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Baboon as a model for the study of insulin sensitivity, beta cell function and subclinical inflammation following islet transplantation

Franco Folli¹, Francesca Casiraghi¹, Alberto Davalli^1,2, Andrea Ricotti^1,3, Subhash Kamath¹, Ana Paez⁵, Zhi Chang¹, Amalia Gastaldelli^1,3, Gregory Abrahamian⁴, Glenn Halff⁴, Ralph DeFronzo¹, Alberto Chavez¹

¹Medicine-Diabetes; ⁴Transplant Center; ⁵Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States; ²Medicine, HS Raffaele, Milan; ³Institute of Clinical Physiology, CNR, Pisa, Italy

Obesity and insulin resistance occur naturally in baboons and may be associated to low grade systemic inflammation. We assessed β-cell function and insulin sensitivity (IS) in baboons, and the relationship between circulating cytokines with glucose levels and anthropometric measures of adiposity. We measured waist, BMI and percent body fat (%BF), and performed a two step hyperglycemic clamp (HC) with arginine stimulus measuring b-cell function and IS in 46 non-diabetic baboons (NDB). Partial correlations were performed between IS (M/I), acute insulin response (AIR_0-12), second phase insulin (AUC_12-180) secretion and arginine potentiated insulin secretion (AUCArg_180-210) in relation to BF composition. On a separate cohort of animals (n=80) representative of BF content in wild-type animals, we measured circulating sTNF-R1 and sIL6-R levels to correlate them with glucose metabolism and adiposity. Waist was strongly correlated with total %BF (r²=0.72 p<0.0001) and trunk fat (r²=0.41, p<0.01). Waist, BMI, and total body weight showed a markedly gender dimorphism although the strong relationship with %BF was maintained in both males and females. During the HC, M/I was negatively correlated with total insulin secretion (r²=0.70, p<), AIR_0-12 (r²=0.12, p=), 2^nd phase ISEC_0-180 and ISEC_ARG (both r²=0.66, p<0.0001) during each stage of clamp and with the insulin/glucagon ratio (r²=0.30, p<0.0001). Finally, sTNF-R1 correlated with fasting plasma glucose (r²=0.19, p<0.0001). Weight correlated with sIL6-R (r²=0.09, p<0.004), sTNF-R1 levels correlated with sIL6-R (r²=0.10, p=0.003). In the non diabetic range, insulin secretion during the HC correlated inversely with IS and fasting plasma glucose progressively increased parallel to an increase in circulating markers of subclinical inflammation strongly correlated to insulin resistance in humans by dysregulation of the TIMP-3/TACE dyad. This characterization of in-vivo baboon islet physiology and subclinical inflammation provide a useful tool for the study of metabolic events following islet transplantation.