High-fat diet–fed obese insulin-resistant mice dosed daily with either vehicle (n = 8–14) or a long-acting glucose-dependent insulinotropic polypeptide receptor agonist (LAGIPRA, n = 8–14) for 14 days. (A) Daily body weight and food intake. (B) Fasting blood glucose and plasma insulin following 14 days of treatment. Hyperinsulinemic-euglycemic clamp following 14 days of treatment. (C) Average glucose infusion rates throughout and during the final 30 minutes of clamp (GIR). (D) Endogenous glucose production (EGP). Insulin-stimulated glucose disposal in (E) soleus, (F) red, and (G) white gastrocnemius skeletal muscle and (H) epididymal white adipose tissue (eWAT) and (I) inguinal white adipose tissue (iWAT). Data are presented as mean ± SEM. *P < 0.05 compared with vehicle. Statistical analyses performed included Student’s unpaired t test, 2-way ANOVA, or Kruskal-Wallis test, where appropriate.