Salivary gland proteins alterations in the diabetic milieu

Abstract

Salivary glands are considered the chief exocrine glands of the mouth and physiologically contribute to the maintenance of the homeostasis of the oral cavity. They consist of the parotid, submandibular and sublingual glands, which come in pairs and are collectively called the major glands, and the minor glands, which are much smaller and are dispersed throughout the buccal cavity. Salivary glands are distinguished by their size, amount of saliva secretion and their location in the oral cavity. Salivary glands pathophysiology has been a subject of interest in various worldwide metabolic disorders, including diabetes mellitus. Diabetes mellitus (DM), a global health concern, with a pathological imprint involved in vasculature, promotes microvascular and macrovascular complications among which periodontitis ranks sixth. Indeed, DM has also been directly associated with oral health lesions. Specifically, salivary glands in the context of diabetes have been a focal point of study and emphasis in the research field. There is evidence that relates salivary secretion content and diabetes progression. In this review, we present all the reported evidence of the deregulation of specific salivary proteins associated with the progression of diabetes in parallel with changes in salivary gland morphology, cellular architecture, and salivary secretion and composition more generally.

Keywords: Biomarkers; Diabetes mellitus; Muscarinic receptors; Salivary glands; Screening.

Fig. 1

CSP1 is a salivary gland specific protein. Immunostaining of CSP1 in salivary (left), thyroid (center) and adrenal gland tissue (right) demonstrated that CSP1 stains specifically and exclusively salivary glands and not the other two tissues rendering it a salivary gland-specific protein. Wang et al., . Journal of clinical laboratory analysis. Taken from: https://doi.org/10.1002/jcla.21963 (Wang et al. 2016)

Fig. 2

Salivary secretion pathway in DM. Consistent hyperglycemia will lead to an increased state of oxidative stress that ultimately impacts salivary secretion and flow. In diabetes, M3R’s binding sites, affinity and drug susceptibility are decreased which in turn result in a lower intracellular Ca2 + ([Ca2 +]i). Combined with a decrease in BH4, a cofactor necessary for the dimerization of uNOS into cNOS, NOS activation is decreased paralleled by a reduction in NO catalyzation and AQP5 translocation. cGMP production is decreased due to NO deficiency and fails to open ion channels (i.e. K + channels, Cl- channels, Na + /K + pumps) to initiate salivary secretion. The obstruction of this pathway in DM leads to reduced salivary flow, secretions and histomorphological changes accompanied by acinar cells degeneration. Administration of pilocarpine, a cholinergic agonist, slightly alleviates those effects, whereas insulin, LLLT and IXD work directly on recruiting and upregulating AQP5 to reverse those effects. M3R, Muscarinic M3 receptor; [Ca2 +]i, intracellular calcium; uNOS, uncoupled nitric oxide synthase; cNOS, coupled nitric oxide synthase; NO, nitric oxide; cGMP, cyclic guanylate monophosphate; AQP5, aquaporin 5; LLLT, low-level laser therapy; IXD, ixeris dentata

Fig. 3

Caspace-3-mediated apoptosis increases in postnatal offspring submandibular glands of diabetic rats. A and C (2 weeks (2w) postnatal control and 4 weeks (4w) postnatal control groups) showing negative caspase-3 reaction. B (2w diabetic group) showing positive caspase-3 reaction in the form of brown discoloration of the cellular acini. D (4w diabetic group) showing very strong positive caspase-3 reaction. (Caspase-3 × 1000). El Sadik et al., . PLoS One. Taken from: https://doi.org/10.1371/journal.pone.0205372 (El Sadik et al. 2018)

Fig. 4

PCNA reduction impedes cell growth in postnatal offspring submandibular glands of diabetic rats. A and C (2w control and 4w control groups) showing strong positive PCNA reaction (arrows) in the cellular nuclei of the acini. B and D (2w diabetic and 4w diabetic groups) showing minimal PCNA reaction (arrows). (PCNA × 1000). El Sadik et al. . PLoS One. Taken from: https://doi.org/10.1371/journal.pone.0205372 (El Sadik et al. 2018)