Figure 5. Oct1 deletion results in reduced hepatic metformin accumulation and phosphorylation of AMPK and ACC in mice receiving oral doses of metformin.

(A) The pharmacokinetics of metformin was similar in age-matched Oct1^+/+ mice and Oct1^–/– mice after an oral dose. Shown here are blood metformin concentration–time profiles. The mice (n = 4 per group) were given an oral dose of metformin (15 mg/kg containing 0.2 mCi/kg of [¹⁴C]metformin), approximating the single dose of 1,000 mg in humans. The radioactivity in blood was determined and converted to mass amounts. Data represent mean ± SD. (B) Hepatic metformin accumulation after an oral dose was much higher for Oct1^+/+ mice than for age-matched Oct1^–/– mice. The mice (n = 4 per group) were sacrificed 1 hour after the oral dose, and the livers were removed immediately. The radioactivity determined in liver homogenates was converted to mass amounts. Data represent mean ± SD. *P < 0.001 versus Oct1^+/+ (2-tailed Student’s t test). (C) OCT1 was required for metformin to fully stimulate hepatic AMPK phosphorylation and ACC phosphorylation in mice. A daily dose of metformin (50 mg/kg) or saline was administered i.p. for 3 consecutive days to 10-week-old male mice. The mice were sacrificed 1 hour after the i.p. administration on the third day. Liver extracts were detected with polyclonal antibodies against phospho-ACC (Ser79), phospho-AMPKα (Thr172), and β-actin.