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CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE |
Diabetes-enhanced Inflammation and Apoptosis—Impact on Periodontal Pathology
D.T. Graves1,*,
R. Liu2,
M. Alikhani1,
H. Al-Mashat1 and
P.C. Trackman1
1 Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, W-202 D, 700 Albany Street, Boston, MA 02118, USA; and
2 Department of Periodontology, Faculty of Stomatology, Capital University of Medical Science, Beijing, China
Correspondence: * corresponding author, dgraves{at}bu.edu
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ABSTRACT
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Diabetes, particularly type 2 diabetes, is a looming health issue with many ramifications. Because diabetes alters the cellular microenvironment in many different types of tissues, it causes myriad untoward effects, collectively referred to as ’diabetic complications’. Two cellular processes affected by diabetes are inflammation and apoptosis. This review discusses how diabetes-enhanced inflammation and apoptosis may affect the oral environment. In particular, dysregulation of tumor necrosis factor and the formation of advanced glycation products, both of which occur at higher levels in diabetic humans and animal models, potentiate inflammatory responses and induce apoptosis of matrix-producing cells. The enhanced loss of fibroblasts and osteoblasts through apoptosis in diabetics could contribute to limited repair of injured tissue, particularly when combined with other known deficits in diabetic wound-healing. These findings may shed light on diabetes-enhanced risk of periodontal diseases.
Key Words: Bacteria • bone • connective tissue • cytokine • cell death • diabetes • gingiva • hyperglycemia • infection • inflammatory • oral • periodontitis
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INTRODUCTION
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Hyperglycemia observed in diabetes mellitus results from inadequate glucose transport from the vasculature into cells of the liver and muscle. There are two major forms of diabetes. Type 1 diabetes, previously called ’insulin-dependent diabetes’, occurs when the beta cells of the pancreas are destroyed, and insufficient amounts of insulin are produced. It is typically caused by an autoimmune reaction in the pancreas. Type 2 diabetes, formerly known as ’non-insulin-dependent diabetes’ is caused by resistance to insulin combined with a failure to produce enough additional insulin to compensate for the insulin resistance. Type 2 diabetes represents approximately 90% of individuals with diabetes in the United States, while most of the remainder have type 1 diabetes (Kahn and Flier, 2000). Type 2 diabetes is commonly linked to obesity, which promotes insulin resistance (Kahn and Flier, 2000). In many obese individuals, insulin resistance is compensated for by increased insulin production, which can occur if there is an increase in β-cell mass (Dickson and Rhodes, 2004). In approximately one-third of obese individuals, there is a decreased β-cell mass caused by a marked increase in β-cell apoptosis, rendering these individuals incapable of compensating for the insulin-resistant state. Similarly, type 1 diabetes is associated with a loss of beta cell mass, typically caused by autoimmune-induced inflammation and apoptosis (Donath and Halban, 2004). Thus, both type 1 and type 2 diabetes are negatively affected by the death of beta cells in the pancreas, resulting in inadequate insulin production. For this reason, the phrase ’non-insulin-dependent diabetes’ is no longer used.
Long-term manifestations of diabetes include retinopathy, neuropathy, nephropathy, angiopathy, atherosclerosis, periodontitis, and other diabetic complications, such as impaired wound-healing. There are several aspects to diabetes that can contribute to these complications. Hyperglycemia-enhanced superoxide production, which inhibits GAPDH activity, has been linked to damage of vascular cells and may represent a common mechanism for several diabetic complications (Du et al., 2003). Sorbitol accumulation and NADPH depletion associated with shunting through the polyol pathway can increase oxidative stress and inflammation (Ramana et al., 2004). This may be important in the microvascular complications of diabetes (Dagher et al., 2004). In some cells, hyperglycemia can lead directly to activation of the MAP kinase or PKC pathways, both of which stimulate cytokine production and promote inflammation (Wilmer et al., 2001; Devaraj et al., 2005). Advanced glycation end-products that accumulate during prolonged hyperglycemia also promote inflammation (Schmidt et al., 2000; Vlassara and Palace, 2002). Thus, metabolic disturbances associated with diabetes can lead to: (1) activation of the polyol pathway; (2) high levels of the cytokine, TNF- ; (3) the formation of advanced glycation end-products (AGEs); (4) high levels of protein kinase C activation; and (5) enhanced oxidative stress (Williamson et al., 1993; Greene and Stevens, 1996; King and Brownlee, 1996; Vlassara, 1997; Koya and King, 1998; Asnaghi et al., 2003). The activation of these pathways may be especially important in initiating events linked to inflammation and apoptosis (De Vriese et al., 2000; Dagher et al., 2004; Xu et al., 2004). This review will focus on how diabetes alters inflammatory and apoptotic processes, and how this might affect healing and matrix production after bacterial injury. Readers are also directed to recent reviews on neuropathy, retinopathy, and cardiovascular disease, where diabetes-altered apoptosis and inflammation are thought to be important etiologic factors in disease progression (Tolkovsky, 2002; Barber, 2003; Adeghate, 2004).
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THE DIABETIC EPIDEMIC
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Diabetes mellitus affects more than 16 million people in the United States and has a dramatic impact on health, causing a high degree of morbidity and mortality in affected individuals, as well as placing an economic burden on the health care system (Zimmet et al., 2001). Although type 1 and type 2 diabetes are initiated by different etiologies, they share common symptoms of glucose intolerance, hyperglycemia, hyperlipidemia, and similar complications (Kahn and Flier, 2000). The National Diabetes Data Group (NDDG) of the NIH cites the incidence of diagnosed and undiagnosed diabetes and impaired glucose tolerance (IGT) at 11% of the general population aged 20–74 yrs, with a considerably higher rate in the population aged 65–74 (Libman et al., 1993; Mandrup-Poulsen, 1998). As the course of diabetes progresses, complications develop that include several micro- and macrovascular abnormalities, altered extracellular matrix production, and poor wound-healing (Patterson and Andriole, 1997; Vlassara and Palace, 2002). Diabetics also exhibit increased susceptibility to infection, as evidenced by a two- to five-fold higher risk for periodontal disease, which is reduced by effective control of hyperglycemia (Löe, 1993; Nishimura et al., 1998; Taylor, 2001). Interestingly, it has been reported that periodontal treatment helps in the stabilization of serum glucose levels (Taylor, 2001; Mealey and Rethman, 2003). This may be an example of how a healthy periodontium benefits the overall health of the individual by lowering the probability of systemic inflammation and its consequences.
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DIABETES AND INFLAMMATION
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Signs of systemic inflammation are elevated in both type 1 and type 2 diabetes. Systemic levels of TNF- and IL-6 are elevated in diabetes and can directly promote insulin resistance (Senn et al., 2002; Borst, 2004). Thus, elevated cytokine levels may not only serve as markers of diabetes, but also may play a causal role in the etiology of type 2 diabetes. The tendency of diabetics to have higher levels of inflammation has serious consequences (Nesto and Rutter, 2002). For example, 80% of individuals with type 2 diabetes die from coronary artery disease (Chiquette and Chilton, 2002).
There is circumstantial evidence in humans that microbial infections are an important risk factor for cardiovascular diseases, which has been linked to anaerobic bacteria, such as Chlamydia pneumoniae, a bacterium that causes respiratory infections (de Luis et al., 1998), Helicobacter pylori (Kusters and Kuipers, 1999), and periodontal pathogens (Beck et al., 1996; Amar and Han, 2003). It is possible that diabetes renders individuals more susceptible to the systemic consequences of local infection. To address this issue, we examined the inflammatory response of the heart/aorta of diabetic db/db mice that develop type 2 diabetes (Lu et al., 2004). Subcutaneous inoculation of lipopolysaccharide stimulated an up-regulation of adhesion molecules, cytokines, and chemokines via an endotoxemia that was significantly more rapid and more pronounced in the cardiovascular tissue of the diabetic compared with normal mice. Thus, diabetes may enhance the inflammatory response to bacteria at both the site of infection and also systemically through a greater response to endotoxemia or bacteremia.
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DIABETES ALTERS THE INFLAMMATORY RESPONSE TO BACTERIA
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Given that diabetes affects oral health, and many oral health problems involve bacteria-induced inflammation, there has been considerable interest in determining whether diabetes alters the inflammatory response to oral pathogens. For example, human gingival crevicular fluid from type 1 diabetics with periodontal disease has higher levels of both PGE2 and IL-1β as compared with those in fluid from matched non-diabetics (Salvi et al., 1997b). Furthermore, monocytes isolated from periodontal patients with type 1 diabetes produce significantly greater amounts of TNF-, IL-1β, and PGE2 in response to lipopolysaccharide (LPS) compared with non-diabetics (Salvi et al., 1997a,b).
The impact of diabetes on the inflammatory response to P. gingivalis in a connective tissue setting is shown in Fig. 1 (Naguib et al., 2004). Cytokine expression and formation of an inflammatory infiltrate were stimulated by P. gingivalis inoculation in the calvarial model. The inflammatory response was similar in diabetic and control mice on day one. However, at three days, the inflammatory infiltrate was reduced in the control group, whereas it remained high in the diabetic mice (Fig. 1A). These results are not limited to type 2 diabetic mice, since similar data were obtained with a type 1 diabetic model (Graves et al., 2005). Moreover, this difference was not due to a deficit in bacterial killing in the diabetic group, since inoculation of fixed bacteria induced a similar persistent inflammation. That TNF played a central role in this process was established by reversal of prolonged chemokine expression, by the specific inhibition of TNF with etanercept (Fig. 1B) (Naguib et al., 2004). Thus, cytokine dysregulation associated with prolonged TNF expression may represent an important mechanism through which diabetes alters the host response to bacterial challenge.
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Figure 1. A more pronounced inflammatory infiltrate was present in diabetic compared with normoglycemic mice three days after inoculation of P. gingivalis. P. gingivalis was inoculated subcutaneously into the scalp. On day 1, there was a pronounced inflammatory infiltrate in both the type 2 diabetic (db/db) mice and the normoglycemic (db/+) mice (data not shown). (A) On day 3, there was still a pronounced infiltrate in the diabetic mice and considerably less in the control group. (B) Effect of TNF inhibition on persistent inflammation in diabetic mice. Diabetic db/db mice were inoculated with P. gingivalis and treated with etanercept (TNF-inh) or vehicle alone (PBS). RNA was extracted 3 days following inoculation and compared with the zero time point (0). The expression of MIP-2 and MCP-1 was measured by the RNase protection assay, and the density of each band was quantified and normalized by GAPDH in the same lane. * MCP-1 and MIP-2 expression was significantly reduced in TNF inhibitor compared with the PBS-treated group (p < 0.05). Adapted from Naguib et al.(2004).
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Diabetes leads to greater net periodontal bone loss and contributes to increased risk of tooth loss (Löe, 1993; Nishimura et al., 1998). It has been suggested that this occurs because diabetes increases periodontal tissue destruction (Ryan et al., 1999). However, diabetes could also lead to a net loss of alveolar bone by impairing the cycle of bone formation that occurs after bone resorption. To examine this process, one must measure resorption and formation separately. This is possible with the in vivo calvarial model, in which a stimulus is inoculated into the scalp, and the impact on bone formation is measured separately (He et al., 2004). Following inoculation of bacteria, diabetes suppresses the amount of reparative bone formation that occurs after P. gingivalis-induced bone resorption (Fig. 2A). Thus, diabetes contributes to the net loss of bone, in part, because it suppresses the coupling of new bone formation that follows resorption. A potential mechanism is shown in Fig. 2B, in which the impact of bacteria on apoptosis of bone-lining cells made up of periosteal cells and osteoblasts was tested. Diabetes greatly prolonged P. gingivalis-induced apoptosis of these cells, which would diminish the capacity to form new bone. Fig. 2C demonstrates the functional significance of this finding; treatment of diabetic mice with a caspase-inhibitor that blocks apoptosis significantly improved the formation of new bone in diabetic mice following inoculation of P. gingivalis (Al-Mashat et al., 2006). More recently, we have applied these principles to a periodontal model in which alveolar bone loss was induced by placement of ligatures in the rat, and a cycle of bone loss and subsequent bone formation was examined (Liu et al., 2006). Consistent with results in the calvarial model, osseous repair following induction of periodontal bone resorption was significantly limited by diabetes. In the diabetic group, the amount of new alveolar bone formation was less than half that of normoglycemic controls. Interestingly, the level of apoptosis of bone-lining cells was also much higher in the diabetics.
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IMPACT OF AGES ON PERIODONTITIS AND WOUND-HEALING
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Advanced glycation end-products (AGEs) form under normal conditions and accumulate in aged individuals. With chronic hyperglycemia, AGE accumulation is greatly accelerated. AGEs form spontaneously from abnormally elevated levels of sugars and oxidized lipids in the blood. AGEs contribute significantly to many complications of diabetes, including kidney fibrosis, atherosclerosis, enhanced periodontal disease, and diminished bone formation (Lalla et al., 2000; Vlassara and Palace, 2002; Santana et al., 2003). In the context of tissue destruction and inflammation, the receptor for AGE, RAGE, has been identified as the principal signal-transducing receptor for the AGE ligand (Schmidt et al., 2000). For other AGE-associated pathologies, there may be other receptors that are more important (Vlassara and Palace, 2002). There are several mechanisms through which AGEs may affect cell behavior, such as enhancing inflammation, stimulating apoptosis, or affecting production of extracellular matrix (Owen et al., 1998; Vlassara and Palace, 2002).
Enhanced inflammation through advanced glycation end-products (AGEs) has been implicated in P. gingivalis-induced bone loss in a murine periodontal model (Lalla et al., 2000). In these studies, soluble RAGE (sRAGE) was used to prevent the binding of AGEs to cell-surface AGE receptors. Treatment with sRAGE decreased the levels of TNF- and IL-6 in gingival tissue and suppressed alveolar bone loss. These findings link AGEs with an exaggerated inflammatory response to P. gingivalis in diabetes-enhanced periodontal disease. Insight into how AGEs may affect the healing process comes from studies with diabetic mice. Goova and colleagues (Goova et al., 2001) demonstrated that inhibition of RAGE signaling enhanced the rate of wound closure and production of collagen in diabetic mice. It also tipped the balance between matrix production and degradation toward formation by down-regulating matrix metalloproteinase activity at later time points.
Bone repair in diabetes is characterized by decreased expression of genes that induce osteoblast differentiation, decreased growth factor production, and diminished extracellular matrix production (Bouillon, 1991; Kawaguchi et al., 1994; Lu et al., 2003). Osseous healing in diabetics may be limited by the effect of AGEs (Santana et al., 2003). This is based on the finding that application of AGEs to calvarial defects in normal animals reduces bone formation (Santana et al., 2003). AGEs mimic cellular changes found in diabetes, including diminished extracellular matrix production and interference with osteoblast differentiation (McCarthy et al., 2001; Cortizo et al., 2003; Santana et al., 2003). Another mechanism by which AGEs may delay wound-healing is through the induced apoptosis of extracellular-matrix-producing cells. Enhanced apoptosis would reduce the number of osteoblasts that could participate in the repair of resorbed bone.
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DIABETES AND APOPTOSIS
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Apoptosis is programmed cell death that can be triggered by various signals and is characterized by well-defined morphologic changes (Nagata, 1997; Li et al., 1998). Apoptosis is important as a critical mechanism for removing unwanted cells during development, as a means of preventing autoimmunity, and as part of a response to protect the host from cells that have been infected or have become tumorigenic. Apoptosis occurs rapidly, within an hour of effector caspase activation. Although the percentage of cells that are apoptotic at any given point in time may seem low, the cumulative effect over a 24-hour period can be quite high. Since adequate healing requires a sufficient number of cells to repair wounds, enhanced apoptosis of matrix-producing cells could reduce tissue formation (Darby et al., 1997; Slomiany and Slomiany, 2002; Carlson et al., 2003). When diabetic mice are treated with curcumin, there is reduced apoptosis of fibroblasts and accelerated wound-healing, suggesting that reduced expression of pro-apoptotic factors enhances the repair process (Sidhu et al., 1999). The opposite is also true: Conditions that promote apoptosis impair healing (Darby et al., 1997; Gastman et al., 2003). Thus, enhanced apoptosis associated with diabetes may contribute to altered healing.
A body of evidence is emerging that apoptosis plays an important role in several diabetic complications. These include apoptosis of neuronal cells in diabetic neuropathy (Li et al., 2002), diabetes-enhanced myocardial apoptosis, which plays a role in cardiac pathogenesis (Cai et al., 2002), and apoptosis of mesangial cells that occurs in diabetic nephropathy (Makino et al., 2000; Yamagishi et al., 2002a). There are several aspects to diabetes that could enhance apoptosis (Fig. 3). Diabetes is associated with activation of the polyol pathway, leading to the formation of AGEs and phospholipase C activation, higher levels of TNF- expression, enhanced protein kinase C activation, and greater oxidative stress (Vlassara, 1997; Koya and King, 1998; Asnaghi et al., 2003; Du et al, 2003). The formation of reactive oxygen species (ROS), TNF, and AGEs could potentially affect oral healing or the response to bacteria-induced periodontitis by direct effects on osteoblastic or fibroblastic cells, such as reduced expression of collagen, or indirectly through promoting inflammation and apoptosis of these matrix-producing cells (Fig. 4). Thus, by enhancing the production of ROS, TNF, and AGEs, diabetes may impair the healing response or progression of periodontal disease.
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Figure 3. This diagram represents a summary of several pathways that may be altered by diabetes to enhance apoptosis. (NB: Not all possible connections are shown, for greater legibility.)
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Figure 4. Mechanisms through which diabetes may affect wound healing. Diabetes-induced production of ROS, TNF, or AGEs can have direct effects on repair that include the inhibition of collagen production by osteoblasts or fibroblasts derived from the gingiva or skin. However, they could also have profound indirect effects by promoting inflammation or, potentially, through enhanced apoptosis. Taken together, direct and indirect effects of AGEs could contribute to impaired healing in diabetics.
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Diabetes enhances apoptosis of fibroblasts and osteoblasts following Porphyromonas gingivalis infection (He et al., 2004; Liu et al., 2004). In the calvarial model, P. gingivalis induces inflammation and injury, which is repaired by fibroblasts. Following P. gingivalis-induced injury, diabetic mice have significantly elevated fibroblast apoptosis and reduced fibroblast density (Liu et al., 2004). The higher rate of fibroblast apoptosis could be explained by enhanced levels of activated caspase-3 (Liu et al., 2004). Thus, healing of tissue injured by bacterial infection may be impaired, in part, by diabetes-enhanced caspase-3 activity, leading to higher levels of fibroblast apoptosis and reduced numbers of these cells. Direct evidence for diabetes-enhanced apoptosis playing a functional role in limiting diabetic repair comes from studies in which the response to a bacterially induced injury is significantly improved by blocking apoptosis with a caspase inhibitor (Al-Mashat et al., 2006).
There are several mechanisms that could be responsible for the higher rate of apoptosis noted in the diabetic group. One mechanism may be through the cytokine activation of receptors with ’death domains’, such as TNF receptor-1 (TNFR1) or fas (Kawakami et al., 1997; Jelaska and Korn, 1998; Tsuboi et al., 1999; Graves et al., 2001; Alikhani et al., 2005b). Diabetes is associated with both enhanced TNF and fas/fas-ligand expression (Hotamisligil et al., 1995; Joussen et al., 2003). IL-1 or interferon-gamma may promote apoptosis, even though their receptors lack death domains, by altering pro-apoptotic gene expression or enhancing production of oxygen radicals (Suk et al., 2001; Hoek and Pastorino, 2002; Schroder et al., 2004). Advanced glycation end-products may also promote apoptosis of critical matrix-producing cells (Alikhani et al., 2005a). Enhanced apoptosis of these cells is associated with diabetic complications such as retinopathy, neuropathy, nephropathy, and accelerated vasculopathy (Huang et al., 2001; Yamagishi et al., 2002b; Kaji et al., 2003). There are several mechanisms by which AGEs can enhance apoptosis: the direct activation of caspase activity, as well as indirect pathways that increase oxidative stress, or the expression of pro-apoptotic genes that regulate apoptosis (Kasper et al., 2000; Yamagishi et al., 2002b; Kaji et al., 2003; Alikhani et al., 2005b).
In vivo experiments have established that AGEs induce fibroblast apoptosis, which is mediated through caspase-3 and signaled through both caspase-8 and caspase-9 activity (Alikhani et al., 2005a). In vitro, AGEs have a global effect of enhancing mRNA levels of pro-apoptotic genes that include several classes of molecules, including ligands, receptors, adapter molecules, mitochondrial proteins, and others (Alikhani et al., 2005a). Interestingly, AGEs stimulate NF β activation, which is anti-apoptotic (Wang et al., 1998). Thus, AGEs and other pro-apoptotic molecules, such as TNF, stimulate both anti- and pro-apoptotic factors, and the net result reflects the overall balance between them. This balance may be influenced by members of the forkhead transcription factors, such as FOXO1, that globally induce expression of pro-apoptotic genes and may represent a mechanism to overcome NFβ-associated anti-apoptosis (Alikhani et al., 2005b).
The periodontium is well-equipped for repair following infection. In periodontitis, there is a net loss of connective tissue attachment to the tooth that does not repair sufficiently to prevent epithelial down-growth. There is also a net loss of bone, which is pathologic, since bone is a tissue that is particularly well-suited for regeneration. Thus, the central issue may center not around the breakdown of tissue, but rather on the failure of adequate repair. One mechanism that might explain inadequate repair is loss of matrix-producing cells. This is supported by a high rate of fibroblast apoptosis in patients with periodontitis, particularly in areas where inflammatory cells have been recruited (Koulouri et al., 1999). We propose that infection induces an inflammatory response that is exaggerated in diabetic individuals and leads to apoptosis of fibroblastic and osteoblastic cells. This, in turn, contributes to the greater net loss of hard and soft connective tissue that occurs in diabetic individuals. Consistent with this principle are findings that reduced apoptosis during wound-repair is associated with qualitative and quantitative improvements in healing (Ono et al., 2004; Al-Mashat et al., 2006). In contrast, conditions that enhance apoptosis are associated with impaired healing (Qu et al., 2003). It is also striking that inhibition of osteoblast apoptosis may be one of the mechanisms through which intermittent exogenous PTH treatment increases bone mass (Jilka et al., 1999; Stanislaus et al., 2000). Thus, apoptosis of matrix-producing cells may be a critical factor in the repair of soft and hard connective tissue and may represent an important mechanism through which diabetes has a negative effect on the periodontium.
Received for publication March 14, 2005.
Accepted for publication July 14, 2005.
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Journal of Dental Research, Vol. 85, No. 1,
15-21 (2006)
DOI: 10.1177/154405910608500103
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ABSTRACT
INTRODUCTION
) and normal littermate control (
) mice was undertaken. (A) New bone formation was measured by image analysis of van Gieson-stained sections and is expressed as the area of new bone per bone length (mm2/mm). (B) Apoptosis of bone-lining cells was measured by the TUNEL assay and is expressed as the number per bone length. For each assay, the mean ± standard error are shown based on 6 specimens per data point. (C) Bacteria were inoculated into the scalps of db/db mice. One group was treated with the pancaspase inhibitor, Z-VAD-FMK, to block apoptosis, and mice were killed 8 days later. The area of newly formed bone matrix was identified in Van Gieson-stained sections. Each value represents the mean area divided by the length of bone ± SEM. * indicates statistical significance in the control compared with diabetic mice, p < 0.05. It should be noted that the period when apoptosis of bone-lining cells was higher in the diabetic group corresponded to the period of peak bone formation. Panels A and B adapted from