It is unclear how hepatic
glucocorticoid receptor (GR) function and hypothalamic-pituitary-adrenal axis tone contribute to the diabetic state and in particular whole-body
glucose fluxes. We have previously demonstrated that long-term exposure to hepatic GR inhibition lowers
glucose levels in ob/ob mice (J Pharmacol Exp Ther 2005;314:191). The purpose of this study was to determine the effects of a novel GR antagonist (A-348441) on whole-body
glucose fluxes in a model of
insulin resistance, the Zucker fatty (fa/fa) rat. After an overnight fast, euglycemic-hyperinsulinemic clamp studies were performed 2 hours after single oral dosing as follows: (1)
A-348441 at 100 mg/kg or (2) vehicle. Furthermore, effects of 1 week of treatment with either vehicle or
A-348441 (3, 10, 30, or 100 mg/kg PO, once per day) were investigated in separate groups of rats fasted overnight and given a final dose of their respective compound, followed 2 hours later by a euglycemic-hyperinsulinemic clamp. One week after
catheter implantation,
body weight returned to presurgery levels, with no difference between groups. A single, 100-mg/kg dose of
A-348441 significantly increased
glucose infusion rate 4-fold (P < .05) and reduced endogenous
glucose production by 37% (P < .05) but did not change
glucose disposal. After 1 week of sub-long-term dosing, fasting
glucose levels were reduced dose-dependently with
A-348441 vs vehicle (-8%, not significant; -14%, -20%, and -25%, P < .05, at 3, 10, 30, and 100 mg/kg, respectively) with no observed
hypoglycemia or change in fasting
insulin levels.
A-348441 increased the
glucose infusion rates after 1-week treatment by 1.3-, 5.7-, 7.3-, and 6.4-fold (P < .05). Endogenous
glucose production was decreased (-25%, -44%, -50%, and -61%, P < .05), whereas
glucose disposal was increased (29% and 13%, not significant; 23% and 34%, P < .05), with
A-348441. In summary, single-dose treatment with the liver-selective GR antagonist
A-348441 decreases
glucose production with no effect on
glucose disposal or fasting
glucose levels. After 1 week of treatment with
A-348441, (1) there was no effect on
body weight, (2) fasting
glucose levels decreased, (3) both
glucose disposal and
glucose infusion rate increased during clamping, and (4) endogenous
glucose production was greatly reduced. In addition, hepatic
glucose production was highly correlated with fasting
glucose levels (r = 0.97). In conclusion, these results indicate that
A-348441 increases
insulin sensitivity at both the liver and peripheral tissues, leading toward a normalization of the
insulin resistant state. Furthermore, with 1-week vs single-dose liver-selective
glucocorticoid antagonism, we have determined that the peripheral effect is secondary to the primary event of reduced hepatic
glucose production. The approach of inhibiting the hepatic GR may be an advantageous treatment paradigm for individuals with
type 2 diabetes mellitus.