Epidemiological and clinical studies have established an association between periodontitis and Type 2 Diabetes Mellitus (T2DM)/obesity. However, the causality and mechanisms linking periodontitis to T2DM are not known. We have established animal models of induced periodontitis to study the causality underlying this association. Using Zucker Diabetic Fatty (ZDF) rats, we demonstrated that periodontitis accelerates the development of insulin resistance (IR) and T2DM in high fat (HF), but not low fat fed animals. Since certain bacterial lipopolysaccharides (LPS) from periodontal lesions and free fatty acids (FFAs) from HF diet promote inflammation through Toll-like-receptor 4 (TLR4), and inflammation in general promotes insulin resistance, we have recently explored the role of TLR4 in mediating periodontitis-enhanced IR using mice with TLR4 loss-of-function (LOF) mutation and wild-type (WT) controls. Our results demonstrate that insulin signaling is impaired in the livers of WT TLR4 vs. TLR4-/- animals with periodontitis and furthermore, the plasma glucose level improves in TLR4-/- animals with periodontitis. Insulin functions to maintain whole body glucose levels in a narrow ideal range by balancing production of glucose by the liver and glucose uptake by skeletal muscle and adipose tissue. We therefore hypothesize that: 1) periodontitis affects insulin target organs (liver, muscle and adipose tissue) by suppressing insulin signaling via TLR4, leading to an alteration in whole body glucose homeostasis, 2) LPS triggers hepatic IR, 3) periodontitis/LPS affects insulin secretion via a TLR- dependent mechanism by influencing beta-cell mass and/or glucose-stimulated insulin secretion. To test these hypotheses, we will 1) determine the effects of periodontitis/LPS on insulin target organs via TLR2 &TLR4 by a) identifying specific sites of inhibition of insulin signaling, and b) determining the expression of key molecules involved in hepatic glucose production (G6Pase, PEPCK) as well as peripheral glucose uptake (AS160) by skeletal muscle and adipose tissue using whole body TLR4 and 2&4 knockout mice, 2) determine the pathways involved in periodontitis-induced hepatic IR and altered glucose homeostasis via TLRs using TLR2&4 adoptive bone marrow chimeric mice, 3) identify mechanisms by which periodontitis influences pancreatic beta-cells by modulating beta-cell compensatory alterations (insulin secretion, beta-cell hyperplasia &apoptosis) via TLRs. The impact of the proposed studies will: 1) advance our understanding of how periodontitis directly influences distant organs/tissues involved in glucose homeostasis, and 2) identify for the first time, specific TLR-mediated effects of periodontitis on insulin sensitivity and glucose homeostasis. The results will impact future treatment modalities, especially for subjects who are consuming a high fat diet where inflammation/LPS resulting from periodontitis may play a central role in IR and diabetes.

Public Health Relevance

It is known that there is a close association between gum disease and diabetes, however the causality of how gum disease affects prediabetes/diabetes is not known. This proposed study will determine pathways by which gum disease influences distant organs, such as the liver and muscle, and modulates glucose levels. This study will lead to a new treatment paradigm to improve gum disease and prediabetic conditions.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral, Dental and Craniofacial Sciences Study Section (ODCS)
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Atkinson, Jane C
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University of Illinois at Chicago
Schools of Dentistry
United States
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Ilievski, V; Bhat, U G; Suleiman-Ata, S et al. (2017) Oral application of a periodontal pathogen impacts SerpinE1 expression and pancreatic islet architecture in prediabetes. J Periodontal Res 52:1032-1041
Ilievski, Vladimir; Kinchen, Jason M; Prabhu, Ramya et al. (2016) Experimental Periodontitis Results in Prediabetes and Metabolic Alterations in Brain, Liver and Heart: Global Untargeted Metabolomic Analyses. J Oral Biol (Northborough) 3:
Bhat, Uppoor G; Watanabe, Keiko (2015) Serpine1 Mediates Porphyromonas gingivalis Induced Insulin Secretion in the Pancreatic Beta Cell Line MIN6. J Oral Biol (Northborough) 2:
Ilievski, Vladimir; Cho, Yale; Katwala, Priya et al. (2015) TLR4 Expression by Liver Resident Cells Mediates the Development of Glucose Intolerance and Insulin Resistance in Experimental Periodontitis. PLoS One 10:e0136502
Bhat, Uppoor G; Ilievski, Vladimir; Unterman, Terry G et al. (2014) Porphyromonas gingivalis lipopolysaccharide upregulates insulin secretion from pancreatic ? cell line MIN6. J Periodontol 85:1629-36
Watanabe, Keiko; Cho, Yale D (2014) Periodontal disease and metabolic syndrome: a qualitative critical review of their association. Arch Oral Biol 59:855-70