Evaluating All Potential Oral Complications of Diabetes Mellitus

Abstract

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.

Keywords: diabetes mellitus; dyslipidemia; hyperglycemia; hypertension; immune dysfunction; insulin resistance; oral complications.

Figure 1

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.

Figure 2

Oral complications of diabetes mellitus. 1A & 1B: Periodontitis. A clinical view of periodontitis is shown in figure 1A, with the corresponding radiograph displayed in image 1B. The green dots in image 1B indicate where the bone level originally was, while the red dots show the actual bone level as a result of inflammation. 2A & 2B: Dental caries. Image 2A displays a clinical view of dental caries, observed from the occlusal view. Picture 2B is a radiograph of an example of a deep carious lesion, marked by the red circle. 3. Hyposalivation. The photo in image 3 shows a clinical view of fissured tongue, caused by severe hyposalivation. 4. Oral candidiasis. Image 4 displays a clinical view of oral candidiasis, located at the palate. 5A & 5B: Oral cancer. At image 5, a clinical representation of leukoplakia and oral cancer is shown at the buccal (5A) and palatal (5B) site. 6A & 6B: Apical periodontitis. Figure 6A shows a fistula, caused by apical periodontitis, with image 6B as the corresponding radiograph, where the lesion at the apex of the tooth is marked by the red circle. 7A & 7B: Temporomandibular disorders. Image 7A indicates the location of pain often seen in patients with temporomandibular disorders, while 7B shows a measurement of limited jaw opening, another symptom of temporomandibular disorders. 8A & 8B: Peri-implantitis. At figure 8A, a clinical view of peri-implantitis is presented, with 8B as the corresponding radiograph. Again, the red dots indicate where ideally, the bone level should be, while the red dots show the actual reduced bone level as a result of the inflammatory process. The authors thank the following colleagues for providing clinical pictures and/or radiographs: Dr. AJP van Strijp (dental caries), Prof. Dr. M Laine (hyposalivation), Dr. P Wetselaar (temporomandibular disorders and apical periodontitis), all from ACTA, the Netherlands; Dr. RJJ van Es (oral cancer), UMC Utrecht, The Netherlands; Prof. Em. Dr. I van der Waal (oral candidiasis).