Links between Insulin Resistance and Periodontal Bacteria: Insights on Molecular Players and Therapeutic Potential of Polyphenols

Abstract

Type 2 diabetes is a metabolic disease mainly associated with insulin resistance during obesity and constitutes a major public health problem worldwide. A strong link has been established between type 2 diabetes and periodontitis, an infectious dental disease characterized by chronic inflammation and destruction of the tooth-supporting tissue or periodontium. However, the molecular mechanisms linking periodontal bacteria and insulin resistance remain poorly elucidated. This study aims to summarize the mechanisms possibly involved based on in vivo and in vitro studies and targets them for innovative therapies. Indeed, during periodontitis, inflammatory lesions of the periodontal tissue may allow periodontal bacteria to disseminate into the bloodstream and reach tissues, including adipose tissue and skeletal muscles that store glucose in response to insulin. Locally, periodontal bacteria and their components, such as lipopolysaccharides and gingipains, may deregulate inflammatory pathways, altering the production of pro-inflammatory cytokines/chemokines. Moreover, periodontal bacteria may promote ROS overproduction via downregulation of the enzymatic antioxidant defense system, leading to oxidative stress. Crosstalk between players of inflammation and oxidative stress contributes to disruption of the insulin signaling pathway and promotes insulin resistance. In parallel, periodontal bacteria alter glucose and lipid metabolism in the liver and deregulate insulin production by pancreatic β-cells, contributing to hyperglycemia. Interestingly, therapeutic management of periodontitis reduces systemic inflammation markers and ameliorates insulin sensitivity in type 2 diabetic patients. Of note, plant polyphenols exert anti-inflammatory and antioxidant activities as well as insulin-sensitizing and anti-bacterial actions. Thus, polyphenol-based therapies are of high interest for helping to counteract the deleterious effects of periodontal bacteria and improve insulin resistance.

Keywords: diabetes; inflammation; insulin resistance; obesity; oxidative stress; periodontal bacteria; polyphenols.

Figure 1

Insulin signaling pathway mediating glucose uptake. Insulin binds to its receptor (IR) and activates its tyrosine kinase activity. IR catalyzes the phosphorylation of tyrosine residue of IRS-1 protein, which in turn activates PI3K. Subsequently, PI3K metabolizes PIP2 to PIP3, leading to PDK1 activation. PDK1 activates Akt by phosphorylation on threonine residue. Activated Akt inhibits AS160 protein. Under basal condition, AS160 hydrolyses Rab-GTP to its inactive form Rab-GDP via its Rab GAP domain. Inhibition of AS160 by Akt promotes the translocation of GLUT-4 transport vesicles to the cell plasma membrane, allowing glucose uptake.

Figure 2

Molecular mechanisms impairing insulin signaling. Periodontal bacteria components and free fatty acids bind to TLRs at the plasma membrane of the target cell. TLRs recruit MyD88 and induce the activation of IRAK and TRAF6 proteins. This leads to the induction of NF-κB and MAPK pathways involving the transcriptional factors NF-κB and AP-1, respectively. These pathways promote the secretion of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1β. At the cell plasma membrane, cytokines bind to specific receptors and induce the activation of JNK and SOCS3. IKK and JNK are involved in signaling pathways downstream of TLRs, and SOCS3 induces insulin resistance by serine phosphorylation of IRS-1. Inactivation of IRS-1 impairs insulin signaling, resulting in the retention of GLUT-4 in the cytoplasm. In parallel, NF-κB/AP-1 pathway activates the expression of genes encoding ROS-producing enzymes like NOX and iNOS. Excessive intracellular ROS levels contribute to insulin resistance by activating IKK and JNK, which directly inhibit IRS-1, and by inducing NF-κB and MAPK pathways that lead to the production of pro-inflammatory cytokines.

Figure 3

Structural classification of dietary polyphenols. Dietary polyphenols are classified into 4 major chemical families, including flavonoids, phenolic acids, stilbenes and lignans. The flavonoids are subdivided into 6 subclasses named flavones, isoflavones, flavonols, flavanones, flavanols and anthocyanins, which share a common structure composed of 2 aromatic rings (A,B) bound together by 3 carbon atoms forming an oxygenated heterocycle (C). The phenolic acids comprise hydroxybenzoic and hydroxycinnamic acids, derivatives of benzoic and cinnamic acids, respectively. The stilbenes are composed of 2 phenyl groups joined together by a methylene bridge. The lignans are composed of 2 phenylpropane units.

Figure 4

Overview of periodontal bacteria detrimental effects related to insulin resistance and therapeutic potential of polyphenols. Periodontitis results from oral microbiota dysbiosis and leads to the progressive destruction of the periodontal tissues. During periodontitis, periodontal bacteria components disseminate into systemic circulation and may reach distant tissues, including adipose tissue, skeletal muscle, liver and pancreas. Locally, periodontal bacteria enhance the production of pro-inflammatory cytokines such as IL-6, TNF-α and MCP-1 and promote oxidative stress. Crosstalk between players of inflammation and oxidative stress induces insulin resistance. Moreover, in the liver, periodontal bacteria alter glucose and lipid metabolism by decreasing glycogen synthesis and increasing fat accumulation. In the pancreas, periodontitis is associated with changes in the islets’ architecture and alteration of insulin secretion. Altogether, these detrimental effects of periodontal bacteria contribute to type 2 diabetes. Interestingly, polyphenols able to exert anti-inflammatory, antioxidant, insulin-sensitizing and anti-bacterial properties may help to counteract the deleterious action of periodontal bacteria and improve insulin resistance.