Ellegaard_Göttingen_Minipigs_Newsletter 53

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implant, with higher values demonstrating a higher degree of osseointegration. While the control group reached average levels of approximately 260 Ncm, both metabolic syndrome and diabetic groups had much lower average values (90 Ncm and 60 Ncm, respectively). Importantly, not only did the compromised groups measure removal torque values that were significantly less than the control group, but the metabolic syndrome group values were not statistically different from those of the diabetic group (Figure 3A). Histomorphometric analysis on bone chamber implants confirmed the trend seen in the biomechanical removal torque experiment. Two different histomorphometric parameters were measured: bone area to implant area (BATA) and bone to implant contact (BIC). The control group, for both BATA and BIC measurements, had significantly higher values than both of the compromised groups (BATA- control: 40%, obese: 25%, diabetic: 25%; BIC- control: 45%, obese: 22%, diabetic: 18%). Importantly, there was no significant difference between the compromised groups for both BATA and BIC measurements (Figure 3B). These measurements were also evident by visual examination of the histological slides, especially in terms of BIC, in that the new bone growth around the implant is less than compared to both compromised groups (Figure 4). Conclusion This study, using an animal model considered physiologically similar to that of humans, demonstrates that bone remodeling is indeed severely affected in obese individuals. Not only was the bone regeneration around implants placed into bone defects less pronounced in obese animals as compared to control, but the biomechanical stability of the newly formed bone seems to be less mature, as demonstrated by mechanical torque out measurements. In line with Doucette et al., the inflammatory factor TNF-α was also found to be only slightly affected by the induction of an obese phenotype. However, previous studies have shown that an alternative inflammatory factor (C-reactive protein (CRP)) is particularly increased in obese humans and suggests a source of infection or inflammation is more common among obese subjects than in nonobese subjects [16] . This study also measured CRP levels and found significantly higher levels of CRP in obese animals, suggesting Minipig models do indeed mirror the pathological events associated with metabolic syndrome found in humans. We demonstrate that after induction of obesity, the animal weight can indeed be stabilized without reversing the disease process itself. Interestingly, this suggests that Minipigs manifest a similar disease process to humans in that the deleterious clinical effects of obesity in human subjects are reversible upon concerted weight loss, not weight stabilization [17] . Biomechanical analysis of implant osseointegration (torqueout) showed significant differences between the control and compromised groups. This further demonstrated that implant osseointegration, and therefore secondary stability, is greatly affected by the animals’ compromised state. Based on the present data, it appears that implant osseointegration is equally compromised in obese and diabetic animals. This corresponds to recent work in humans demonstrating that bone mineral density is already reduced in metabolic syndrome adolescents [18] . Here, we demonstrate it is possible to induce a mild state of diabetes (with detectable glucose metabolism deficiency) using a dose (twice 20 mg/kg STZ) previously reported to have no metabolic effect of Göttingen Minipigs. However, we first induced metabolic syndrome in the animals before STZ administration, contrary to previous studies that administered STZ on healthy Figure 4: Histological sections demonstrating the differences between the study groups in terms of new bone formation surrounding implants. Top row = Hematoxylin and eosin stained sections; bottom row = Region of interest defined for BATA calculations. New bone is clearly distinguished from existing bone by color (new bone = slightly darker pink) and morphology (new bone = higher percentage of trabeculae; less mature). 12
individuals. It appears that healthy individuals are resistant to low doses of STZ, whereas metabolic syndrome animals are not, further highlighting that a compromised state is present already in obese animals. While this remains a pilot study, these data also suggest that the aberrant bone remodeling previously reported in type 2 diabetic individuals could have its origins in obesity rather than diabetes. In line with this, the aberrant bone remodeling may be related to the pro-inflammatory status present during metabolic diseases, with severe pro-inflammation at diabetes and more mild pro-inflammation at pre-diabetes or metabolic syndrome. In the present study, the minipigs were fed a cafeteria diet containing substantial amounts of hydrogenated oils, consisting of trans-fatty acids which are known to induce chronic inflammation [19] . It may well be that the aberrant bone remodeling in obese pigs is amplified by using dietary trans fatty acids, thereby creating a more severe state of pro-inflammation at obesity. The increase of inflammatory factors also shown to be increased in human obese patients shows that the systematic inflammation present in this animal model more closely resembles that of the human disease state [20] . References 1 Suresh S, Mahendra J. Multifactorial relationship of obesity and periodontal disease. J Clin Diagn Res 2014;8:ZE01–3. 2 Alabdulkarim M, Bissada N, Al-Zahrani M, Ficara A, Siegel B. Alveolar bone loss in obese subjects. J Int Acad Periodontol 2005;7:34–8. 3 Engebretson S, Chertog R, Nichols A, Hey-Hadavi J, Celenti R, Grbic J. Plasma levels of tumour necrosis factor-alpha in patients with chronic periodontitis and type 2 diabetes. J Clin Periodontol 2007;34:18–24. 4 Di Benedetto A, Gigante I, Colucci S, Grano M. Periodontal disease: linking the primary inflammation to bone loss. Clin Dev Immunol 2013;2013:503754. 5 National Institutes of Health Consensus Development Conference statement on dental implants June 13-15, 1988. J Dent Educ 1988;52:824–7. 6 Marchand F, Raskin A, Dionnes-Hornes A, Barry T, Dubois N, Valéro R, et al. Dental implants and diabetes: conditions for success. Diabetes Metab 2012;38:14–9. 7 Mellado-Valero A, Ferrer García JC, Herrera Ballester A, Labaig Rueda C. Effects of diabetes on the osseointegration of dental implants. Med Oral Patol Oral Cir Bucal 2007;12:E38–43. 8 Bollen P, Ellegaard L. The Göttingen Minipig in pharmacology and toxicology. Pharmacol Toxicol 1997;80 Suppl 2:3–4. 9 Johansen T, Hansen HS, Richelsen B, Malmlöf R. The obese Göttingen Minipig as a model of the metabolic syndrome: dietary effects on obesity, insulin sensitivity, and growth hormone profile. Comp Med 2001;51:150–5. 10 Larsen MO, Rolin B, Wilken M, Carr RD, Svendsen O. High-fat high-energy feeding impairs fasting glucose and increases fasting insulin levels in the Göttingen Minipig: results from a pilot study. Ann N Y Acad Sci 2002;967:414–23. 11 Larsen MO, Wilken M, Gotfredsen CF, Carr RD, Svendsen O, Rolin B. Mild streptozotocin diabetes in the Göttingen Minipig. A novel model of moderate insulin deficiency and diabetes. Am J Physiol Endocrinol Metab 2002;282:E1342–51. 12 Ionut V, Liu H, Mooradian V, Castro AVB, Kabir M, Stefanovski D, et al. Novel canine models of obese prediabetes and mild type 2 diabetes. Am J Physiol Endocrinol Metab 2010;298:E38–48. 13 Te Pas MFW, Koopmans S-J, Kruijt L, Calus MPL, Smits MA. Plasma proteome profiles associated with diet-induced metabolic syndrome and the early onset of metabolic syndrome in a pig model. 14 Friedmann A, Friedmann A, Grize L, Obrecht M, Dard M. Convergent methods assessing bone growth in an experimental model at dental implants in the minipig. Ann Anat 2014. 15 Gottlow J, Dard M, Kjellson F, Obrecht M, Sennerby L. Evaluation of a new titanium-zirconium dental implant: a biomechanical and histological comparative study in the mini pig. Clin Implant Dent Relat Res 2012;14:538–45. 16 Aronson D, Bartha P, Zinder O, Kerner A, Markiewicz W, Avizohar O, et al. Obesity is the major determinant of elevated C-reactive protein in subjects with the metabolic syndrome. Int J Obes Relat Metab Disord 2004;28:674–9. 17 Shapses SA, Sukumar D. Bone metabolism in obesity and weight loss. Annu Rev Nutr 2012;32:287–309. 18 Nóbrega da Silva V, Goldberg TBL, Mosca LN, Bisi Rizzo A da C, Teixeira A dos S, Corrente JE. Metabolic syndrome reduces bone mineral density in overweight adolescents. Bone 2014;66:1–7. 19 Lee L, Alloosh M, Saxena R, Van Alstine W, Watkins BA, Klaunig JE, et al. Nutritional model of steatohepatitis and metabolic syndrome in the Ossabaw miniature swine. Hepatology 2009;50:56–67. 20 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006;444:860–7. 13
Page 1 and 2: 53 WINTER 2018 NEWSLETTER ••
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Ellegaard_Göttingen_Minipigs_Newsletter 53

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