The proposed mechanisms by which diabetes may af- risk that poorly controlled DM patients will suffer from
fect the periodontium also parallel the pathophysiologi- accelerated periodontal tissue destruction.¹⁰⁸
cal routes by which diabetes can result in classic diabetic
complications. Because of this, some have suggested that Just as inflammatory mediators alter gingival crevicular
periodontitis be included as the “sixth complication of di- fluid composition, excess serum glucose also may en-
abetes” along with retinopathy, neuropathy, nephropathy, ter periodontal pockets in hyperglycemic patients.^109,110
macrovascular diseases, and altered wound healing.⁹⁸ At one time, this was thought to change the subgingival
The main influences of DM on periodontal disease appear microbiota of DM patients and to be a possible explana-
to be related to alterations in host immunoinflammato- tion for increased periodontal destruction. However, most
ry reactions and tissue homeostasis. Diabetes alters the studies have demonstrated no real differences in the sub-
function of immune cells directly involved in the host’s gingival microbiota between DM and non-DM patients
response to periodontal infection, such as neutrophils, with gingivitis or periodontitis.^78,111-113 Nevertheless, an
monocytes, and macrophages.⁹⁹ Neutrophils, the first line increased glucose concentration in the gingival crevicular
of immune cell defense in the periodontal pocket, demon- fluid has been shown to prevent attachment and spread-
strate reduced adherence, chemotaxis, and phagocytosis ing of fibroblasts and may thus impact periodontal wound
in diabetic patients.^100,101 Diabetic patients with severe healing.¹¹⁴
periodontitis have less neutrophil chemotaxis than pa-
tients with DM and mild periodontitis or non-DM patients Blood vessel alterations secondary to AGE accumulation
with severe periodontitis.^100,102 The result is reduced bac- are evident in the periodontium and may contribute to
tericidal activity, which favors increased bacterial prolif- the classic macrovascular and microvascular complica-
eration and may enhance periodontal inflammation and tions of DM.^115,116 AGEs produced in the periodontium of
destruction. DM patients may form on collagen resulting in increased
collagen cross-linking. This results in highly cross-linked

In contrast to down-regulated neutrophil activity, mono- collagen macromolecules with reduced solubility that ac-cytes and macrophages in DM patients are hyperrespon- cumulate in the walls of periodontal blood vessels, binding sive to periodontal infection, resulting in increased pro- low-density lipoprotein and leading to atheroma forma-duction of proinflammatory cytokines, especially IL-1β, tion and vessel lumen reduction.⁹⁹ Vascular smooth mus-TNF-α, and PGE .^64,103,104 Potent bacterial products in the cle cells proliferate in the presence of AGEs and increase

2

periodontal lesion, such as P. gingivalis endotoxin, en- vessel wall thickness. In addition, because the basement
hance TNF-α production significantly more in peripheral membranes of capillaries also are thickened by AGE ac-
blood monocytes from DM patients than in monocytes cumulation, oxygenation and perfusion of nutrients from
from non-DM patients.⁶⁴ the vasculature into the periodontium are reduced.¹⁰⁸
These changes result in decreased tissue vascular supply

The increased response of monocytes and macrophages and ultimately may affect the progression of periodontitis from DM patients may be related to the interaction of el- and the potential for homeostatic repair. evated levels of AGE in the periodontium with AGE receptors on these immune cells.¹⁰⁵ AGEs, such as non-enzy- In diabetes, collagen metabolism is significantly disrupt-matically glycated proteins, lipids, and nucleic acids, form ed, which affects tissue homeostasis and wound healing. in direct relationship to glucose concentration and time in AGE modification of collagen in the periodontium inhibits the hyperglycemic environment. Besides playing a signifi- normal tissue turnover.¹⁰⁸ In addition, formation of new cant role in diabetic complications, AGEs modify extra- collagen is reduced and matrix metalloproteinases such cellular matrix activity and cell-matrix interactions.^105,106 as collagenase are elevated, resulting in a fundamental AGEs and cytokines also are able to enter the gingival alteration in wound-healing capacity.^117,118 Neutrophils crevicular fluid, a serum transudate, in elevated quanti- appear to be the primary source of collagenase in the gin-ties when serum levels increase.¹⁰⁴ Cytokine levels of IL-1β gival crevicular fluid of DM patients, whereas in non-DM in gingival crevicular fluid also increase with worsening patients most collagenase is derived from fibroblasts,¹¹⁹ glycemic control.¹⁰⁷ AGEs in gingival crevicular fluid may and more of the collagenase in DM patients is in the active induce changes in the periodontium, such as elevation form.¹¹⁹ Importantly, the solubility of collagen can be re-of oxidant stress, that may lead to vascular injury, and turned to near-normal with insulin treatment and normal together with elevated cytokine levels, may increase the glycemic control.^120,121