HFD exacerbates insulin resistance and glucose metabolism in diabetic Pik3r1 R649W mice. Blood glucose (A) and serum insulin (B) levels after 8 weeks of diet in the fed state and after a 16-h fast. HOMA-insulin resistance (IR) index calculated from fasting insulin and glucose levels (C), and glucose tolerance (D) and insulin tolerance (E) tests after 8 weeks on the CD or HFD. Results shown as mean ± SEM. *P < 0.05, **P < 0.01, compared with controls, t tests (n = 6–8 animals per group). F: Immunoblot analysis of insulin signaling capacity (antibodies against p-IR, IR, p-Akt, Akt, and actin) in liver tissue after 10 min of insulin (5 units) or vehicle administration.