The Zucker fatty (ZF) rat, an established model of obesity-related insulin resistance with pre-diabetes, hyperinsulinemia, hyperlipidemia, and glucose intolerance ( Bray, 1977), has been reported to have greater alveolar bone resorption in comparison with normal Sprague-Dawley rats ( Perlstein and Bissada, 1977). However, no experimental study has demonstrated either that insulin resistance exists in the gingiva or the mechanism for its induction in obese and diabetic states. Thus, it is possible that insulin resistance may also play an important role in the acceleration of periodontitis in patients with metabolic syndrome or diabetes. Insulin resistance, observed in diabetes and obesity, has been associated with increased risk of cardiovascular disease, hypertension, and chronic kidney disease ( Rask-Madsen and King, 2007). (2005) reported that body mass index (BMI) was positively correlated with the severity of periodontal attachment loss and insulin resistance. Recent studies have suggested that overweight and obesity are associated with periodontal disease progression ( Chaffee and Weston, 2010), independent of glycemic control ( Saito and Shimazaki, 2007) or the diagnosis of diabetes ( Gorman et al., 2012). Analysis of our data suggested that PKC activation and oxidative stress may selectively inhibit insulin-induced Akt and eNOS activation, causing endothelial dysfunction and inflammation. This provided the first documentation of obesity-induced insulin resistance in the gingiva. General PKC inhibitor and an anti-oxidant normalized the action of insulin on Akt and eNOS activation in the gingiva from ZF rats. Analysis of the gingiva showed that insulin-induced phosphorylation of IRS-1, Akt, and eNOS was significantly decreased in ZF rats, but Erk1/2 activation was not affected. Immunohistochemistry revealed that NF-κB activation was also increased in the gingival endothelial cells from transgenic mice overexpressing NF-κB-dependent enhanced green fluorescent protein (GFP) and on a high-fat vs. Expression of oxidative stress markers (mRNA) and the p65 subunit of NF-κB was significantly increased in ZF rats. Endothelial nitric oxide synthase (eNOS) expression was decreased, and activities of protein kinase C (PKC) α, ß2, δ, and ϵ isoforms were significantly increased in the gingiva from ZF rats compared with those from ZL rats. Gingival samples were collected from fatty (ZF) and lean (ZL, control) Zucker rats. We studied the effects of insulin in periodontal tissues during the state of obesity-induced insulin resistance. Obesity is a risk factor for periodontitis, but the pathogenic mechanism involved is unclear.
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