Markers, Pathways, and Current Evidence for Periodontitis-associated Insulin Resistance: A Narrative Review

ABSTRACT

Aims and Objectives:

The aim of the present paper is to provide a narrative review of the markers and pathways of periodontitis-associated insulin resistance (IR).

Materials and Methods:

Research papers published in peer-reviewed scientific journals from 2000 to 2021 were searched systematically in Online Cochrane Library, Google Scholar, and MedLine/PubMed database. The medical subject headings (MeSH) terms used for literature search were “diabetes AND periodontal disease,” “diabetes AND periodontitis,” “inflammation AND insulin resistance,” “Insulin resistance AND periodontal disease,” and “insulin resistance AND periodontitis.” Manual search for applicable work in review article peer-reviewed print journals, and latest editions of standard textbooks of pharmacology and pathology were searched for updated additional information. Relevant papers in English language on the topic and abstracts of pertinent articles after excluding the duplicates, animal studies, and in-vitro studies were also scrutinized thoroughly and finally included as required in this narrative review.

Results:

Literature search in MedLine/PubMed with MeSH words mentioned above revealed 4,621, 4,993, 19,349, 414, and 434 papers, respectively. Seven out of 13 systematic reviews and a total of 18 randomized clinical trials to evaluate periodontitis-induced IR were short-listed to update current evidences. The current literature in the past two decades has evaluated the effect of periodontal therapy on various type-2 diabetes (T2D) biomarkers following periodontal therapy. These indicators of periodontal disease activity and surrogate biomarkers of T2D in periodontitis may be an important diagnostic tool for the early prediction of complications due to IR. This increased systemic burden of proinflammatory cytokines by periodontitis can be reduced by periodontal therapy, thus improving the patient’s overall systemic condition.

Conclusion:

The inflammatory response in periodontitis is characterized by dysregulated secretion of host-derived mediators of inflammation and tissue breakdown that may lead to IR. It can be comprehended that periodontal disease is a recognized amendable risk factor for T2D.

INTRODUCTION

Diabetes mellitus (DM) and periodontal diseases are among the most prevalent chronic diseases in the world. DM is speedily developing as one of the highest universal health challenges of the twenty-first century.[1] Epidemiological studies have observed a rapidly increasing trend in DM epidemic mainly in Indian subcontinent countries.[2,3]

DM, mainly type-2 diabetes (T2D) that accounts for 90% of all DM cases,[4,5,6] is an intricate, chronic endocrinal disorder of metabolic imbalance in protein, fat, and carbohydrate metabolism produced by either resistance to insulin action or augmented compensatory insulin release, or in unison of both.[7,8] Insulin resistance (IR) has evidently appeared as an important source of glucose intolerance leading to T2D.[9,10] Chronic exposure to proinflammatory (PI) cytokines and/or oxidative stress (OS) mediators activates cytokine signaling proteins that eventually obstruct the activation of insulin signaling receptors in β-cells of pancreatic islets, thus producing IR.[11,12,13,14,15]

Current evidence suggests that periodontitis being a low-grade infection is proficient enough to advance a low-grade systemic inflammation, thus able to impact the overall systemic health.[16] However, literature providing the molecular mechanisms interlinking periodontitis-related DM in a single paper is scanty. Therefore, the present paper intends to provide a narrative review based on partial PRISMA guidelines for plausible molecular events, pathways, and current update interlinking the mechanism for periodontitis-associated DM.

MATERIALS AND METHODS

Research papers published in peer-reviewed scientific journals from 2000 to 2021 were searched in Online Cochrane Library, EMBASE, Google Scholar, and MedLine/PubMed database. The medical subject headings (MeSH) terms used for literature search in MedLine/PubMed search engine were “diabetes AND periodontal disease,” “diabetes AND periodontitis,” “inflammation AND insulin resistance,” “Insulin resistance AND periodontal disease,” and “insulin resistance AND periodontitis” and revealed 4,621, 4,993, 19,349, 414, and 434 papers, respectively. Relevant papers in English language on the topic and abstracts of pertinent articles after excluding the duplicates, animal studies, and in-vitro studies were scrutinized thoroughly and finally included in this narrative review. Seven out of 13 systematic reviews and 18 randomized clinical trials that evaluated periodontitis-induced IR were included to update current evidences. Manual search for applicable work in review article from peer-reviewed print journals and latest editions of standard textbooks of pharmacology and pathology were searched for updated additional information [Figure 1].

Figure 1.

Flow chart showing literature search strategy

RESULTS

Review of literature in the past few decades has revealed update in pathways, markers, and pathophysiology that connect IR with periodontitis. The summary of the findings from the pertinent literature can be divided into the following subheadings.

INSULIN SYNTHESIS, RELEASE, AND REGULATION

Insulin is initially synthesized in the Golgi apparatus of beta-cells in pancreas as pre-proinsulin (110 amino acids) consisting of single polypeptide chain, B chain, C-peptide chain, and A-chain [Figure 2]. Insulin and C-peptide (31 amino acids) are stored in secretory granules and co-secreted in equimolar quantities by exocytosis from cell membranes.[17,18] Insulin secretion and control are monitored by a well-synchronized interaction between nutrients (extracellular glucose, fatty acids, ketone bodies, and amino acids), gastrointestinal hormones (incretins, GIP and GLP-1), pancreatic hormones (glucagon and somatostatin), and autonomic neurotransmitters. Stimulation of alpha-2 receptors, e.g., by hypoxia, hypoglycemia, exercise, hypothermia, surgery, or severe burns, impedes insulin discharge, whereas β2 adrenergic and vagal nerve stimulation enhances insulin secretion.[19,20]

Figure 2.

Structure and function of insulin [modified from Maitra[17]]

Rorsman and Braun[19] reviewed the regulation of insulin secretion from a pancreatic beta-cell in detail. The pancreatic beta-cell in a resting or fasting state is hyperpolarized. On entry into pancreatic beta-cells via glucose transporter-1 (GLUT-1) in humans, glucose is quickly phosphorylated producing G6P which enters the glycolytic pathway in mitochondria leading to elevation of ATP. This ATP binds to and inhibits Kir 6.2 subunits of the ATP-mediated K channel. Diminished K deportment results in depolarization of the local membrane and stimulation of Na⁺ and Ca⁺⁺ channels, and this increases the Ca⁺⁺ excitation of stored insulin exocytosis.[18,19] Both acetylcholine and incretins activate the Gq-PLC-IP3-Ca-PKC pathway via M3 receptors and the Gs-AC-cAMP-PKa/EPAC2 pathway via GPC receptors, respectively, resulting in increase in the exocytosis of insulin. Elevated levels of cAMP also further enhance the exocytosis by inhibiting ATP-mediated K channel, whereas somatostatin receptors SST2/3 with G_i/0 reinstate cell membrane hyperpolarization [Figure 3].[19]

Figure 3.

Insulin release and signaling mechanism [modified from Maitra[17] and Powers and D’Alessio 2018[18]

INSULIN SIGNALING AND ACTION

Almost all mammalian cells express the insulin receptor forms; however, the liver, skeletal muscle, fatty tissue (adipocytes) as well as specific areas of the brain and the pancreatic islet are critical for the regulation of blood glucose. Insulin performs its action via receptor tyrosine kinase similar to the IGF-1 receptor. Insulin binds to its receptor and triggers cascade of signaling events that stimulate intrinsic tyrosine kinase of the receptor dimer. This results in the tyrosine phosphorylation of the receptor’s beta subunits, and small numbers of specific substrates (IRS proteins, Gab-1 and Shc), and a caveolar pool of insulin receptor phosphorylates caveolin (Cav), adaptor protein with PH and SH2 domains (APS), and Cbl-associated protein (CAP) within the membrane. Crucial event in the target tissue is the translocation of GLUT-4 from intracellular vesicles to the plasma membrane, which is stimulated by both the caveolar and non-caveolar pathways. Insulin also stimulates the plasma membrane Na⁺ and K⁺-ATPase that enhances pump activity and a net accretion of K⁺ in the cell [Figure 3].[18,19]

The role of insulin on glucose transport rests on the stimulation of phosphatidylinositol 3-kinase (PI3K), which is triggered after interaction with IRS proteins. This generates phosphatidylinositol 3,4,5-trisphosphate phosphatase (PIP3) that further controls the action of downstream kinases [PKB (Akt), protein kinase C (PKC), and mTOR]. PKB (or Akt) is the collective name for a set of three serine/threonine-specific kinases that mediate its effector functions via phosphorylation-dependent events and plays a role in multiple cellular processes, e.g., glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. Insulin’s action on a target cell that mediated via insulin binding to the tetrameric receptor activates “insulin receptor substrate-phosphoinositide 3-kinase/Akt” (IRS-PI-3-kinase/Akt) signaling. Akt phosphorylates and inhibits the function of the tuberous sclerosis complex proteins, leading to activation of the downstream mammalian TOR (mTOR) complex which enhances protein synthesis. Akt also inhibits the function of Forkhead box O (FOXO) protein, which, in turn, reduces glucose synthesis, whereas inhibition of glycogen synthase kinase 3 (GSK3) enhances glycogen production [Figure 3]. Akt also enhances intracellular glucose uptake by translocation of GLUT-4 vesicles to the cell membrane.[17,18,19,20]

INSULIN RESISTANCE (GLUCOSE INTOLERANCE)

The measured quantity of glucose that is removed from the blood by a static dosage of insulin is known as insulin sensitivity, and the failure of normal amounts of insulin to elicit the expected response is referred to as IR. IR can be established by genetic and environmental factor and leads to impaired glucose tolerance. Defective signaling of insulin receptor at manifold levels is essential to the pathogenesis of T2D.

Petersen and Shulman[21] summarized all linking putative mediators of IR and proposed that IR is triggered by rising nutrient-derived toxic metabolites (DAG, acylcarnitine, ceramide, branched-chain amino acids), overdoing nutrient consumption (oxidative and endoplasmic reticulum stress), or answering to nutrient stress-mediated cellular toxicity (inflammation). Various mechanisms proposed for developing IR are as follows:

1. Intramyocellular lipid metabolites trigger IR through activation of seine kinase cascade leading to abridged insulin stimulation of IRS-1 tyrosine phosphorylation.[1]

2. In “fat-induced hepatic IR” linked to non-alcoholic fatty liver, increase in hepatocellular diacylglycerol leads to activation of PKC, causing “reduction in insulin stimulation” of IRS-2 tyrosine phosphorylation. This decreases insulin stimulation of glycogen synthase activation and downregulates phosphorylation of FOXO protein, thus resulting in an increase in hepatic gluconeogenesis.[1]

3. Errors in “mitochondrial oxidative phosphorylation activity” cause IR in both the elderly and young-thin “insulin-resistant offspring” of parents with T2D.[1]

4. According to the adjustable threshold hypothesis, insulin is the body’s “ration stamp” to restrict glucose utilization by peripheral tissues, in contrast to common belief that insulin promotes glucose disposal.[4]

5. Various PI mediators and pathways interfere with insulin signaling pathways and develop IR that subsequently increases OS in beta-cells of pancreatic islets and peripheral tissues. This impairs insulin secretion and insulin sensitivity in β-cells of pancreatic islets and peripheral tissues, respectively [Table 1].[14,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42]

6. PI cytokines, pattern recognition receptors (PRRs), e.g., TLRs, RAGEs, and so on, cellular stress markers ROS, ER, ceramides, and PKC isoforms activate JNK and IKKB/NFK-B pathways relating to IR, via activation of NADPH oxidase by lipid accumulation in adipocytes. Activation of JNK and IKKB/NFK-B leads to serine phosphorylation of IRS-1, resulting in IR.[43]

Table 1.

Processes, signaling pathways, and mediators involved insulin metabolism and resistance[14,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42]

AMP-activated protein kinase (AMPK)

Autophosphorylation

Chemokines-induced IR: CCL2, CCL3, and CCR5 and its ligand MCP-1

c-Jun N-terminal kinases (JNKs)

Endoplasmic reticulum stress

Forkhead box O (FOXO) proteins

Glucolipotoxicity (glucotoxicity and lipotoxicity)

IL-1-beta

IL-6

Inhibitor kB kinase (IKK) and protein kinase C (PKC)

Inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ)

Mitogen-activated protein kinase (MAPK or MAP kinase)

Myeloid differentiation primary response 88 (MyD88)

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)

Phosphatidylinositol 3-kinase (PI3K)

PI3K/AKT/mTOR pathway

Protein kinase A (PKA) AKT [also known as protein kinase B (PKB)]

Protein kinase C (PKC)

TNF-alpha

Toll-like receptors (TLR-2 and -4)

Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) Toll-interleukin-1 receptor-domain (TIR)-containing adapter-inducing interferon-β (TRIF-β)

TRIF-related adaptor molecule (TRAM) [also known as TIR-containing adaptor molecule (TICAM)-2]

ASSESSMENT OF IR

Estimation of IR is essentially accomplished on the basis of clinical indicators (signs and symptoms) and biological and serum markers. Appropriate measurement required measure of whole-body insulin action, and the euglycemic hyperinsulinemic clamp technique (considered gold standard method for quantifying insulin sensitivity) is the direct method of estimation of IR. Table 2 shows various biological, clinical, and surrogate makers of IR.[44,45,46,47]

Table 2.

Clinical markers and biological and surrogate markers of diabetes mellitus[44,45,46,47]

Clinical markers
Waist circumference
Body mass index
Neck circumference and bust
Waist circumference-to-hip circumference ratio
Waist circumference-to-height ratio
Biological or candidate markers
Euglycemic hyperinsulinemic (EH) clamp: gold standard
Fasting insulin
Oral glucose tolerance test
Glucose insulin (GI) product
Insulinemia
Glycemia/insulinemia ratio
Homeostasis Model Assessment Insulin Resistance (HOMA-IR)
Modified insulin suppression test
Fasting insulin resistance index
Quantitative Insulin Sensitivity Check Index (QUICKI)
Minimal model analysis of frequently sampled intravenous glucose tolerance test
Surrogate markers
Adiponectin (adipokines; adipocytes)
Adrenomedullin
Alanine aminotransferase (ALT) and the γ-glutamyl transferase (GGT)
Angiotensinogen
Avignon index
C-reactive protein
Estimated glucose disposal rate (eGDR)
Ferritin
Fetuin-A
Fibrinogen Ghrelin
Glycosylated hemoglobin (HbA1c)
Gutt index
Homeostasis model assessment adiponectin (HOMA-AD)
Insulin-like growth factor (IGF1)-binding protein
Interleukins (TNF-alpha, IL-6) (proinflammatory cytokines, adipocyte-associated activated macrophages, and other cells)
Leptin (adipokines; adipocytes)
Leptin/adiponectin ratio (adipokines; adipocytes)
Lipoprotein (HDL) cholesterol ratio
Matsuda index
Monocyte chemoattractant protein-1 [proinflammatory cytokines, adipocyte-associated activated macrophages, and other cells]
Plasminogen activator inhibitor (PAI-1) (proinflammatory cytokines, adipocyte-associated activated macrophages, and other cells)
Protein kinase C (PKC) in microangiopathy
Retinol-binding protein 4
Resistin
Sex hormone binding globulin in hyperandrogenic syndrome
Sialic acid
Soluble sCD36
Stumvoll index
Triglycerides
Triglycerides/high-density
Visfatin (proinflammatory cytokines, adipocyte-associated activated macrophages, and other cells)

PATHOGENESIS OF PERIODONTITIS

Periodontitis is a chronic multifactorial inflammatory disease linked with dysbiotic plaque biofilms and is characterized by progressive destruction of supporting structures of teeth. Case definition of periodontitis by World Workshop 2017 is as follows: “Interdental clinical attachment loss (CAL) that is detectable at more than equal to 2 non-adjacent teeth, or buccal or lingual CAL of more than equal to 3 mm with pocketing of more than 3 mm is detectable at more than equal to 2 teeth.”[48]

Virulent factors of periodontal pathogens in forms of toxins, lipopolysaccharides (LPS), and lipoteichoic acid pose significant challenges to the patients who exacerbated the host immune-inflammatory response. LPS secreted from periodontal pathogens is located in the outer membrane of Gram-negative bacteria that are recognized by TLR-4 and interact with CD14/TLR-4/MD-2 receptor complex on immune cells such as macrophages, monocytes, dendritic cells, and B cells, with resulting release of PI mediators and inflammatory mediators such as prostaglandin E2 (PGE2), resistin, and CRP from these cells. Lipoteichoic acid, a component of Gram-positive cell walls, stimulates immune responses through TLR-2. Alveolar bone loss as a protective mechanism to prevent bacterial invasion of the bone ultimately leads to tooth mobility and its loss. Multinucleated osteoclasts cause bone resorption after activation by a variety of mediators such as PI cytokines, oncostatin M, bradykinin, thrombin, and various other chemokines via the RANK/RANL/OPG signaling pathway.[49] These host-mediated products are determinantal to the host tissue itself, thus amplifying the destructive disease process.[16] The infectious and inflammatory burden of chronic periodontitis due to microbial interaction with genetics, immunity, and environmental factors (such as tobacco and stress) modifies the host response and thus is thought to have an important systemic impact.[50]

Locally formed inflammatory intermediaries may also be “dumped” into the systemic circulation and may affect distant organs and tissues,[16] including hepatocytes, skeletal muscles as well as pancreatic cells. Noxious products (bacterial components such as major outer membrane proteins and endotoxins, i.e., LPS) can gain access to the systemic circulations through the ulcerated lining of the periodontal pocket, into the circulation. Loos[51] hypothesized “possibly daily episodes of a bacteremia originating from periodontal lesions are the cause for the changes in systemic markers in periodontitis; the cumulative size of all periodontal lesions in the untreated severe periodontitis patient may amount to 15 to 20 cm².”

MECHANISM OF PERIODONTITIS-ASSOCIATED INSULIN RESISTANCE

The normal pathway of insulin functioning commences with attachment of insulin to insulin tyrosine kinase receptor. The insulin receptor phosphorylates IRS-1 which in turn phosphorylates PI3-kinase. PI3-kinase then phosphorylates PIP2, which then activates Akt/protein kinase B (PKB), eventually leading to GLUT4 translocation to the plasma membrane of skeletal muscle cells and adipocytes, thus allowing the cell to absorb extracellular glucose, lowering interstitial glucose levels and thus plasma glucose concentration.[17] Peroxisome proliferator-activated receptor-gamma (PPAR-γ) complements insulin signaling and has been shown to regulate adipocyte differentiation, FA storage, and glucose metabolism. PPAR-γ agonist improves IR by opposing the effect of tumor necrosis factor (TNF)-α in adipocytes and by enhancing the expression of a number of genes encoding proteins involved in glucose and lipid metabolism.[12]

The inflammatory response in periodontitis is characterized by dysregulated secretion of host-derived mediators of inflammation and tissue breakdown. Important PI biomarkers characteristically increased in periodontitis are interleukin (IL)-1β, IL-6, PGE2, and TNF-α.[52] Other mediators most extensively investigated in periodontitis are PGE2, RANKL, high-sensitive C-reactive protein, resistin, and matrix metalloproteinases (MMPs) (particularly MMP-8, MMP-13, and MMP-9), along with T cell regulatory cytokines (e.g., IL-12, IL-18) and other chemokines. Pertinent data from the articles reviewed have been summarized in Table 3.[53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70] Among them, the most significant cytokine concerned to be related with the commencement and development of IR is TNF-α. Increase in TNF-α resulted in the development of IR by (a) modification in intracellular insulin signaling by inhibiting tyrosine kinase activity of the insulin receptor (IRS), (b) reduction in insulin-responsive glucose transporter synthesis, and (c) macrophage-dependent pancreatic islets cytotoxicity in diabetes.[12,71,72,73] Constant elevations of IL-1β/TNF-α resulting from longstanding chronic inflammation and infection result in pancreatic β-cell destruction.[12,74] Increase in L-1β enables PKC activation leading to apoptotic pancreatic β-cell demolition. Further, IL-6 significantly targets liver (hepatic glycogenolysis and gluconeogenesis), resulting in an amplified inflammatory response with impaired insulin signaling and action and resulting in diminished insulin production.[75,76]

Table 3.

Randomized and non-randomized clinical trials* showing markers in serum used to evaluate periodontitis-induced insulin resistance

Year	Author	Population studied	Sample size	Parameters investigated
2020	Montero et al.[53]	Spain	63	High-sensitivity C-reactive protein (hsCRP), cytokines, markers of prothrombotic states, carbohydrate, and lipid metabolism
2019	Nishioka et al.[54]	Japan	71/74	Fasting or post-load serum glucose and insulin, body mass index (BMI), HOMA-IR, HOMA-β, and Matsuda index
2019	Javid et al.[55]	Ahvaz, Iran	43	Fasting blood glucose, insulin, serum levels of fasting insulin and insulin resistance (homeostasis model assessment of insulin resistance), TGs
2018	D'Aiuto et al.[56]	London, UK	264	HbA1c
2017	Zare Javid et al.[57]	Ahvaz, Iran	43	Fasting blood glucose, insulin, insulin resistance (homeostasis model assessment of insulin resistance), TGs
2017	Bizzarro et al.[58]	Amsterdam, The Netherlands	110/110	Waist circumference, systolic/diastolic blood pressure (BP), HDL-cholesterol, triglycerides, glucose
2017	Hayashi et al.[59]	Meikai University Hospital, Japan	12	Total protein, albumin, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyl transpeptidase (GGT), urea nitrogen, creatinine, uric acid, IgG, IgM, IgA, IgD, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in blood samples were measured by the commercial laboratory (BML Inc.)
2017	Mammen et al.[60]	Kerala, India.	40	Fasting serum C-peptide, Homeostasis Assessment (HOMA) Index-Insulin Resistance, and HOMA-Insulin Sensitivity
2017	Joseph et al.[61]	Kerala, India	60	HbA1c, FBG, lipid profile, HbA1c
2013	Bharti et al.[62]	Tokyo, Japan	29	Glycated hemoglobin (HbA1c), hsCRP, TNF-α, IL-6, adiponectin, leptin, and resistin
2012	López et al.[63]	Santiago, Chile	165	Serum lipoprotein cholesterol, glucose, body mass index (BMI), C-reactive protein (CRP), and fibrinogen concentrations
2012	Moeintaghavi et al.[64]	Mashhad, Iran	40	Fasting plasma glucose (FPG), HbA1c, total cholesterol (TC), triglyceride (TG), and cholesterol levels
2011	Sun et al.[65]	Zhejiang University, China	190	Adiponectin, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), lipid profile, glucose, insulin, homeostasis model of assessment-insulin resistance (HOMA-IR), and homeostasis model assessment of β-cell function (HOMA-β)
2010	Kardeşler et al.*[66]	Izmir, Turkey	25	Serum levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, C-reactive protein (CRP), soluble intercellular adhesion molecule-1, adiponectin, and leptin
2009	Dağ et al.*[67]	Dicle University, Turkey	45	HbA1c value and circulating TNF-alpha
2009	Matsumoto et al.[68]	Gakkocho-Dori Niigata, Japan	27	Adiponectin
2005	Promsudthi et al.[69]	Bangkok, Thailand	52	FPG and HbA1c
2005	Kiran et al.[70]	Isparta, Turkey	44	Fasting plasma glucose (FPG), 2-h post-prandial glucose (PPG), glycated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), HDL-cholesterol, LDL-cholesterol, and microalbuminuria

Usually, obesity is considered as a recognized cause of both T2D and periodontitis. Adipokines released from adipocytes result in low-grade chronic inflammation through inflammatory mediators. Periodontal disease further can aggravate hyperlipidemia, abnormal fat metabolism, and consequent inflammatory changes in adipose tissue, which upsurge the serum PI cytokines and adipokines, thus worsening periodontal inflammatory status.[72,77,78] In disparity with the aforesaid nearby connotation between periodontitis, obesity, and T2D, Song et al.[77] observed that normal waist circumference or non-abdominally obese volunteers with IR were more expected to have severe periodontitis. However, variation for IR associated with severe periodontitis, among “at risk” obese, metabolically healthy, but obese (MHO), metabolically obese, normal-weight (MONW), and metabolically healthy (MH),[79] is still awaited.

OS due to imbalance in redox balance of innate immune response to periodontal pathogens resulted in the damage of supporting local tissues in chronic periodontitis.[80,81] Reactive oxygen species (ROS) overproduced mostly from mitochondria and peroxisomes of hyperactive neutrophils and monocytes (innate immune cells) in periodontitis may characteristically result in increased metabolites of lipid peroxidation, DNA damage, mitochondrial dysfunction (mitochondrial fission), and protein damage that may be responsible for pancreatic beta-cell dysfunction, IR, and T2D.[16] ROS causes IR in the marginal tissues by distressing insulin receptor signal transduction (due to the production of NADPH oxidase, GLUT4 is transported to lysosomes for degradation rather than to the plasma membrane). ROS also directly stimulates NF-kB, JNK, and p38 MAPK, resulting in mitochondria-induced stress responses characterized by mitochondrial fission subsequently, resulting in actions on the insulin receptor pathways [Figure 4].[82]

Figure 4.

Diagram depicting role of periodontitis in the development of IR

DISCUSSION

Reviewing the pertinent literature revealed that inflammatory cytokines and mediators originating from periodontal resources can interact systemically with lipids, free fatty acids, and advanced glycation end products (AGE) in diabetic patients. Potentially environmental host threats (ROS, AGEs, PI cytokines fatty acids, etc.) are recognized by cell components of innate immune cells via PRRs. This interaction induces activation of intracellular pathways like JNKs, NF-KB, IKKB, IkB (a cytosolic inhibitor of NF-KB), as well as downregulation of PPAR-γ. This results in phosphorylation of IRS-1 and IRS-2 at serine and threonine residues (instead of tyrosine kinases) by kinases like JNKs leading to suppression of insulin signaling and thus results in downregulation of Akt/PKB.[16] IKKB causes IR via transcriptional activation of NF-Kb that induces immune inflammatory genes for the release of cytokines, growth factors, adhesion molecules, and acute phase proteins. Activation of IKKB also results in phosphorylation of IKB, freeing NF-KB to translocate into nucleus that regulates target genes for IR.[43]

Highly specific and sensitive indicators of periodontal disease activity and surrogate biomarkers of T2D in periodontitis may be an important diagnostic tool for early detection of IR. This, increased systemic burden of PI cytokines by periodontitis, can be reduced by periodontal therapy, thus improving the patient’s overall systemic condition.[45] Studies have assessed the effect of periodontal therapy on various T2D biomarkers following periodontal therapy.[52,83,84] In initial systemic review, Esteves Lima et al.[85] concluded that scientific evidence cannot affirm a positive association between periodontitis and gestational DM due to heterogeneity in substantial clinical, methodologic, and statistical analysis, among the studies. Pushparani[86] in a narrative review outlined physiologic mechanisms, clinical studies, and scientific evidences that reveal the interrelationship between zinc and DM with periodontal disease and suggested that disturbance in the zinc micronutrient and increased OS in T2D may bring down IR and formation of diabetic complications. Nibali et al.,[87] Martinez-Herrera et al.,[88] Daudt et al.,[89] and Gobin et al.[90] in systematic reviews suggested an association between metabolic syndrome or obesity and periodontitis and concluded that patients suffering from periodontal disease should be screened for metabolic syndrome and vice versa. They further suggested that individuals unveiling features of metabolic syndrome must maintain their oral health. Similarly, Alvarenga et al.[91] in a systematic review suggested a low grade of association of diabetic retinopathy and periodontitis. Systematic reviews hypothesized that association may have occurred due to IR developed in response to persistent source of inflammatory mediators as a result of chronic bacterial challenge.[87,91]

STRENGTH AND LIMITATIONS

The biggest strength of this narrative review is that it is focussed on highlighting the mediators and pathways to better understand the role of periodontitis in the pathogenesis of IR in a single paper. However, extraction of data as required in systematic review and meta-analysis could not be performed due to nature of the paper and is the limitation of the paper.

FUTURE DIRECTION

From the current evidence, it can be comprehended that periodontal disease is a well-known modifiable risk factor for T2D. Further, besides conventional periodontal therapy, novice future treatment strategies including IL-1 receptor antagonist, salicylates, polyphenols,[92] anti-TNF approaches, anti-chemokine approaches, pharmaceutical chaperons, and thiazolidinediones need to be focussed for better outcomes. Understanding factors and molecular mechanism involved in the development of IR may serve as the basis for developing target strategy for the management of T2D. It becomes more imperative when recent studies are reporting IR markers’ association with early signs of periodontal breakdown among adolescents.[93] However, it has often been ignored to be an imperative element of “interprofessional collaborative management approach” for T2D.[2] Therefore, oral and non-oral (medical) health professionals should line up efforts in the management of T2D-susceptible subjects with periodontitis.

FINANCIAL SUPPORT AND SPONSORSHIP

Self-funded by authors.

CONFLICTS OF INTEREST

None to declare.

AUTHORS’ CONTRIBUTIONS

Conception or design: VKB, JM

Acquisition, analysis, or interpretation of data: VKB, JM

Drafting the work or revising: VKB, JM, LM, MM, GV

Final approval of the manuscript: VKB, JM, LM, MM, GV

ETHICAL POLICY AND INSTITUTIONAL REVIEW BOARD STATEMENT

Not applicable.

PATIENT DECLARATION OF CONSENT

Not applicable.

DATA AVAILABILITY STATEMENT

Data presented in this paper is procured from original articles and all the relevant data is included in the manuscript.