The in alloxan induced DM which may serve

The histologicalstructure of the salivary glands is linked to the physiological function of thegland.

An alteration in the structure of the gland will manifest itself as adysfunction of the gland with serious pathological consequences. Change in structureof the salivary glands can be attributed to the hyperglycemia associated withDM. The cause of change cannot be assumed to be a single mechanism but rather acomplex interaction of multiple factors which result in the observed changes.This study focuses on the actual histological changes that occur within theparotid gland and not the mechanism by which they occur since they aremultifactorial. Numerous studieson the submandibular, sublingual and lingual salivary glands have beenperformed and changes in histological structure in DM have been reported. Thegreatest of these changes occur in the parenchyma of the gland whereby acinaratrophy and death have been observed. The blood vessels within the glands haveshown significant changes in luminal diameter and wall thickness and stiffness.

In addition to this, the ductal system in the gland, responsible for essentialmodification of saliva, also undergoes changes in their epithelium and luminaldiameter which then results in a significant alteration in the composition ofsaliva. All these factors must remain unaltered to ensure the normalfunctioning of the gland.  The parotid gland is the largestsalivary gland and secretes the largest amount of saliva compared to thesubmandibular and the sublingual glands.

The saliva not only aids inmastication but contains protective constituents that prevent against oralinfections. Diabetes has been shown to affect the parotid gland by reducing thesalivary flow rate resulting in xerostomia. (S. Conner et al, 1970). Moststudies done on the parotid have studied the changes in the salivary flow rateand changes in the ion concentrations that occur in poorly controlled DM andtherefore are mostly physiological. However, there is no adequate anatomicaldescription of the actual histological changes that occur in the acini, bloodvessels and excretory ducts of the parotid gland in alloxan induced DM whichmay serve to explain the changes in salivary flow rate and alterations incomposition that have been previously observed.

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Therefore, this study aims toexplore these areas in depth to characterize these changes as they occur over aperiod of time. LITERATURE REVIEW Diabetes mellitus is a disease with asignificant impact on salivary glands’ histoarchitecture which leads to adecline in the secretory capabilities of the glands. (Antonio D. Mata et al,2004). The changes that take place within the structure of the gland cannot beattributed to a single mechanism but are a combination of a network of factorsthat work in tandem to bring about the changes.

With the secretory capabilitiescompromised, saliva production reduces, leading to dry mouth also known asxerostomia and other numerous complications. Therefore, understanding the changes that take place in the histomorphologyof the parotid gland (albeit they are multifactorial) is crucial since theparotid is the principal and most essential salivary gland, indispensable tooral function.   NORMAL STRUCTURALANATOMY OF THE PAROTID GLAND The parotid gland is the largest of the paired salivaryglands in the human and weigh about 30 to 40 grams.

It is located bilaterallyin the preauricular region along the posterior border of the mandible. Thefacial nerve runs through the gland, separating it into a superficial and adeeper lobe. The superficial lobe is lateral to the facial nerve and overliesthe lateral surface of the buccinator muscle. The deep lobe is medial to thefacial nerve and is found between the mastoid process and the ramus of themandible. (F. Christopher Holsinger andDana T. Bui, 2007)The parotid gland is confined to a space that is boundedsuperiorly by the zygomatic arch, inferiorly by the sternocleidomastoid muscle,posteriorly by the mastoid and anteriorly by the buccinator muscle.

The deeplobe lies within the Para-pharyngeal space. (Grant J, 1972). In some cases, anaccessory parotid gland is present over the masseter muscle. (Frommer J.

, 1977)The deep fascia of the neck continues superiorly over the parotidgland to form the parotid fascia that then splits into a superficial and a deeplayer. The superficial layer is the thicker of the two and extends from themasseter and sternocleidomastoid muscles to the zygomatic arch while the deeplayer extends to the stylomandibular ligament. (Orabi AA et al,2002).All glands are derived from epithelial cells and consist ofparenchyma (the secretory unit) and the stroma (connective tissue). Salivaryglands are exocrine glands that secrete their products into ducts.

This isbecause they secrete their saliva from blind-ended secretory units called theacinus. There are 3 main types: Serous, mucinous and seromucous. The parotidgland has exclusively serous acini which are roughly spherical and produce awatery protein secretion that is minimally glycosylated or non-glycosylatedfrom secretory granules. The individual acinar cells are pyramidal with basallylocated nuclei. Flat myoepithelial cells envelop the acini by their filamentousprocesses to aid in forced secretion thus allowing rapid salivary secretion.

These myoepithelial cells have also been found around intercalated ducts butare spindle in shape and vary in size (Junquera L et al, 2003)The acini secrete saliva that is isotonic however, the saliva thatenters the oral cavity is hypotonic which suggests that there is some degree ofductal modification. The striated duct cells are the principal cellsresponsible for reabsorption of sodium chloride which render the salivahypotonic (Thaysen JH et al, 1958). The acinar cells and ductal cells alsosecrete bicarbonate which buffers any acidic pH in the oral cavity thusprotecting the enamel from demineralization. (Qin L et al, 2012)Other important constituents of saliva secreted by the parotidgland include statherin, carbonic anhydrase, secretory IgA and IgG, albumin,lysozyme, lactoferrin, interleukin 8 and defensin.

These components playsignificant roles in preventing caries formation and act as immune modulatorysubstances. (Gordon B. Proctor, 2016)The numerous essential roles that saliva plays in normalfunctioning of the oral cavity cannot afford to be underestimated.

However, oneof the most common diseases attributed alteration of gland structure anddecline of saliva production and salivary flow rate leading to oral pathologiesis diabetes mellitus. DIABETES MELLITUS Diabetes mellitus (DM) is one of themost prevalent diseases that affects individuals of all age groups withoutdiscrimination of age or gender. It is a metabolic disorder of multipleetiologies characterized by chronic hyperglycemia with the impairment ofcarbohydrate, fat and protein metabolism resulting from defects in insulinsecretion, insulin action, or both (carlos Antonio, Olinda tarzia, 2010).Glucose levels in the human body are regulated very closely within a range.This range set out by the World Health Organization (WHO) is as follows:Fasting plasma glucose concentration of between 5.

5 to 7.0mmol/L (126 mg/dl)while the range for the whole blood is between 3.2 to 6.7mmol/L (120mg/dl). Anyvalue above this range may be considered diabetic (K.G.

M.M Alberti, P.Z Zimmetfor WHO consultation, 1998).

The disease can be categorized into two maingroups: Diabetes mellitus type 1 and type 2. Diabetes type 1 indicates theautoimmune processes of beta-cell destruction that may ultimately lead to DM inwhich insulin is required to prevent the development of ketoacidosis, coma anddeath. Type 2 diabetes indicates disorders of insulin action and insulinsecretion, either of which may be the predominant feature. DM type 1 is themost common disease of childhood with 1 in every     400 – 600 children being diagnosed with itand it constitutes 5% of all diabetic cases worldwide (Romesh Khardori, 2017) The long-term consequences of DMinclude polyuria, retinopathy, neuropathy, nephropathy, Charcot joints,features of autonomic dysfunction, cardiovascular diseases, peripheral vascularand cerebrovascular diseases (carlos Antonio, Olinda tarzia, 2010).

Besidesdamaging the kidneys, eyes, nerves, blood vessels, and heart, chronichyperglycemia can also be associated with histological changes of the salivaryglands that leads to physiologic alterations in the quantity and quality ofsaliva production from the glands. The reduction in salivary flow leads totaste alterations, burning mouth syndrome, greater tendency to buccalinfections, delayed healing process, decays coated tongue and halitosis (CarlosAntonio Negrato, Olinda Tarzia, 2010) PARENCHYMAL CHANGES OF SALIVARY GLANDS IN DIABETESMELLITUS The parenchyma of salivary glandsrefers to the secretory unit of the gland. This includes: the acini,intercalated ducts and the myoepithelial cells that surround the acini. Theparotid gland is the only salivary gland that has a parenchyma consisting ofexclusively serous acini while other glands contain either mucinous orseromucous acini (Nagao T et al, 2012).  The parotid gland is affected in diabetesin an adverse way, leading to decreased saliva output and bilateralsialadenosis. Hypertrophy of the acini have been documented in diabetic rats,however the details on other aspects such as cellular density changes, bloodvessel wall changes and ductal changes still remain vague and imprecise.

 A study done by C. O Reuterving et allin 1987 on rat submandibular glands showed that the salivary gland weight wassignificantly reduced in diabetic rats and only the diabetic rats had lipidinclusions within the acini while none of this was observed in non-diabeticrats. The acinar cell size was significantly increased in long term diabeticrats compared to short term diabetic rats. The conclusion from this studystated that there is a relationship between the duration of the diabetes andthe extent of changes observed in the salivary glands. However, no suchinformation is available for the parotid gland.

 A separate study on the submandibulargland has described and numerous striking changes that were seen to occur: significantacinar alterations and epithelial degeneration was observed; dilationof many ducts within the gland were seen, with an eosin-stained material andlime material observed in most of the cases. In the stroma, a round-cellinfiltration was seen, as well as a fibrous proliferation around ducts andblood vessels; collagen fibers entrapped in the acini in a localized fashion,thus showing the destruction of parenchymal architecture (Jun Masuno et al 1984).The autonomic nerves to the glands that supply the salivary glands also undergoa process of degeneration in hyperglycemia that causes the acini within theglands to die. After death, they are replaced with connective tissue. (C. O Reuterving et all, 1987) Thesublingual glands have been shown to exhibit changes in diabetes as well.

Lightmicroscopy showed vacuole-like structures with various sizes in the cells ofthe serous Demilune cells. In addition to this, there were granule-likestructures within the cells that appeared to be lipid droplets. This suggeststhat the sublingual mucous cells become dysfunctional during the development ofdiabetes (Masaki Kamata et al, 2007)  Perivascularfoci of lymphatic infiltration and glandular disorganization of normal salivarygland structure was observed in the lingual salivary glands. Diabetes causesstructural changes that increase the susceptibility to oral tissue inflammation,infection and caries owing to the reduction in salivary flow and decrease insalivary protein (Ahmed Elayat, 2000) Keepingin mind that the salivary glands do not have the same secretory cells anddiffer in the composition of secretions, different salivary glands have showndifferent responses to diabetes. Therefore, it is of importance to characterizethe changes that would possibly occur in the parotid gland considering itsimportance in the functioning of the oral cavity and hence its impact on systemichealth. Theparotid gland bears a striking to resemblance to the structure of the pancreassince both these glands are serous and are exocrine in part. Therefore, anychanges that occur in diabetes to the exocrine portion of the pancreas may alsobe extrapolated to the parotid gland.

The pancreas shows a 33% reduction involume in diabetic rats compared with normal controls which was statisticallysignificant (Matteo Piciucchi et al,2015).  Histomorphological studies also describedacinar fibrosis and atrophy including diminution of pancreatic size, fattyinfiltration and loss of acinar cells in diabetes mellitus (Philip D. Hardt etal, 2002) BLOOD VESSEL CHANGESIN DIABETES MELLITUS Diabeticangiopathy is one of the most significant processes that occurs in diabetes andleads to serious conditions such as retinopathy and glomerulonephritis. The DMmanifests as endothelial cell dysfunction, structural changes of large andsmall arteries, deficits in tissue perfusion and hypoxia. The structuralchanges that occur are due to altered lumen to wall ratio since DM causes acharacteristic thickening of the of the tunica intima and media along withincreased stiffening (Gaia Spinetti et al, 2008). If these changes take placein the eye and the kidney then it is also possible that they do occur inparotid gland as well and is worth investigating.

 In thesubmandibular gland, a sclerotic alteration was seen in arteries and also inarterioles and capillaries, making the latter appear numerous. Also,alterations indicating a certain diabetic vascular lesion were also observed.(Jun Masuno et al 1984). A separate study performed on the blood vessels in thesubmandibular gland found that the greatest histological differences were foundin the endothelium of small arteries and consisted of significant proliferationof swollen endothelial cells, obliterating the lumen, marked fibrosis andhyalinization (Arthur R. Colwell 1960).  Similarly,another study done on the submandibular gland showed that the lumen of theblood vessels was changing as the DM progressed over time indicating pronounceddiabetic microangiopathy. The endothelial cells showed signs of damage by day 42and by day 56 the morphometry of the endothelial cells was significantlyaltered and the lumen of the capillaries was far smaller compared to thecontrols (Kotyk Taras et al, 2014)Thelingual salivary glands showed degenerative changes of the blood vessels inform of hyalinized thickenings of their walls (Ahmed Elayat, 2000). Increasedcapillary density in streptozotocin induced diabetic rat submandibular glandswas observed and positively correlated to the edema seen in the gland.

Thislead to significant dysfunction of the salivary gland (Anderson et al, 1992) Theincreased capillary density is due to the fact that the diabetes causes hypoxiain tissues by reduction in luminal size and increased wall thickness of theblood vessels. Therefore, the tissues release intrinsic angiogenic factorswhich are responsive to changes in the oxygen tension and so are elevated inDM. The support for this theory comes from a study performed on thesubmandibular gland which showed that chronic hypoxia causes an increase in thecapillary density (Scott and Gradwell, 1989). DUCTALCHANGES IN DIABETES MELLITUS Theducts of salivary gland begin at the acinus. The acini secrete into theintercalated ducts (intralobular ducts) which link the acinar lumen with thelarger components of the duct system within the salivary gland. Intercalatedducts drain into the secretory or striated ducts (interlobular ducts). Theintercalated ducts are composed of a simple squamous and in some cases, lowcuboidal epithelium, while the secretory ducts are of a simple columnarepithelium. The striated ducts are the principal ducts that are responsible forionic exchange from the saliva.

The secretory ducts drain into excretory ductswhich vary in histological appearance from simple columnar to stratifiedsquamous epithelium. Stenson’s duct is the main excretory duct of the parotidgland. (Francesca Testa riva et al, 1995) The Stensen’s duct emerges from the gland and runs forwardalong the lateral side of the massetermuscle. In this course, the duct is surroundedby the buccal fat pad. (Ruiz Liard et al, 2005) It takes a steep turn at the border of the masseterand passes through the buccinatormuscle, opening into the vestibule of the mouth, the region of the mouth between the cheek and the gums, at the parotid papilla, which lies across the secondsuperior molar tooth. (Bath-Balogh and Fehrenbach, 2011) It is a well-established fact that diabetes causes achange in the composition and volume of saliva produced by the salivary glands (AntonioD.

Mata et al 2004). As mentioned previously, the ducts cause modification insalivary composition, this suggests that there may be alterations with theductal epithelium which result in a deficiency of ion exchange. There is littleliterature to this effect regarding the parotid gland. However, thesubmandibular glands and the lingual glands have been observed to show ductalchanges in DM. A study done by M.M Moneteiro in 2016 showed that themorphology of the submandibular ducts was affected in the hyperglycemic statewith a reduction of the convoluted duct area which was observed by morphometry.

In addition to this, a separate study on the submandibular glands showed thatthere was a clear reduction in size and number if the granular ducts as earlyas three weeks after the initial induction of diabetes (Leigh C. Anderson et al1994). This study also found that the most striking feature at lightmicroscopic level involved the granular ducts of the gland and theiralterations in DM.  The lingual salivary gland’s striated ducts also showedhypotrophic changes in response to the DM. Periductal foci of lymphocyticinfiltration was observed which can explain the dysfunction associated with thegland (Ahmed Elayat, 2000).

 Theliterature available regarding the ductal changes in the submandibular andlingual glands is abundant, however, changes in the parotid gland ducal systemstill, to this day remain scarcely documented. Literature on the main excretoryduct of the parotid gland (Stenson’s duct) is even more so scarce. Therefore,this study is set to explore these vague areas and describe the changes whichoccur within the main excretory duct of the parotid gland.