1265-OR: Tirzepatide: Effect on Insulin Resistance and Human Fat Cells

Introduction and Objective: We tested the hypothesis that tirzepatide (TZ), a dual GLP-1/GIP agonist, improves metabolic health independent of weight loss via GIP effects on adipose cells. Dual GLP-1/GIP agonists are known to lower blood glucose to a greater degree than selective GLP-1 agonists. We quantified insulin resistance (IR) and adipose cell function after 6 and 22 weeks of treatment of humans with obesity. Weight loss was matched for the first 6 weeks to assess the independent effect of TZ. Methods: Adults with BMI 27-39.9 and fasting glucose 126 mg/dL were randomized to TZ (n=30) or hypocaloric diet (n=23), matched for weight loss at week 6 but not week 22. Fat biopsies were obtained at weeks 0, 6, and 22 for adipocyte size, differentiation, and lipolysis assay. Insulin resistance was measured at the same timepoints with a steady-state plasma glucose (SSPG) test. Results: Despite matched weight loss (4 kg) at 6 weeks, SSPG improved significantly more with TZ vs diet (41% vs 10%, p0.0001). Lipolysis increased in both groups, but response to isoproterenol was greater in the TZ group, as was metabolic flexibility (ΔIsoproterenol -Insulin) (3.2 vs 0.6 μM, p=0.048). Adipocyte size and differentiation decreased with weight loss in both groups (NS). Conclusion: This is the first study to quantify insulin resistance and adipocyte function with matched dietary weight loss in TZ-treated humans. TZ improves insulin sensitivity independent of weight loss, and improves metabolic flexibility of adipocytes. Disclosure R.L. Huynh: None. N. Turk: None. J. Yang: None. E. Yandle: None. I. Jain: None. C. Leong: None. H. Chen: None. T. McLaughlin: Research Support; Ended; Lilly. Advisory Panel; Ended; Regeneron Pharmaceuticals Inc. Research Support; Current; Recordati S.p.A. Stock/Shareholder; Current; January, Inc. Research Support; Current; WW International, Inc. Consultant; Ended; Eiger BioPharmaceuticals. Advisory Panel; Current; Amylyx. Consultant; Current; Oura. Research Support; Current; Dexcom, Inc.