2442-P: Distinct Physiologic Platforms for Assessing Insulin Sensitivity in Nonhuman Primates: Hyperinsulinemic-Euglycemic Clamp and Insulin Tolerance Testing for Translational Diabetes Research

Introduction and Objective: This study investigated two distinct physiologic platforms—the hyperinsulinemic-euglycemic clamp (HEC) and the insulin tolerance test (ITT)—to assess insulin sensitivity across different metabolic states in cynomolgus monkeys, emphasizing their translational relevance for modeling type 2 diabetes and pharmacologic responses. Methods: Studies in lean, obese, and diabetic monkeys used two protocols: With HEC (n = 8/group), insulin was infused at 5 mU/kg/min while maintaining plasma glucose within ±10% of basal fasted glucose concentrations. Steady-state glucose infusion rates (GIR, mg/kg/min) were determined over the final 30 min of clamping. With ITT, monkeys received 0.5 IU/kg regular insulin IV, and glucose concentrations were measured serially to calculate the K index (KITT, %/min). Normal obese and obese diabetic monkeys (n=3/group) received Semaglutide SC over 4 weeks to assess changes in KITT at baseline and post-treatment. Results: HEC results showed that lean monkeys had higher GIR (11.97 ± 1.80 mg/kg/min) than obese/diabetic monkeys (2.96 ± 1.36 mg/kg/min, p<0.001), indicating greater insulin sensitivity while obese/diabetic monkeys showed marked insulin resistance. Baseline KITT was lower in obese/diabetic monkeys (1.1 ± 0.6 %/min) compared to obese/normal animals (5.0 ± 1.8 %/min). Semaglutide improved insulin sensitivity in diabetic monkeys, increasing KITT to 4.2 ± 0.7 %/min (p<0.01 vs baseline). Conclusion: The HEC and ITT provide distinct, complementary platforms for assessing insulin sensitivity in cynomolgus monkeys. The clamp directly quantifies insulin-mediated glucose disposal, while the ITT offers a practical, sensitive index for detecting treatment-induced outcomes. These approaches enhance the translational utility of monkey models for evaluating metabolic dysfunction and therapeutic interventions in type 2 diabetes. Disclosure F.P. De Villa: None. Z. Zhu: None. L. Yang: None. R. Perez: None.