Graduation Year

2015

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Brant R. Burkhardt, Ph.D.

Committee Member

Amy Alman, Ph.D.

Committee Member

Meera Nanjundan, Ph.D.

Committee Member

Stan Stevens, Ph.D.

Keywords

circadian rhythms, cytokines, diabetes, hyperglycemia, saliva

Abstract

Diabetes has afflicted 8.3%, approximately 25.8 million, of the United States population and is the seventh leading cause of death [1]. Type I diabetes (T1D) accounts for 5 to 10% of all diagnosed cases of diabetes in the United States [2]. If present trends continue, the rate of T1D incidence among children under the age of 14 will increase by 3% globally [3]. T1D is an autoimmune disorder in which the β-cells of the pancreatic islets are destroyed, leading to high blood sugar. Hyperglycemia and loss of immunological tolerance to self-antigens are common associations of T1D [4]. Periodontal disease impacts as much as 47% of the U.S. population and is a significant cause for tooth loss in adults [5]. Chronic infections from bacterial populations that colonize the tooth root surface result in the activation of immunological mediators and various metabolic byproducts, such as cytokines, chemokines, and tissue-destructive enzymes [6, 7]. Studies have demonstrated that the increased systemic inflammation associated with periodontal disease appears to contribute to several systemic diseases, particularly diabetes [8, 9], with a strong, bi-directional, relationship between diabetes and periodontal disease in which glycemic control is a major determinant. Improved biomarkers for T1D prediction are needed.

Cytokines serve an important part in the onset of T1D and strongly determine the ultimate fate of β cell destruction [10]. Such cytokines include interleukin 1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10), interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α). Th1 cytokines such as IL-1β, IFN-γ, and TNF-α have been demonstrated to induce pancreatic β-cell apoptosis. Matrix metalloproteinases (MMPs) have been demonstrated to participate in the pathogenesis of periodontitis. Hence, the measurement of these inflammatory cytokines and MMPs may serve as a marker for the onset or progression of T1D and glycemic control. There have been no previous studies describing the distribution of salivary biomarkers of inflammation in T1D. Saliva represents a suitable bioreservoir for cytokines and can be collected noninvasively with very little to no stress upon the donor allowing for multiple collections if needed and it is easy to collect, store, and transport [11], however there are circadian patterns that must be accounted for. Therefore, we measured the levels of cytokines and MMPs in the saliva of T1D patients, characterized diurnal patterns of salivary cytokines in healthy subjects, and explored sources of inflammation to increase our understanding of salivary biomarkers of inflammation as a prediction of the progression of T1D and gum health and glycemic control.

This work demonstrated that specific salivary inflammatory markers - MMP-8, MMP-9, and TNF-α - in T1D subjects are associated with decreased glycemic control. Diurnal patterns of salivary proteins must be accounted for upon collection due to the unique rhythms of cytokine expression within each individual. Upon glucose stimulation, pro-inflammatory (Th2) cytokines, such as IFN-γ and IL-13, tend to decrease, whereas anti-inflammatory (Th1) cytokines, such as IL-10, tend to increase. Hyperglycemic conditions may promote an anti-inflammatory profile of human submandibular gland cells.

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