Introduction
Insulin resistance (IR) and subsequent type 2 diabetes are leading causes of cardiovascular disease in obese people. However, the exact mechanism by which obesity induces IR is unknown. It is hypothesized that obesity increases tissue aging, most particularly, adipose tissue (AT), and causes an increased number of senescent cells that influences insulin resistance by inducing local inflammation1-2.

Methods
We collected mesenteric, omental and subcutaneous AT from 61 non-diabetic subjects of the Bariatric Surgery in Amsterdam cohort (BARIA), BMI> 35. We immunohistochemically stained for p16, an important marker of cellular senescence, and analysed the biopsies using a validated algorithm. Multiple regression was used to test if baseline characteristics and parameters measured during a mixed meal test significantly predicted p16 expression in mesenteric AT.

Results
There is a significant difference in the mesenteric AT p16 expression in different metabolic states defined by the ADA criteria (p < 0.01). Whereby the prediabetes group showed the highest expression of p16. Other AT compartments showed no difference in p16 expression. Metformin users have lower p16 expression than non-metformin users (p < 0.01). The results of the multiple regression showed a significant relation ship for age and the area under the curve of incremental insulin concentration (adjusted-R2 = 0.19, F(2,43) = 6.12, p<0.005). No significant relationship was found for other likely predictors like BMI, glucose and HbA1c.

Discussion
This is the largest study associating senescence with IR in humans, after several studies establishing a link with development of insulin resistance and senescence in mice and humans. We see an increase in p16 expression with a concomitant increase in insulin production and worsened metabolic state, except for the subjects using metformin. This can be explained by studies that have shown metformin to have anti-senescence properties3. Our results suggest that increased insulin production can have an effect on insulin resistance via increased aging of adipose tissue.

References
1.	Muñoz-Espín, Daniel and Manuel Serrano. “Cellular senescence: from physiology to pathology.” Nature Reviews Molecular Cell Biology 15 (2014): 482-496.
2.	Minamino, Tohru, Masayuki Orimo, Ippei Shimizu, Takeshige Kunieda, Masataka Yokoyama, Takashi Ito, Aika Nojima, Akira Nabetani, Yuichi Oike, Hisahiro Matsubara, Fuyuki Ishikawa and Issei Komuro. “A crucial role for adipose tissue p53 in the regulation of insulin resistance.” Nature Medicine 15 (2009): 1082-1087.
3.	Barco, S Del, Alejandro Vázquez-Martín, Sílvia Cufí, Cristina Oliveras-Ferraros, Joaquim Bosch-Barrera, Jorge Joven, Begoña Martín-Castillo and Javier A. Menéndez. “Metformin: Multi-faceted protection against cancer.” Oncotarget (2011).

07 - ADIPOSE TISSUE SENESCENCE IS ASSOCIATED WITH INSULIN RESISTANCE IN OBESE INDIVIDUALS