Markers, Pathways, and Current Evidence for Periodontitis-associated Insulin Resistance

Abstract

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.[23] DM, mainly type-2 diabetes (T2D) that accounts for 90% of all DM cases,[456] 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.[78] Insulin resistance (IR) has evidently appeared as an important source of glucose intolerance leading to T2D.[910] 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.[1112131415] 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 strategyRESULTS 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.[1718] 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.[1920]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.[1819] 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 Gi/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].[1819] 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.[17181920] 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: Intramyocellular lipid metabolites trigger IR through activation of seine kinase cascade leading to abridged insulin stimulation of IRS-1 tyrosine phosphorylation.[1] 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] Errors in “mitochondrial oxidative phosphorylation activity” cause IR in both the elderly and young-thin “insulin-resistant offspring” of parents with T2D.[1] 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] 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].[14222324252627282930313233343536373839404142] 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]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.[44454647]Table 2: Clinical markers and biological and surrogate markers of diabetes mellitus[44 45 46 47]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.[535455565758596061626364656667686970] 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.[12717273] Constant elevations of IL-1β/TNF-α resulting from longstanding chronic inflammation and infection result in pancreatic β-cell destruction.[1274] 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.[7576]Table 3: Randomized and non-randomized clinical trials* showing markers in serum used to evaluate periodontitis-induced insulin resistanceUsually, 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.[7277,78] 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.[8081] 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 and protein damage that may be for pancreatic beta-cell IR, and IR in the tissues by insulin receptor to the production of NADPH GLUT4 is to for than to the plasma also stimulates and resulting in stress responses characterized by mitochondrial resulting in on the insulin receptor pathways [Figure role of periodontitis in the development of the pertinent literature revealed that inflammatory cytokines and mediators originating from periodontal can interact with fatty acids, and products in environmental host PI cytokines fatty acids, are recognized by cell components of innate immune cells via This interaction activation of intracellular pathways of as well as of This results in phosphorylation of IRS-1 and IRS-2 at serine and of tyrosine by kinases leading to of insulin signaling and thus results in of IR via activation of that immune inflammatory genes for the release of cytokines, and proteins. Activation of also results in phosphorylation of to into that target genes for IR.[43] specific and indicators of periodontal disease activity and surrogate biomarkers of T2D in periodontitis may be an important for of IR. increased systemic burden of PI cytokines by periodontitis, can be by periodontal thus the overall systemic have the effect of periodontal on various T2D biomarkers following periodontal In systemic et that scientific evidence a between periodontitis and DM due to in clinical, and among the in a narrative review clinical studies, and scientific that the between and DM with periodontal disease and that in the and increased OS in T2D may IR and of et et et and et in systematic reviews an between metabolic or obesity and periodontitis and that patients from periodontal disease be for metabolic and further that of metabolic et in a systematic review a of of and periodontitis. reviews hypothesized that may have due to IR in response to source of inflammatory mediators as a result of chronic bacterial AND The of this narrative review is that is on the mediators and pathways to the role of periodontitis in the pathogenesis of IR in a single However, of data as required in systematic review and be due to of the paper and is the of the the current can be that periodontal disease is a factor for T2D. Further, periodontal including receptor and to be for factors and molecular mechanism involved in the development of IR may as the basis for developing target for the of T2D. more studies are IR with of periodontal among However, has been to be an of for Therefore, and health in the of with periodontitis. AND by OF to or or of the work or of the AND OF in this paper is from articles and all the data is included in the The to and for supporting the of this

Topics & Concepts