, since we know that T1DM is a form of diabetes that is caused by autoimmune destruction of pancreatic β cell. These patients are also susceptible to develop other autoimmune diseases: Graves' disease, Hashimoto's thyroiditis, Addison's disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia (
The previous section explained that chronic complications of DM are the result of persistent metabolic and hemodynamic disturbances that mainly target endothelial cells, typically affecting specific regions in the body. It has been proposed in literature that the oral cavity of patients with DM might be one of those regions, with an increased susceptibility for oral complications as a result (
Oral complications of diabetes mellitus.
Periodontal disease can be subdivided into
Periodontal disease is the result of an aberrant inflammatory host response to the biofilm that resides around the teeth. In some susceptible subjects, an initial gingivitis can progress into chronic periodontitis (
Periodontal disease has been linked with DM for a long time. Since Loë suggested to consider periodontal disease as the sixth complication of DM in 1993 (
Many cross-sectional studies show an increased prevalence of periodontitis in patients with DM. However, longitudinal studies are relatively scarce, even though these studies are necessary for establishing causal relationships. An important source of evidence is the research conducted with the Pima Indians in the 1990s, a population with one of the highest T2DM prevalence in the world. Indeed, diabetic subjects within this population displayed an increased prevalence of periodontal disease (
The majority of studies used the former classification of chronic periodontitis or at least did not specify the presentation of the disease. Since a new classification and case definition for periodontitis has recently been proposed, we decided not to distinguish different types of periodontitis in relation to DM in this review (
From an epidemiologic point of view, DM has an adverse effect on periodontal health. A limited number of longitudinal studies even indicate a possible causal relationship. However, the biologic mechanisms behind this relationship are still not completely understood. Several studies do show pathologic changes in the gingival vasculature of patients and animals with diabetes, compared to control subjects without DM. Examples are basement membrane thickening, angiogenesis, and an increase in osmotic tissue pressure (
As we discussed earlier, poor glycemic control increases the risk for periodontitis in patients with DM, and improvement in HbA1c levels reduces periodontal inflammation (
Of the downstream effects of hyperglycemia (
There is limited evidence that the
Analysis of periodontal pocket depth in a large population without DM showed an independent association with our second pathogenic mechanism; insulin resistance. However, the association was interpreted as periodontal inflammation being a risk factor for insulin resistance, rather than the other way around (
The independent effect of lipid dysregulation on periodontal health has been studied in several populations without DM (
It is hypothesized that hypertension is associated with periodontal disease, although the majority of studies interpret this relationship as periodontitis being a risk factor for hypertension through inflammation (
As we stated in the background section, periodontitis is a chronic disease characterized by an aberrant inflammatory host response to the biofilm. However, in patients with DM, this pro-inflammatory state seems to be even more exaggerated. PMNs, but also monocytes and macrophages, produce more inflammatory mediators and ROS, which could contribute to tissue destruction in periodontal disease (
We discussed before that patients with DM are susceptible for opportunistic infections because of an impaired innate and adaptive immune response. In the case of periodontitis, especially the PMN response seems to be impaired, characterized by reduced chemotaxis (
Overview of studies investigating the association between diabetes mellitus and periodontal disease.
Chavarry et al. ( |
49 cross-sectional studies (17 on T1DM [ |
Systematic review with meta-analysis | T2DM increased the risk for development and progression of periodontal disease. The meta-analysis revealed statistically significant mean differences in pocket depth (0.46, 95% CI: 0.01–0.91) and clinical attachment loss (1.00, 95% CI: 0.15–1.84) when comparing patients with T2DM and healthy controls. The positive mean differences indicated more periodontitis. This could not be established for patients with T1DM. | |
Chiu et al. ( |
Group 1: Patients without DM (FPG < 100 mg/dL) ( |
Prospective cohort study | After correcting for all possible confounding factors, patients with (pre-diabetes had a higher incidence of periodontal disease (community periodontal index [CPI] of 3 [a 4–5 mm pocket] or 4 [a pocket ≥6 mm]) compared to subjects with normal FPG levels at baseline. | |
Demmer et al. ( |
Group 1: Diabetes free subjects ( |
Prospective cohort study | Patients with uncontrolled T2DM had a significant higher increase in pocket depth over 5 years, compared to the healthy subjects. Patients with either uncontrolled T1DM or T2DM had significant higher increase in attachment loss over 5 years, compared to diabetes free subjects. | |
Jimenez et al. ( |
Group 1: Patients with T2DM (self-reported; |
Prospective cohort study | Patients with T2DM had an adjusted 29% greater risk of developing periodontitis, compared to patients without DM (HR = 1.29; 95% CI:1.13–1.47). | |
Löe ( |
Group 1: Pima Indians with T2DM ( |
Retrospective cohort study | Both prevalence and incidence were increased in patients with DM, compared to the control subjects. Furthermore, in the subjects with DM, a higher prevalence of edentulism was found, which also increased with a longer duration of the diabetic conditions. | |
Nelson et al. ( |
Group 1: Pima Indians with T2DM ( |
Cohort study | Both incidence and prevalence of periodontal disease was higher in patients with DM, compared to subjects without DM, after correction for age and gender. They conclude that periodontal disease should be considered as a non-specific complication of T2DM. | |
Taylor et al. ( |
Group 1: Patients with poorly controlled T2DM (HbA1c ≥9.0%) ( |
Retrospective cohort study | Patients with poorly controlled DM had a greater risk for alveolar bone loss progression. Also, this progression was more severe in patients, compared to controls. | |
Kador et al. ( |
Group 1: Control rats ( |
Longitudinal animal study | Injection of LPS resulted in significant bone loss in the control group and untreated diabetic rats. However, in the group treated with ARI, this was not observed. This might indicate that by obstructing a crucial step in the polyol pathway, alveolar bone loss in a diabetic rat model was prevented. | |
Kador et al. ( |
Group 1: Diabetic rats ( |
Longitudinal animal study | Aldose reductase inhibitors indeed prevented alveolar bone loss in diabetic rats, but in control rats as well. | |
Chang et al. ( |
Group 1: T1DM rats ( |
Longitudinal animal study | Healing of bony defects was significantly lower in diabetic rats, compared to healthy rats. The AGE-RAGE interaction was enhanced by both inflammatory status and diabetic conditions, indicating a role in the impaired periodontal wound healing seen in patients with DM. | |
Lalla et al. ( |
Group 1: T1DM mice ( |
Longitudinal animal study | Blockade of RAGE reduced alveolar bone loss and lowered levels of inflammatory cytokines such as TNF-α and IL-6. This indicates a link between levels of RAGE and periodontal destruction in patients with DM. | |
Schmidt et al. ( |
Cross-sectional human and animal study | AGEs appeared to accumulate in the gingival tissue of both mice and humans with DM. In parallel with this, enhanced oxidative stress was observed in patients with DM, compared to controls without DM, linking AGE accumulation to periodontal destruction. | ||
Takeda et al. ( |
Group 1: Patients with T2DM and periodontitis ( |
Cross-sectional study | AGEs were the only biomarker in serum that showed a significant relationship with periodontal disease. | |
Yoon et al. ( |
Group 1: Patients with DM ( |
Cross-sectional study | Significantly more AGEs were found in saliva of patients with DM, indicating involvement in the pathogenesis of periodontal disease as a complication of DM. | |
Zizzi et al. ( |
Group 1: Periodontally healthy subjects without DM ( |
Cross-sectional study | In patients with T1DM or T2DM and periodontal disease, gingival AGEs are increased. In this study, duration of DM could be a determining factor for the accumulation of AGEs. | |
Karima et al. ( |
Group 1: Patients with DM ( |
Cross-sectional study | Neutrophils of patients with DM produced significantly higher levels of superoxide and displayed higher protein kinase C activity compared to those of healthy controls. This indicates a more pro-inflammatory state. Furthermore, there was an association between metabolic control and severity of periodontal disease in patients with DM. | |
Demmer et al. ( |
Patients without DM ( |
Cross-sectional study | An association between periodontal pocket depth and insulin resistance was found. However, the cross-sectional design leaves the association open for interpretation. Also, in the regression analysis, insulin resistance was considered as outcome variable, and pocket depth as risk factor. | |
Genco et al. ( |
Group 1: Patients with obesity (BMI ≥27 kg/m2), without DM ( |
Cross-sectional study | Multiple regression analysis showed that obese patients with high levels of insulin resistance were more likely to suffer from severe periodontitis, compared to obese patients with low levels insulin resistance. | |
Islam et al. ( |
Group 1: Patients with periodontitis ( |
Cross-sectional study | There were no differences in insulin resistance between patients with or without periodontitis. However, patients with periodontitis had decreased pancreatic β cell functioning, compared to patients without periodontitis. | |
Lim et al. ( |
Group 1: Men with periodontitis ( |
Cross-sectional study | An association was found only in post-menopausal women, who showed a higher periodontitis prevalence when their insulin resistance increased. This was not found for pre-menopausal women or men. | |
Mizutani et al. ( |
Group 1: Male Zucker Fatty rats (ZF- |
Cross-sectional animal study | The obesity induced insulin resistance resulted in increased oxidative stress, activation of PKC, decreased gingival endothelial functioning and increased inflammation, possibly contributing to the progression of periodontitis. | |
Timonen et al. ( |
Adult subjects without diabetes ( |
Prospective cohort study | Insulin resistance predicted the formation of periodontal pockets (4 mm or deeper) over a period of 4 year (IRR = 1.7, 95% CI: 1.1–2.7) after adjusting for confounders. | |
Timonen et al. ( |
Adult subjects without diabetes ( |
Cross-sectional study | There was a crude association between insulin resistance and periodontal infection (measured by number of teeth with deepened pockets). However, when corrected for BMI, this association disappeared. | |
Awartani and Atassi ( |
Group 1: Otherwise systemically healthy female subjects with hyperlipidemia ( |
Cross-sectional study | Mean probing pocket depth and attachment loss was significantly higher in the hyperlipidemic group, who also had a higher bleeding on probing index. | |
Bastos et al. ( |
Group 1: Patients with poorly controlled T2DM and dyslipidemia ( |
Cross-sectional study | Markers for lipid peroxidation were significantly increased in patients with T2DM. These increased values significantly correlated with periodontal parameters (% sites with bleeding, pocket depth ≥6 mm and pocket suppuration) and several inflammatory markers (IL-6, IL-10, TNF-α). | |
Fentoglu et al. ( |
Group 1: Subjects with hyperlipidemia ( |
Cross-sectional study | The hyperlipidemic group showed higher values of periodontal parameters (mean probing pocket depth, clinical attachment loss, bleeding on probing and plaque index). | |
Lee et al. ( |
Adult subjects ( |
Cross-sectional study | Multivariate logistic regression analyses showed an association between dyslipidemia (hyper TC, hyper TG and hypo HDL-c) and periodontitis, after correction for demographic and general health characteristics (including DM). | |
Sangwan et al. ( |
Group 1: Normolipidemic subjects ( |
Cross-sectional study | Hyperlipidemic patients without statin treatment had increased probing pocket depth and gingival index, compared to normolipidemic subjects and hyperlipidemic patients with statin treatment. Pocket depth was associated with TC, TG and LDL-c, while clinical attachment loss was associated with TC and LDL-c. | |
Araujo et al. ( |
Group 1: Healthy Wistar albino rats ( |
Longitudinal animal study | Anti-hypertensive treatment with TELM, especially the 10 mg/kg dose, resulted in decreased levels of inflammatory markers (IL-1β, TNF-α), reduced expression of markers for bone loss (MMP-2, MMP-9, RANKL/RANK, OPG), and actually reduced alveolar bone loss. It should be noted that normotensive rats were used in this study. | |
Bastos et al. ( |
Group 1: Normotensive Wistar rats ( |
Longitudinal animal study | In both treated and untreated hypertensive rats, increased bone loss and decreased bone density were observed, compared to the normotensive rats. | |
Castelli et al. ( |
Group 1: Normotensive control rats ( |
Longitudinal animal study | Morphologic changes to the gingival blood vessels were observed in the hypertensive rats, but not in the control rats. However, alveolar arterioles and pulp tissues were not affected. | |
Leite et al. ( |
Group 1: Normotensive Wistar rats ( |
Longitudinal animal study | In the hypertensive rats, all ligated sites – where periodontitis was induced – showed moderate to severe alveolar damage. In the normotensive rats, only mild or even no damage was observed at the ligated sites. Hypertension possibly aggravates tissue damage in periodontitis. | |
Duarte et al. ( |
Group 1: Periodontally healthy subjects without DM ( |
Cross-sectional study | Levels of IL-1β and IL-6 in periodontally inflamed tissue of patients with DM were significantly higher than those in the control group. | |
Duarte et al. ( |
Group 1: Periodontally healthy subjects without DM ( |
Cross-sectional study | Lower levels of IL-10 (an anti-inflammatory cytokine) and OPG (an anti-resorption molecule) are observed in patients with DM. Together with the increased levels of their antagonists (IL-6 and RANKL, respectively), the balance between bone resorption and formation is negatively influenced by the diabetic state, leading to a greater periodontal breakdown. | |
Engebretson et al. ( |
Patients with T2DM ( |
Cross-sectional study | Higher levels of HbA1c were associated with higher levels of the pro-inflammatory cytokine IL-1β in GCF. This was on its turn correlated with worse clinical periodontal measures (pocket depth, clinical attachment loss, bleeding). | |
Engebretson et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | Patients with DM showed an insufficient PMN response in the crevice (measured in GCF), which may (partly) contribute to the development and severity of periodontal disease. | |
Gyurko et al. ( |
Group 1: Chronic hyperglycemia mice (Akita; |
Longitudinal animal study | Mice with hyperglycemia had an exaggerated inflammatory response as their leukocytes were primed for marginalization and superoxide production. However, transmigration was impaired. This could contribute to periodontal tissue damage by a weakened immune response to periodontal pathogens as well as by increased local production of free radicals. | |
Kardeşler et al. ( |
Group 1: Patients with periodontitis and T2DM ( |
Cross-sectional study | The researchers did find increased levels of certain cytokines associated with inflammation in the GCF of patients with DM, compared to the healthy control subjects. However, there were no differences between group 1 (patients with DM and periodontitis) and group 2 (systemically healthy patients with periodontitis). | |
Kardeşler et al. ( |
Group 1: Patients with periodontitis and T2DM ( |
Cohort study | After initial periodontal treatment, both groups showed clinical improvement. However, after 1 month the situation in the group with DM worsened, reflected by an increase in cytokines associated with increased inflammation, measured in the GCF (IL-6, tPA, and PAI-2). | |
Lappin et al. ( |
Patients with T1DM ( |
Cross-sectional study | Patients with DM displayed lower RANKL:OPG ratio, which would suggest that they are not susceptible for increased bone resorption via that specific pathway. However, lower levels of osteocalcin (a marker for bone formation) were also observed in patients with DM. It is suggested that this causes an insufficient repair response following bone loss, explaining the susceptibility for periodontal disease progression often seen in patients with DM. | |
Liu et al. ( |
Group 1: Diabetic rats (type-2 Zucker diabetic fatty (ZDF)). Group 2: Normoglycemic control rats. Periodontitis was induced by tying silk ligatures soaked with |
Longitudinal animal study | There was a significant difference in retention of the inflammatory infiltrate (PMNs and mononuclear cells) between diabetic and non-diabetic rats after inducing experimental periodontitis. Consequently, a greater periodontal destruction was found in diabetic rats. | |
Mahamed et al. ( |
Group 1: Diabetic mice (T1DM model, NOD/LtJ). Group 2: Normoglycemic mice. Periodontitis was induced by oral inoculation with |
Longitudinal animal study | Diabetic mice presented higher alveolar bone breakdown compared to normoglycemic mice. The expression of RANKL by t-cells seemed to play an important role, and treatment with OPG prevented alveolar bone loss. | |
Manouchehr-Pour et al. ( |
Group 1: Patients with T1DM and severe periodontitis ( |
Cross-sectional study | Patients with DM suffering from severe periodontitis exhibited a significant decrease in neutrophil chemotaxis, compared to patients with DM and mild periodontal | |
Group 3: Patients without DM, with severe periodontitis ( |
disease and patients without DM. Impaired PMN chemotaxis might contribute to the severity of periodontitis in patients with DM. | |||
McMullen et al. ( |
Group 1: Patients with a family history of diabetes, without overt DM themselves and with severe generalized alveolar bone loss ( |
Cross-sectional study | Patients with a family history of DM had impaired PMN chemotaxis, compared to patients without a family history of DM. They suggest that this impaired PMN function or number predisposes a diabetes patient to develop more severe periodontal disease. | |
Naguib et al. ( |
Group 1: Diabetic mice ( |
Longitudinal animal study | Diabetic mice that were inoculated with a periodontal pathogen ( |
|
Ross et al. ( |
Group 1: Patients without DM and periodontitis ( |
Cross-sectional study | There were significant differences in periodontal expression of IL-6 between all groups. Patients with both periodontal disease and DM had the highest levels, the controls showed the lowest expression. | |
Salvi et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | Patients with DM showed a significant higher monocytic TNF-α secretion in the presence of a periodontal pathogen ( |
|
Salvi et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | Concentrations of prostaglandin E2 (PGE2) and IL-1β in the GCF of patients with DM was significantly higher compared to the concentrations in subjects without DM. Furthermore, as a response to exposure to periodontal pathogens, monocytes in diabetic produced more PGE2 and IL-1β than those in controls. | |
Santos et al. ( |
Group 1: Patients with well-controlled T2DM ( |
Quasi-experiment | Overall, RANKL/OPG ratios were higher in patients with poorly controlled DM. Furthermore, after initial treatment, these ratios decreased in the well-controlled patients, but not in the poorly controlled. Therefore, metabolic control seems to play a role in periodontal bone resorption. | |
Sima et al. ( |
Group 1: Diabetic mice (Akita). Group 2: Healthy mice (wild-type C57BL/6). | Cross-sectional animal Study | The elevated blood glucose levels in diabetic mice resulted in increased leukocyte marginalization and macromolecule extravasation in the gingival vasculature. This represented a pro-inflammatory state, which might contribute to periodontal disease. | |
Vieira Ribeiro et al. ( |
Group 1: Patients with T2DM and chronic periodontitis ( |
Cross-sectional study | Higher levels of OPG, sRANKL, IFN-γ, IL-17, and IL-23 (pro-inflammatory) and lower levels of IL-4 (anti-inflammatory) were observed in the GCF of patients with DM, compared to control subjects. |
A definition often used to describe dental caries (i.e., tooth decay or cavities) is: “the localized destruction of susceptible dental hard tissues (enamel, dentine, root cementum) by acidic by-products from bacterial fermentation of dietary carbohydrates” (
As can be deduced from the earlier mentioned definition, on the one hand, dental caries is the result of a complex interaction between acid producing bacteria and fermentable carbohydrates (such as: sucrose, fructose, and glucose). On the other hand, the ecology of the mouth, in this case determined to a great extent by the pH of saliva and competing non-cariogenic bacteria, is also important. In the healthy situation, there is a balance between the bacterial biofilm and the tooth minerals. If this balance is disturbed (often referred to as the ecological shift), bacteria in the dental biofilm (including
Several literature reviews that discuss the association between diabetes and dental caries, point to the lack of solid evidence for a clear correlation (
There is limited research available on the epidemiology of caries and T2DM. Some papers found an increased prevalence of dental caries (
Longitudinal research with children and adults into the effect of DM on the development of dental caries is very rare. A prospective cohort study reported that poor glycemic control was associated with increased caries incidence within T1DM children (
In general, the cross-sectional design of most studies, varying definitions of dental caries that limit generalizability, and possible differences between the mostly young T1DM and the generally older T2DM population, make it difficult to establish a clear epidemiologic association between DM and dental caries. It is worth noting that some studies even report a decreased prevalence of dental caries in patients with DM (
In contrast to periodontal disease, less is known about biologic explanations for the possible association between DM and dental caries. Nevertheless, we will review the same five pathologic mechanisms we discussed before. However, it is important to note several complicating factors. First, adult and elderly individuals with DM often suffer from periodontitis as discussed before. This is associated with gingival recession (i.e., receding gums), which exposes dental root surfaces that then become susceptible to root caries (
Only a limited number of studies investigated the direct effect of hyperglycemia on dental caries. One animal study with diabetic rats showed that prevention of hyperglycemia by insulin treatment prevented the progression of dental caries (
Interestingly, hyperglycemia results in increased levels of glucose in saliva of patients with DM (
One study compared the decayed, missing, and filled teeth (DMFT) index—a marker for experienced and current caries—between obese, insulin-resistant (OB-IR) patients and healthy controls. The DMFT index, as well as one of its components (decayed teeth), were increased in patients with insulin resistance (
Research into the involvement of dyslipidemia in dental caries is limited to those studies we mentioned above, which investigated dyslipidemia as a component of metabolic syndrome. None of those found a relationship, as only hyperglycemia was significantly associated with decayed teeth (
A recent study with indigenous Brazilian adolescents revealed that hypertension was significantly associated with dental caries (OR = 1.95, 95% CI: 1.03–3.66) (
There is no evidence that inflammation plays a role in dental caries, as is the case for periodontitis or the chronic systemic complications of DM. However, the impaired immune defense against opportunistic pathogens might influence the number of cariogenic bacteria in saliva and dental biofilm. Increased counts of streptococci and lactobacilli were observed in the supragingival plaque (the biofilm on teeth along and above the gum margins) of patients with DM, which was associated with increased caries incidence (
Summarizing the findings of the studied literature in
Overview of studies investigating the association between diabetes mellitus and dental caries.
Alves et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | No significant difference was found in DMFT and def-t between patients with DM and controls. | |
Arheiam and Omar ( |
Group 1: T1DM children ( |
Cross-sectional study | Children with DM showed higher means for the amount of decayed teeth and missing teeth, compared to healthy controls. | |
Saes Busato et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | A significantly higher DMF index was observed in patients with DM, compared to controls. No influence of metabolic control was found, possibly caused by the small sample size. | |
Cherry-Peppers and Ship ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | More coronal caries were present in patients with DM compared to the other groups. | |
Collin et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | No difference in prevalence of root and coronal caries was observed in patients, compared to controls. | |
Edblad et al. ( |
Group 1: Young adults with T1DM ( |
Cross-sectional study | Patients with DM showed more initial buccal caries, compared to the healthy controls. | |
Gómez-Díaz et al. ( |
Patients with T1DM ( |
Cross-sectional study | More buccodental conditions were found in patients with poorly controlled DM (HbA1c >8.5%). | |
Hintao et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | Patients had a higher prevalence of root surface caries and a higher number of decayed or filled root surfaces compared with subjects without DM. | |
Jawed et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | A higher DMFT score was observed in patients, compared to controls. The role of glycemic control, salivary flow and salivary calcium level were pointed out. | |
Jawed et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | A higher DMFT score was seen in patients, compared to controls. Also, a role of glycemic control was observed. | |
Johnston and Vieira ( |
1,281 subjects, aged 6–94 years (mean age = 47.71 years). No data about the number of subjects with DM. | Cross-sectional study | Cross-sectional analysis of the subjects regarding caries experience and systemic diseases revealed a significant association between dental caries and DM. | |
Jones et al. ( |
Group 1: Adults with non-specified DM ( |
Cross-sectional study | Patients suffered from a higher rate of caries than controls. | |
Kodama et al. ( |
Group 1: Type 1 diabetic rats (type: WBN/KobSlc). Group 2: Age- and gender matched non-diabetic rats (type: F344). | Longitudinal animal study | The diabetic conditions in the rats lead to elevated and more advanced caries development, compared to the non-diabetic rats. | |
Lin et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | After correction for the available teeth surfaces, the prevalence of coronal and root-surface caries was not increased in patients with DM. | |
Marín et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | No differences between patients with DM and controls were found with regard to dental caries. | |
Miko et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | A higher DMFT and an increased number of filled teeth were found in patients with T1DM, compared to the control group. The number of decayed teeth was lower in patients with DM, which the authors ascribe to early dentist consultation and treatment of caries in that group. | |
Miralles et al. ( |
Group 1: Patients with T1DM, ( |
Cross-sectional study | DM patients showed a higher prevalence (authors incorrectly report incidence) of caries (measured as CAO index). Poor metabolic control (HbA1c >7.5%), disease duration and the presence of other complications were not associated with caries. | |
Moore et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | Patients with DM did not show higher DFS compared to controls. A slightly increased RDFS was observed, which was associated with periodontal disease at older age. | |
Rai et al. ( |
Group 1: T1DM children ( |
Cross-sectional study | A higher caries prevalence (authors incorrectly report incidence) was seen in patients with DM, compared to healthy controls. | |
Sandberg et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | Patients with DM displayed an increase in initial caries lesions compared to the controls without DM, as well as a larger need for caries prevention. | |
Sano et al. ( |
Group 1: Type 2 diabetic mice ( |
Cross-sectional animal study | The diabetic mice showed a higher prevalence of dental caries, compared to the control mice. | |
Swanljung et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | The patients with DM did not show a significantly higher DMF, DMFS or initial caries lesions compared to the controls. Important note: all patients with DM were well regulated. | |
Tagelsir et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | There was no significant difference in caries experience between patients and controls. | |
Tavares et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional | No significant differences in numbers of buccal surface sites with gingival recession or in numbers of root caries were found between the patients with DM and the control subjects. | |
Yeh et al. ( |
Group 1: Type 1 diabetic mice ( |
Longitudinal animal study | A strong link between glycemic control and salivary dysfunction was found. The combination of hyperglycemia and hyposalivation had a negative influence on enamel mineralization, increasing the risk for tooth decay. | |
Bakhshandeh et al. ( |
Dentate patients with DM (both T1DM and T2DM; |
Cross-sectional study | An association between metabolic control (HbA1c >8.5%). and duration of DM (≥ 7 years) and mean DMFT was found in men, not in women. | |
Cao et al. ( |
Group 1: Patients with MetS ( |
Cross-sectional study | After adjustment for multiple confounders, stratified regression analysis showed an association between dental caries and hyperglycemia as part of MetS (OR = 1.14, 95% CI: 0.98–1.34). | |
Siudikiene et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | In the total population, patients with DM even showed fewer caries compared to the controls. However, amongst patients with DM, well-to-moderately regulated patients had fewer caries, compared to poorly regulated patients. | |
Syrjälä et al. ( |
Patients with T1DM ( |
Cross-sectional study | HbA1c levels were not directly associated with caries prevalence. However, in poorly regulated patients (HbA1c >8.5%), a positive association of mutans streptococci and lactobacilli with dental caries was found. | |
Timonen et al. ( |
Group 1: Patients with MetS ( |
Cross-sectional study | Despite a significant association between MetS as a whole and dental caries, no independent association was found between hyperglycemia (as a component of MetS) and caries after multiple adjustments. | |
Twetman et al. ( |
Children with T1DM ( |
Prospective cohort study | Children with poor glycemic control (HbA1c >8.0%) showed a higher 3-year incidence of caries, compared to children who were well controlled (HbA1c ≤ 8.0%). Other risk factors included: poor oral hygiene, previous caries experience and high levels of salivary lactobacilli. | |
Yonekura et al. ( |
Group 1: Patients with well-controlled T2DM ( |
Cross-sectional study | The prevalence of decayed teeth (DT) was higher in patients with poorly controlled T2DM. Logistic regression analysis showed significant association between HbA1c levels and the absolute number of DT. | |
Loyola-Rodriguez et al. ( |
Group 1: Patients with obesity and insulin resistance ( |
Cross-sectional study | Obese patients with insulin resistance showed a higher DMFT index and number of decayed teeth, compared to the control group. A multivariate regression analysis revealed odds ratios for insulin resistance of 3.1 for DMFT index and 3.3 for decayed teeth. | |
Timonen et al. ( |
Group 1: Patients with MetS ( |
Cross-sectional study | Despite a significant association between MetS as a whole and dental caries, no independent association was found between insulin resistance (as a component of MetS) and caries after multiple adjustments. | |
Cao et al. ( |
Group 1: Patients with MetS ( |
Cross-sectional study | After adjustment for multiple confounders, stratified regression analysis showed no association between dental caries and dyslipidemia (OR = 1.01 for hypertriglyceridemia [95% CI: 0.85–1.19] and 0.84 for low HDL-c [95% CI: 0.70–1.00]). | |
Timonen et al. ( |
Group 1: Patients with MetS ( |
Cross-sectional study | Despite a significant association between MetS as a whole and dental caries, no independent association was found between dyslipidemia (as a component of MetS) and caries after multiple adjustments. | |
Cao et al. ( |
Group 1: Patients with MetS ( |
Cross-sectional study | After adjustment for multiple confounders, stratified regression analysis showed no association between dental caries and hypertension (OR = 0.96; 95% CI: 0.86–1.13). | |
Johnston and Vieira ( |
1,281 subjects, aged 6–94 years (mean age = 47.71 years). No data about the number of subjects with DM. | Cross-sectional study | Both primary (DMFT) and secondary (DMFS) caries experience were independently associated with hypertension. | |
Ribeiro et al. ( |
Adult subjects ( |
Cross-sectional study | Patients with hypertension ( |
|
Timonen et al. ( |
Group 1: Patients with MetS ( |
Cross-sectional study | Despite a significant association between MetS as a whole and dental caries, no independent association was found between hypertension (as a component of MetS) and caries after multiple adjustments. | |
Collin et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | There was no difference in cariogenic microorganisms and yeasts between patients with or without DM. It should be noted that they also did not find a higher prevalence of dental caries. | |
Goodson et al. ( |
Adolescents ( |
Cross-sectional study | Increasing salivary glucose levels—presumably caused by obesity and/or DM—reduced the total bacterial load in saliva. The authors hypothesize that glucose metabolism by acidogenic bacteria lowers the salivary pH, which disturbs the oral microbiome and favors cariogenic bacteria species. | |
Kampoo et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional | Patients with DM showed higher numbers of total streptococci and lactobacilli in supragingival plaque, compared to the control subjects. Lactobacillus numbers were also increased in saliva and supragingival plaque of patients with DM and active caries, compared to patients with DM, without active caries. | |
Siudikiene et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | Patients with DM showed more frequent presence of yeasts, and poorly controlled patients also had higher numbers of mutans streptococci. | |
Syrjälä et al. ( |
Patients with T1DM ( |
Cross-sectional study | In poorly regulated patients (HbA1c ≥8.5%), a positive association of mutans streptococci and lactobacilli with dental caries was found. |
The term “dry mouth” can be interpreted in several ways. Usually, two distinctive phenomena are referred to in literature when speaking of dry mouth. The first is the
When defining hyposalivation as an unstimulated whole saliva flow rate of < 0.1 mL/min, research showed that approximately 20% of individuals across all ages were affected, while the prevalence was ~3% when using the stimulated whole saliva flow rate definition (< 0.7 mL/min) (
The experience of a dry mouth is one of the most frequently mentioned oral complaints by patients with DM. In a way, this is not surprising, considering the fact that the population with T2DM generally consists of relatively older individuals, and we now know that the prevalence of xerostomia and hyposalivation increases with age. Also, many patients with DM suffer from one or more complications and/or comorbidities, for which they possibly receive medication that increases the risk for oral dryness (e.g., anti-cholinergic and anti-hypertensive medication).
Varying definitions and methods of diagnosing hyposalivation and xerostomia make it difficult to establish a direct association with DM. Nevertheless, many cross-sectional studies reported a diminished salivary flow rate in patients with DM, compared to control subjects without DM. This finding applies for patients with T1DM (
Although many cross-sectional studies report an increased prevalence of xerostomia and a decreased salivary flow rate in patients with DM, the mechanisms underlying these observations remain unclear. Secretion of saliva by the parotid gland—the largest salivary glands—is regulated by the autonomic nervous system, which led to the hypothesis that diabetic neuropathy might somehow be involved in the development of dry mouth experience. However, studies investigating this theory present contradictory results. Decreased (
There are a few studies that actually observed structural changes in the salivary glands of patients with DM, in particular in the parotid glands. Vacuolization of acini (the saliva secretory cells) in the parotid gland was observed, which indicated an early form of degeneration (
In general, patients with poor glycemic control present significantly lower salivary flow rate and higher prevalence of xerostomia, compared to subjects with well-controlled DM (
Hyperglycemia in patients with DM can cause polyuria and osmotic diuresis, possibly leading to dehydration, which is associated with hyposalivation (
Research into the role of insulin resistance in the pathogenesis of hyposalivation and xerostomia is limited to a few animal studies. Increased ROS production, an upregulated inflammatory response (
As we mentioned earlier, some studies observed an accumulation of lipid droplets in epithelial cells of the salivary glands (
One study showed that patients with hypertension and without DM had reduced submandibular and sublingual salivary flow rates, compared to healthy controls. The salivary flow rates of the hypertensive patients were comparable with those of patients with DM, while stimulated parotid and unstimulated whole salivary flow did not differ across the groups. However, it was not clear whether these differences were a consequence of the hypertension itself, possible anti-hypertensive medication use, or both (
As described above, DM and its metabolic disturbances could be associated with dry mouth, sometimes mediated by inflammatory processes. However, this remains rather speculative, since most of those studies investigated diabetic animal models. Moreover, the inflammatory state observed in some studies did not necessarily affect salivary flow rate, xerostomia or salivary gland morphology.
Some studies suggest that Sjögren syndrome—an autoimmune disease affecting the salivary glands—could be the underlying cause of dry mouth in patients with DM (
Dry mouth is a very often heard complaint by patients with DM, and the majority of epidemiological studies indeed report an increased prevalence of xerostomia and a decreased salivary flow rate. Especially poor glycemic control negatively impacts both the prevalence and severity of dry mouth. Older age, dehydration and medication use also seem to be important determinants in this association. However, there is hardly any research into other pathogenic pathways that could explain the association between DM and dry mouth, and longitudinal studies are also lacking.
Overview of studies investigating the association between diabetes mellitus and dry mouth.
Ben-Aryeh et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | Patients with DM showed significantly lower salivary flow. Also, higher glucose, potassium and protein levels were seen in saliva of patients with DM, indicating affected salivary gland. No differences in xerostomia experience were observed. | |
Ben-Aryeh et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | Patients with T1DM showed a significantly lower salivary flow compared to patients with T2DM, but not compared to controls. Potassium and IgA concentrations were different between the groups. No difference in the complaint of xerostomia was observed between the groups. | |
Busato et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | DM appeared to be associated with a high prevalence of xerostomia, which in turn was predictive of a poor oral health related quality of life. | |
Carda et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | Xerostomia was observed more often in patients with DM. Increased levels of urea and proteins were found in saliva of patients with DM, while albumin was decreased. Increased levels of salivary glucose were associated with poor metabolic control. | |
Ivanovski et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | The authors conclude that patients with DM have significantly higher salivary levels of urea and glucose. Also, they claim diabetes causes xerostomia, and a significant correlation exists between the degree of xerostomia and the salivary glucose concentrations. | |
Jawed et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | Patients with DM had a lower salivary pH, flow rate, and calcium levels compared to controls. Fasting blood glucose, HbA1c, and DMFT score were significantly increased in patients with DM. | |
Kao et al. ( |
Group 1: Patients with T2DM and xerostomia ( |
Cross-sectional study | Patients with DM and xerostomia (group 1) showed significantly lower saliva production and excretion, compared to the other two groups. | |
Karjalainen et al. ( |
Group 1: Newly diagnosed T1DM children ( |
Cross-sectional | At initial T1DM diagnosis, hyperglycemia was reflected as increased levels of salivary glucose and a decreased salivary flow. Patients with long-term diabetes did not show such a clear relationship. | |
Khovidhunkit et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | A significantly higher prevalence of xerostomia and hyposalivation was observed in patients with DM, compared to the subjects without DM. | |
Lasisi and Fasanmade ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | Patients with DM showed reduced salivary flow, and increased salivary concentrations of glucose and potassium. Total protein, Na+, Ca2+, Cl−, and |
|
Lin et al. ( |
Group 1: Patients with T2DM and xerostomia ( |
Cross-sectional study | Salivary scintigraphy revealed that salivary function (expressed as production and secretion) was significantly lower in patients with DM and xerostomia, compared to patients with DM, without xerostomia and healthy controls. | |
López et al. ( |
Group 1: Children with T1DM ( |
Cross-sectional study | Children with diabetes showed a lower salivary pH, a decreased flow, higher concentrations of sugars, glucose, urea, and total proteins and decreased levels of calcium, compared to the controls. | |
Malicka et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | A significantly decreased salivary flow and increased prevalence of xerostomia were observed in patients with T1DM compared to controls. For patients with T2DM, these differences were not significant, but a trend was observed. | |
Mata et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | Patients with DM showed a significant decrease in salivary flow and secretion capacity, while protein and Ca2+ levels were increased. Levels of Mg2+, Zn2+, and K+ were significantly lower compared to the control group. | |
Montaldo et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | Mean salivary flow appeared to be lower in the diabetes group, compared to the control group. | |
Quirino et al. ( |
Group 1: Patients with controlled T2DM ( |
Cross-sectional study | Hyposalivation was observed more often in patients with DM, compared to controls. | |
Sandberg et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | Xerostomia was significantly more prevalent in patients with DM (53.5%) compared to the control group (28.4%). | |
Silveira Lessa et al. ( |
Group 1: Patients with T1DM and T2DM (combined |
Systematic review and meta-analysis | The prevalence of xerostomia in patients with DM was higher (37.4% for T1DM and 46.1% for T2DM), compared to the control subjects without DM (24.2%). Furthermore, a significant association between DM and xerostomia was found when analyzing case-control studies (OR = 3.15, 95% CI: 2.11–4.70), indicating an increased risk for xerostomia when diabetes is present). | |
Vasconcelos et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | Both resting and stimulated salivary flow was lower in patients with DM, compared to the control group. However, no significant difference in the prevalence of xerostomia was found. | |
Chávez et al. ( |
Group 1: Patients with better controlled T2DM (HbA1c ≤ 9%) ( |
Prospective cohort study | Patients with poorly controlled diabetes showed lower stimulated parotid saliva flow rates, both at baseline and after 1 year follow-up. Also, patients with DM reported more complaints of thirst, though not of xerostomia. No changes over 1 year of follow-up were observed. | |
Chavez et al. ( |
Group 1: Patients with well controlled T2DM (HbA1c ≤ 9%) ( |
Cross-sectional study | Patients with poorly regulated diabetes displayed a significant decrease in stimulated parotid salivary flow rates compared to well-controlled patients and subjects without DM. | |
Fukuoka et al. ( |
Group 1: Control rats ( |
Longitudinal animal study | The diabetic rats showed an upregulated AGE/RAGE expression in the salivary glands, which resulted in an inflammatory response through activation of the NF-κB pathway. Therapy with the low-power laser irradiation suppressed this inflammatory state, and reduced apoptosis caused by diabetes. | |
Moore et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | Patients with DM complained more often of dry mouth and had decreased salivary flow rates compared to controls. Furthermore, decreased salivary flow rates were associated with increased fasting glucose levels. | |
Sreebny et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | Patients with DM showed a decreased salivary flow compared to the control subjects. Also, an inverse relationship between metabolic control (HbA1c) and salivary flow was observed. | |
Ittichaicharoen et al. ( |
Group 1: Normal diet fed Wistar rats ( |
Longitudinal animal study | Rats fed with a high-fat diet developed obese-insulin resistance, with increased apoptosis, ROS production, inflammation and mitochondrial dysfunction in their salivary glands as a result. When treated with the anti-diabetic drug, these changes were reduced. | |
Matczuk et al. ( |
Group 1: Normal diet fed rats ( |
Longitudinal animal study | A high-fat diet, inducing insulin resistance and obesity, resulted in a changing lipid composition in rat salivary glands. Phospholipids and triacylglycerols were increased; FFAs and diacylglycerols were not. | |
Mozaffari et al. ( |
Group 1: Obese rats ( |
Cross-sectional animal study | The obese rats develop insulin resistance, which resulted in an increased expression of ICAM-1 and an upregulation of the NF-κB pathway in the salivary glands. However, morphological changes were not observed. | |
Shikama et al. ( |
Human parotid and submandibular salivary gland epithelial cell lines, treated with various types of FFAs to mimic dyslipidemic conditions. | Treatment with saturated (not unsaturated) fatty acids (SFA) activates the NF-κB and MAPK pathway, resulting in increased IL-6 production in human parotid and submandibular salivary gland epithelial cell lines. | ||
Dodds et al. ( |
Group 1: Healthy controls ( |
Cross-sectional study | Patients with hypertension had lower unstimulated submandibular/sublingual (US) and stimulated submandibular/sublingual (SS) salivary flow rates, compared to healthy controls. US flow rates were also comparable with patients with DM. |
The name oral mucosal lesion is used as an umbrella term for any abnormal change to the mucosal surface in the oral cavity. This concerns numerous different types of lesions, and it is beyond the scope of this review to discuss them all individually. Often, oral mucosal lesions are classified based on the pathology, morphology, or location of the lesion. Shulman et al. classify: “
Despite the heterogeneity of oral mucosal lesions, several studies tried to estimate their prevalence. A large epidemiologic study from the U.S. (17,235 individuals >17 years old) concluded that 27.9% of the population had at least one lesion (
The large majority of studies investigating the association between DM and oral mucosal lesions focus on
This section will discuss the pathogenesis of candidal lesions in relation to DM, again by means of the previously utilized pathologic phenomena related to DM: hyperglycemia, insulin resistance, dyslipidemia, hypertension, and immune dysfunction.
Several studies found that the increased prevalence of
As we have discussed before, salivary glucose levels are often increased in patients with DM due to hyperglycemia. Similar to the suggestions for cariogenic oral streptococci, glucose can also act as a source of nutrition for yeast species such as
Two animal studies observed an increased systemic infection with
Currently, there are no studies that investigated the effect of insulin resistance or hypertension on
As we discussed before, patients with DM are susceptible for hyposalivation. Saliva has several innate immune defensive mechanisms to protect the oral mucosa against microorganisms such as
We discussed before that the impaired innate immune response makes patients with DM susceptible to infections. The decreased phagocytosis and killing capabilities of the PMNs might cause overgrowth of
Several studies investigated only one non-candida related mucosal lesions (
Overview of non-candidal lesions that are possibly associated with diabetes mellitus.
Traumatic ulcer | Damaged mucosa caused by mechanical, thermal, chemical, electrical or irradiation trauma. | Guggenheimer et al. ( |
Actinic cheilitis | Premalignant disorder of the lip characterized by inflammation, caused by exposure to sunlight. | Silva et al. ( |
Melanin pigmentation | Pigmentation of oral mucosa with a broad range of clinical signs, caused by both exo- and endogenous factors. | Conflicting results, as some found an increased prevalence in patients with T1DM or T2DM ( |
Fissured tongue | Deep grooves on the dorsal side of the tongue. | A few studies observe an increase in prevalence, and hypothesize that fissured tongue might be the result of aging and a dry mouth ( |
Benign migratory glossitis (geographic tongue) | An inflammatory condition of the dorsal mucosal surface of the tongue, with loss of lingual papillae as a result. This is visible as a red, smooth surface, with a shifting positioning. | Several studies reported a significant increase in the prevalence of geographic tongue in patients with T1DM or T2DM ( |
Leukoplakia | Literally: white patch. It is a “predominantly white (premalignant) lesion of the oral mucosa that cannot be characterized as any other definable lesion.” | Studies investigating the relationship between leukoplakia and DM show contradictory results. Some found an association ( |
Lichen planus and lichenoid lesions | An inflammatory condition with varying clinical appearances, affecting the skin, the oral mucosa, or both. It might cause white patches, red and swollen tissue, pain in varying degrees and a burning sensation. It can be considered as a premalignant disorder. | Again, there is no consensus in the literature, as some report an increased prevalence of lichen planus ( |
From an epidemiologic point of view, the prevalence of candida-related oral mucosal lesions is increased in patients with DM. However, longitudinal studies are lacking, and not much is known about the pathogenesis behind the increased prevalence. It is highly likely that the impaired immune response enables
Overview of studies investigating the association between diabetes mellitus and oral candidal lesions.
Bremenkamp et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | There were no differences in the frequency of |
|
Darwazeh et al. ( |
Group 1: Patients with DM ( |
Cross-sectional study | Patients with DM did not show higher |
|
de Lima et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | There were no significant differences in oral mucosal lesions, including |
|
de Souza Bastos et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | A significantly higher prevalence of total fungal infections was observed in patients with DM, compared to the control subjects. | |
Dorocka-Bobkowska et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | The prevalence of denture stomatitis and its associated oral complaints, angular cheilitis, glossitis and oral dryness were significantly increased in patients with DM, compared to the controls. | |
Guggenheimer et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | The prevalence of several manifestations of candidal lesions (median rhomboid glossitis, denture stomatitis and atrophy of the tongue papilla) was increased in patients with DM, compared to controls. | |
Saini et al. ( |
Group 1: Patients with DM ( |
Cross-sectional study | The prevalence of denture stomatitis and angular cheilitis was increased in patients with DM, compared to the controls. | |
Al Mubarak et al. ( |
Patients with T2DM ( |
Cross-sectional study | Patients with poor metabolic control (HbA1c >9%) had more candidal infections, compared to well-controlled patients (HbA1c < 6%). | |
Al-Maweri et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | The prevalence of denture stomatitis and angular cheilitis was increased in patients with DM, compared to the controls. Within the group with DM, poor glycemic control was associated with increased prevalence of the same conditions. | |
Guggenheimer et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | The presence of |
|
Sashikumar and Kannan ( |
Group 1: Well-controlled diabetic subjects ( |
Cross-sectional study | Colony-forming units of |
|
de Souza Ferreira et al. ( |
Group 1: Control rats, no AMG treatment ( |
Cross-sectional animal study | Microbicidal activity of the PMNs against |
|
Netea et al. ( |
Group 1: Low-density-lipoprotein-receptor-deficient mice (type: |
Longitudinal animal study | The |
|
Vonk et al. ( |
Group 1: Apolipoprotein E-deficient mice ( |
Cross-sectional animal study | VLDL levels were 8 times higher in |
|
Darwazeh et al. ( |
Group 1: Patients with DM ( |
Cross-sectional study and |
There was increased adhesion of |
|
Dorocka-Bobkowska et al. ( |
Group 1: T2DM denture-wearing patients ( |
Cross-sectional study and |
Not only did they found an increased prevalence of denture stomatitis in the diabetic group, but also an increased adherence of |
|
Ueta et al. ( |
Group 1: Patients with symptomatic oral candidiasis and DM ( |
Cross-sectional study | White blood counts, levels of CRP and erythrocyte sedimentation rates were all increased in patients with DM and oral candidiasis. Oral PMNs in these patients produced less ROS and showed impaired phagocytosis and intracellular killing of |
This section focuses on cancers of the lip, tongue, oral cavity, and oropharynx. Oral and oropharyngeal cancers together are ranked as the sixth most common type of cancer, but prevalence and incidence vary greatly between countries and regions (
Patients with DM have an increased risk for developing cancer in several organs and tissues, as well as an increase in cancer mortality, compared to subjects without DM (
There are also several longitudinal studies investigating the incidence of—and risk for—oral cancer in diabetic cohorts. One Danish population-based cohort study compared the incidence of several types of cancer in a large diabetic population (
Besides its effect on cancer incidence, DM also negatively affects the prognosis of patients with oral squamous cell carcinoma (OSCC). In another Taiwanese study, overall survival, recurrence-free survival, and cancer-specific survival were all decreased in patients with OSCC and DM, compared to patients with OSCC without DM (
The pathogenesis behind the epidemiologic association between DM an oral cancer is complex and remains to be fully elucidated. In an attempt to explain the increased risk for oral cancer by means of the pathological mechanisms that we have been using throughout this review, it appears that only hyperglycemia and dyslipidemia have been studied, albeit very limited. There is no data available on the role of hypertension, insulin resistance and immune dysfunction.
Although it is likely that hyperglycemia is important for the increased risk of oral cancer in patients with DM, there is only limited evidence for that hypothesis. In one study, elevated levels of HbA1c were associated with an increased risk for oral leukoplakia, a pre-malignant oral mucosal lesion (
One
One study had a closer look at the individual components of the metabolic syndrome (hyperglycemia, elevated triglycerides, lowered HDL levels, hypertension, and central obesity), which revealed that subjects with hypertriglyceridemia had a higher risk for developing oral pre-malignancies (
Overview of studies investigating the association between diabetes mellitus and oral cancer.
Bosetti et al. ( |
Group 1: Patients with cancer of the oral cavity/pharynx ( |
Integrated case-control studies | The risk for oral and pharyngeal cancer was increased in patients with DM, compared to the group without DM (OR = 1.58, 95% CI = 1.15–2.18), after adjustment for gender, age, study center, year of interview, education, alcohol drinking, tobacco smoking, and BMI. | |
Campbell et al. ( |
Subjects free of cancer at baseline ( |
Prospective cohort study | After multivariable adjustment, diabetes was associated with an increased mortality from cancer of the oral cavity and pharynx in men (RR = 1.44, 95% CI: 1.07–1.94). | |
de Souza Bastos et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | The prevalence of potentially malignant disorders (actinic cheilitis, lichen planus, leukoplakia and nicotinic stomatitis) was significantly increased in patients with T2DM. | |
Dietrich et al. ( |
Group 1: Patients with oral leukoplakia ( |
Cross-sectional study | Oral leukoplakia was more prevalent in patients with DM (0.92%), compared to patients without DM (0.37%). Besides smoking, age, and socio-economic status, DM was found to be an independent predictor for the development of oral leukoplakia (OL). Patients with DM were 3 times more likely to develop OL (weighed OR = 3.03, 95% CI: 1.28–7.21). | |
Dikshit et al. ( |
Group 1: Patients with leukoplakia ( |
Case-control study | In women, DM was an independent risk factor for oral leukoplakia (OR = 2.0, 95% CI: 1.4–2.9) and erythroplakia (OR = 3.2, 95% CI: 1.3–7.9). For men, no such association was found. | |
Gong et al. ( |
13 epidemiological studies on the association between oral cancer and DM (4 case-control and 9 cohort studies, combined |
Systematic review with meta-analysis | Analysis of 4 case-control studies and 9 cohort studies revealed a significant association between oral cancer (SRR = 1.15, 95% CI: 1.02–1.29) and oral cancer related mortality (SRR = 1.41, 95% CI: 1.16–1.72) and T2DM. Meta-analysis of the case-control study revealed a positive association between T2DM and the risk for precancerous lesions (SRR = 1.85, 95% CI: 1.23–2.80). | |
La Vecchia et al. ( |
Group 1: Patients with histologically confirmed incident cancer ( |
Integrated case-control studies | There was no significant increase in the risk for cancer of the oral cavity (RR = 0.50, 95% CI: 0.2–1.1) in patients with DM. | |
Saini et al. ( |
Group 1: Patients with DM ( |
Cross-sectional study | There was no association between the presence of DM and the prevalence of oral precancerous lesions. | |
Tseng ( |
Group 1: Patients with T2DM ( |
Retrospective cohort study | After multivariable adjustment, there was no significant association between T2DM and incidence oral cancer after 2-year follow-up (RR = 1.195, 95% CI: 0.892–1.601). | |
Tseng et al. ( |
Group 1: Patients with DM ( |
Retrospective cohort study | The risk for developing oral cancer and oropharyngeal cancer was significantly higher in patients with DM, compared to the matched controls (adjusted HR = 1.74, 95% CI 1.47–2.06 for oral cancer and 1.53, 95% CI: 1.01–2.31 for oropharyngeal cancer). | |
Ujpál et al. ( |
Cross-sectional study | The first cross-sectional analysis showed an increased prevalence of benign tissue accumulations (14.5%) and precancerous lesions (8%) in patients with T1DM or T2DM, compared to control subjects without DM (6.4% and 3.2% respectively). The second cross-sectional analysis showed an increased prevalence of diabetes in the oral cancer patient group, compared to the cancer-free controls. | ||
Wideroff et al. ( |
Group 1: Patients diagnosed with diabetes ( |
Population-based cohort study | The observed numbers of incident cancers of the mouth in the diabetic population were compared with the expected incidence, based on the national cancer registry records. Even after adjustment for multiple variables, the relative incidence ratios remained significantly increased (1.8, 95% CI: 1.2–2.6). | |
Wu et al. ( |
Group 1: Patients with OSCC and DM ( |
Retrospective cohort study | OSCC patients with DM showed a decreased overall survival (HR = 2.22, 95% CI: 1.27–3.88), recurrence-free survival (HR = 2.42, 95% CI: 1.49–3.92), and cancer-specific survival (HR = 2.16, 95% CI: 1.17–3.97), compared to the OSCC patients without DM, even after multivariable adjustment. | |
Meisel et al. ( |
Group 1: Patients with leukoplakia ( |
Cross-sectional study | Conditional regression analysis revealed a higher probability for leukoplakia with increasing HbA1c levels (OR = 1.51, 95% CI: 1.08–2.12). When correcting for the interaction with smoking status, the OR for never-smokers was 1.96 (95% CI: 1.15–3.37), and for ever-smokers 1.29 (95% CI: 0.80–2.09). | |
Bhawal et al. ( |
The number of cells expressing RAGE was significantly higher in metastatic tumors, compared to normal mucosal cells. Also, suppressing the expression of RAGE in oral squamous cell carcinoma cell lines resulted in a decreased invasive activity and absolute number of invasive cells. This suggests that RAGE expression is involved in the invasiveness of oral malignant tumors. | |||
Ko et al. ( |
Oral cancer cell lines (SAS), treated with AGEs or BSA (negative control). | Increased cell migration was observed when the oral cancer cells were treated with AGEs. This was probably the result of increased expression of RAGE, MMP-2 and MMP-9. The authors suggest that this increases the invasiveness of oral cancer cells, since migration is an important feature of malignancy. | ||
Ko et al. ( |
Oral cancer cell lines (SAS), treated with AGEs or BSA (negative control). | The oral cancer cells that were treated with AGEs, showed a decreased p53 expression. A decreased expression of p53 usually promotes cell survival and suppresses cell death. The authors therefore conclude that AGEs are probably involved in the survival rate of oral cancer cells, which might worsen the prognosis of oral cancer in patients with DM. | ||
Sasahira et al. ( |
Group 1: Patients with OSCC and high expression of RAGE ( |
Prospective cohort study | High expression of RAGE in OSCCs was associated with the depth of invasion and local recurrence of the cancer. Disease-free survival was negatively impaired by high expression of RAGE. | |
Su et al. ( |
Group 1: Patients with oral cancer ( |
Cross-sectional study | Patients with a specific RAGE polymorphism had an increased risk for oral cancer (aOR = 2.053, 95% CI: 1.269–3.345), even after correction for multiple confounders (age, gender, betel nut chewing, and tobacco consumption). | |
Saxena et al. ( |
Group 1: Control diabetic mice ( |
Longitudinal animal study | By inhibiting the polyol pathway, significantly fewer premalignant lesions were observed in the colons of diabetic mice. This indicates that the polyol pathway is involved in the development of diabetes-associated colon cancer. Perhaps the same accounts for oral cancer as well. | |
Meisel et al. ( |
Group 1: Patients with leukoplakia ( |
Case-control study | Besides HbA1c, LDL and total cholesterol levels were also increased in patients with leukoplakia. The conditional regression analysis for LDL-cholesterol revealed an OR of 3.01 in “never smokers” and an OR of 1.47 in “eversmokers.” | |
Yen et al. ( |
Group 1: Patients with metabolic syndrome ( |
Cross-sectional study | The prevalence of at least one oral premalignant lesion was significantly higher in the group with metabolic syndrome, compared to the control group. Multivariate logistic regression analysis revealed that hyperglycemia (aOR = 1.30, 95% CI: 1.02–1.67) and hypertriglyceridemia (aOR = 1.43, 95% CI: 1.17–1.75) independently increased the risk for an oral premalignant lesion. |
Gustatory dysfunction (i.e., taste disturbance) is generally classified into three major types:
Epidemiologic research into the association between DM and taste disturbances is limited to a few cross-sectional studies. Nevertheless, both hypogeusia and ageusia were observed more frequently in patients with T1DM (
Unfortunately, there is no literature available that investigated the same pathogenic pathways we have been using throughout this report. However, a few explanations why patients with DM more frequently suffer from taste impairment have been proposed. For example, the increased susceptibility for dry mouth we discussed in section Dry Mouth, might increase the risk for taste disturbances. One study found that, of all patients with a subjective complaint of taste disturbance, 63% also had a sensation of oral dryness, often regardless of the actual salivary flow (
Studies investigating the association between taste impairments and DM can be found in
Overview of studies investigating the association between diabetes mellitus and taste impairment.
De Carli et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | Thresholds for sweet, salt, sour, and bitter taste recognition were increased in patients with T2DM, compared to the controls. | |
Gondivkar et al. ( |
Group 1: Patients with well controlled T2DM ( |
Cross-sectional study | Patients with either well or poorly controlled diabetes suffered from hypogeusia and ageusia more often, compared to healthy controls. Especially sweet taste was impaired, followed by sour and salt. They hypothesize that the impaired taste for sweet might result in increased consumption of sweet food, and beverages, (mostly high in sugar) worsening the hyperglycemia. | |
Khobragade et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | The taste thresholds for sweet, salt, sour and bitter was significantly increased in the patients with DM, which indicates an impaired taste sensation. | |
Le Floch et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | Hypogeusia was observed in significantly more patients with DM than in control subjects without DM. This concerned all four primary tastes, and the taste impairment was significantly associated with other diabetic complications. The association with peripheral neuropathy was the strongest. | |
Naka et al. ( |
Group 1: Patients with uncomplicated DM ( |
Cross-sectional study | There was no significant difference in gustatory function (for the four basic tastes) between patients with DM and control subjects without DM, assessed by using impregnated taste strips. | |
Perros et al. ( |
Group 1: Patients with newly diagnosed T2DM ( |
Cross-sectional study | The patients with newly-diagnosed diabetes had increased EGT, detection threshold for glucose, and recognition threshold for glucose and salt. This might indicate a preference for sweet nutrients, increasing the risk for elevated blood glucose levels. | |
Stolbova et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | The gustometric threshold was significantly higher in the diabetic and obese subject, compared to the controls. Also, hypogeusia and ageusia were observed in patients with T1DM or T2DM, as well as in obese patients, but not in the control subjects. | |
Wasalathanthri et al. ( |
Group 1: Control subjects without DM ( |
Cross-sectional study | The patients with T2DM had impaired sweet taste sensitivity, compared to the controls. Furthermore, even though the taste sensitivity of the patients with pre-diabetes lay in between those of patients with DM and controls, this could not be statistically proven. | |
Cheng et al. ( |
Group 1: Diabetic rats (induced with high-fat diet and streptozotocin injection). Group 2: Non-diabetic rats Rats used: male, Wistar, 8–10 weeks old, 180–200 g. | Cross-sectional animal study | The diabetic rats showed increased cell apoptosis of the taste buds, compared to the non-diabetic rats. Further analysis seems to hint that the apoptosis of the cells in the taste buds is mediated by the intrinsic mitochondrial pathway through increased BCL2 and decreased BAX expression. | |
Le Floch et al. ( |
Group 1: Patients with DM ( |
Prospective cohort study | The EGT, which is an indicator for taste loss, significantly increased in both groups, but was higher in the patients with DM. Moreover, this increase was significantly associated with other degenerative complications, especially neuropathy, which indicates a similar biologic mechanism. | |
Le Floch et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | The EGT was significantly higher in the diabetic group, compared to the control subjects without DM. The increased EGT was significantly associated with diabetic peripheral neuropathy and nephropathy, suggesting that taste impairment is another degenerative complication of DM. | |
Pai et al. ( |
Group 1: Diabetic rats (induced by streptozotocin injection). Group 2: Non-diabetic control rats. rats used: adult, male, Sprague-Dawley rats, weighing 300–350 g. | Cross-sectional animal study | The number of nerve fibers in the papillae and taste cells in the taste buds were decreased in the diabetic rats after 20 weeks of streptozotocin injection. After this period, the diabetic rats also had fewer numbers of these fibers and cells, compared to the control rats. This might indicate that taste impaired in patients with DM is caused by neuropathic damage and/or morphological changes in the taste buds | |
Pavlidis et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | Patients with DM had increased taste thresholds, measured by EGM. Furthermore, differences in gustatory anatomical structures were observed between the two groups. The patients with DM had a decreased density of fungiform papillae and worsened vascularization of the tongue tip, measured by contact endoscopy. |
The following conditions affecting the oral cavity have been mentioned in the literature as possible complications of DM, but evidence for an epidemiologic or pathologic association is too scarce to dedicate a separate section.
Overview of studies investigating the association between diabetes mellitus and other oral complications.
Collin et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | Severe temporomandibular joint (TMJ) dysfunction was significantly more prevalent in the diabetic group (27.3%), compared to the control group (15.8%). Also, peripheral diabetic neuropathy emerged as independent risk factor for TMJ dysfunction. | |
Uemura et al. ( |
Group 1: Diabetic rats ( |
Cross-sectional animal study | The thickness of the articular disk of the TMJ was significantly lower in the diabetic rats, compared to the healthy controls. Also, in the retrodiscal tissue, the diameter of the capillaries was significantly decreased, possibly indicating microangiopathy. | |
Collin et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | The prevalence of glossodynia (burning sensation of the tongue) was significantly higher in the diabetic group (18%) than in the control group (7%). | |
Eltas et al. ( |
Group 1: Patients with DM ( |
Cross-sectional study | BMS was significantly more prevalent in the diabetic group (40.9%), compared to the control group (11.1%). | |
Moore et al. ( |
Group 1: Patients with T1DM ( |
Cross-sectional study | The prevalence of BMS without any apparent pathology did not differ between the groups. However, within the diabetic group, BMS was significantly associated with diabetic peripheral neuropathy. | |
Vesterinen et al. ( |
Group 1: Patients with DM and chronic kidney disease ( |
Cross-sectional study | There were no statistical significant differences in the prevalence of BMS between the patients with chronic kidney disease and diabetes, compared to the control patients with only chronic kidney disease. | |
Arya et al. ( |
Group 1: Patients with T2DM ( |
Prospective cohort study | Periapical healing after endodontic treatment was significantly lower in patients with DM (43%), compared to the group without DM (80%). | |
Catanzaro et al. ( |
Group 1: Healthy control rats ( |
Longitudinal animal study | Several inflammatory markers were elevated in the pulp of diabetic rats compared to the controls, such as nitrite concentrations, kallikrein and myeloperoxidase activity and alkaline phosphatase concentration. Collagen concentration was decreased in diabetic rats. | |
Fouad and Burleson ( |
Group 1: Patients with T1DM ( |
Prospective cohort study | Of the included subjects, 540 non-surgically treated endodontic patients (of which 73 with DM) completed follow-up. Multivariate analysis revealed that a history of DM in patients with preoperative periradicular lesions (indicating endodontic infection) decreased the success of endodontic treatment. | |
Garber et al. ( |
Group 1: Healthy control rats ( |
Cross-sectional animal study | Inflammation was observed significantly more often in dental pulp of diabetic rats, compared to controls. Also, the formation of dentin bridges, which indicates healing, was impaired more often in diabetic rats. | |
Lopez-Lopez et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | AP was more prevalent in patient with T2DM (74%) than in the control group (42%, |
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Marotta et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | Patients with DM had significantly more teeth affected by AP (15%), compared to the control subjects (12%, p = 0.05). | |
Nakajima et al. ( |
Expression of RAGE and several inflammatory pathway markers (S100A8, S100A9, and IL-1β) were increased in pulp of diabetic rats, compared to the control rats. The dental pulp cell lines were treated with AGE, which resulted in increased expression of the same inflammatory pathways. | |||
Sanchez-Dominguez et al. ( |
Group 1: Patients with poorly regulated T2DM ( |
Cross-sectional study | In a multivariate logistic regression analysis, the presence of AP in at least 1 tooth was significantly associated with poor metabolic control (HbA1c ≥6.5%). | |
Segura-Egea et al. ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | The prevalence of AP in at least one teeth was higher in the diabetic group 81.3%), compared to the control group (58%, p = 0.040). Also, in patients with DM, 7% of the teeth was affected by AP, compared to 4% in the control group ( |
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Segura-Egea et al. ( |
7 epidemiological studies, including patients with root canal treatment (total |
Systematic review and meta-analysis | In patients with DM, the prevalence of periapical radiolucent lesions was significantly increased, compared to the control subjects (OR = 1.42; 95% CL: 1.11–1.80; |
|
Smadi ( |
Group 1: Patients with T2DM ( |
Cross-sectional study | The prevalence of teeth with AP and teeth with endodontic treatment were both increased in patients with T2DM. Patients with poorly controlled T2DM had a higher prevalence of AP and teeth with endodontic treatment, compared to well-controlled subjects. | |
Al-Sowygh et al. ( |
Group 1: Patients with HbA1c 6.1–8% ( |
Cross-sectional study | Plaque index, bleeding on probing, pocket depth and jaw bone loss were all increased in the diabetic groups, compared to the control group. Especially the poorly controlled groups (2 and 3) showed higher values. AGEs measured in peri-implant sulcular fluid showed a significant correlation with pocket depth and jaw bone loss. | |
Daubert et al. ( |
Patients with dental implants ( |
Retrospective cohort study with cross-sectional analysis | Having DM at baseline (placement of dental implants) increased the risk for developing peri-implantitis (RR = 3.0, 95% CI: 1.2–7.7) and for implant loss (RR = 4.8, 95%: 1.8–12.9) | |
Ferreira et al. ( |
Group 1: Patients with DM (unspecified type, |
Cross-sectional study | The prevalence of peri-implantitis was significantly increased in patients with DM (24%) compared to the patients without DM (7%). | |
Gomez-Moreno et al. ( |
Group 1: Patients with HbA1c ≤ 6% ( |
Cross-sectional study | Bleeding on probing was significantly different between the groups, with the lowest values in group 1 and the highest values in group 4. Jaw bone loss and pocket depth did not significantly differ between the groups. | |
Monje et al. ( |
7 epidemiological studies—including 2 prospective cohort studies, 1 retrospective cohort study and 4 cross-sectional studies—were found suitable for meta-analysis (patients with DM: combined |
Systematic review and meta-analysis | Patients with hyperglycemia had an almost 50% higher risk for developing peri-implantitis, compared to normoglycemic controls (RR = 1.46, 95% CI: 1.21–1.77). |
Temporomandibular disorder (TMD) is an umbrella term that comprises several conditions affecting the temporomandibular region. The principal clinical feature of TMD is pain during mastication, often accompanied by joint sounds and/or limited opening of the jaw. It is estimated that ~10% of the adult population suffers from TMD (
Burning mouth syndrome (BMS) is a chronic pain syndrome. Usually, two types are distinguished: primary (i.e., idiopathic) BMS if there are no underlying diseases that can explain the complaints, and secondary BMS, when there is an oral or systemic disorder that could explain the condition. In the literature, many synonyms for BMS are used (e.g., glossodynia, sore tongue, or stomatodynia), which complicates estimations regarding epidemiology. BMS rarely affects individuals younger than 30, and estimations of the total prevalence range from 0.7 to 4.6% (
Dental pulp necrosis is the death of cells and tissue inside the root canals and pulp chamber, which can be either symptomatic or asymptomatic. The effect of DM on the dental pulp has mainly been investigated in animal studies. Both acute and chronic effects of hyperglycemia on dental pulp were observed in diabetic rats, characterized by increased inflammation and damage to structural components of the dental pulp (
Closely related to pulp necrosis is periapical or apical periodontitis (AP), a condition in which the periodontal ligament and surrounding alveolar bone around the apex of the tooth is affected. AP is the result of an inflammatory response to an infection of the pulp canals, often caused by caries, trauma, or attrition (
Peri-implant diseases are inflammatory lesions in the tissues around dental implants. As in periodontal diseases, two entities of the condition are recognized: peri-implant mucositis and peri-implantitis (
Prevention and management of well-known complications of DM, such as retinopathy, nephropathy, and neuropathy, are crucial aspects of modern diabetes care. In order to achieve the same for oral complications, this review has provided diabetes care professionals with extensive background knowledge about potential oral complications that can occur in patients with DM. A considerable body of evidence suggests that several oral complications are more prevalent in patients with DM, including periodontitis, dry mouth, dental caries, oral candida infections, oral cancer, and taste disorders. In the case of periodontitis and oral cancer, there are even longitudinal studies that show a temporal association. Some studies suggest that the pathogenic pathways that cause microvascular complications of DM also seem to be involved in oral complications. Even though this is not so evident for all oral complications we discussed, their generally increased prevalence cannot be ignored. Often, there is a lack of decent research that prevents us from establishing or rejecting clear associations between DM and oral diseases and conditions. Therefore, thorough, well-designed research is necessary.
Considering the major impact of oral complications on quality of life, prevention and early management of oral pathologies in diabetes care practice will be crucial. Although this review has provided some insight, recognizing signs and symptoms of oral complications will remain a major challenge for diabetes care professionals. Therefore, as is already the case for the well-known diabetic complications, we strongly encourage an interdisciplinary approach of DM care professionals together with the dental field professionals, to manage potential oral complications.
MV, BL, VG, and WT contributed to the conception and drafting of the review. MV and WT reviewed the literature.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.