Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

Abstract

The aim of this study was to determine the effect of prolonged 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibition on basal and hormone-stimulated glucose metabolism in fasted conscious dogs. For 7 days prior to study, either an 11β-HSD1 inhibitor (HSD1-I; n = 6) or placebo (PBO; n = 6) was administered. After the basal period, a 4-h metabolic challenge followed, where glucagon (3×-basal), epinephrine (5×-basal), and insulin (2×-basal) concentrations were increased. Hepatic glucose fluxes did not differ between groups during the basal period. In response to the metabolic challenge, hepatic glucose production was stimulated in PBO, resulting in hyperglycemia such that exogenous glucose was required in HSD-I (P < 0.05) to match the glycemia between groups. Net hepatic glucose output and endogenous glucose production were decreased by 11β-HSD1 inhibition (P < 0.05) due to a reduction in net hepatic glycogenolysis (P < 0.05), with no effect on gluconeogenic flux compared with PBO. In addition, glucose utilization (P < 0.05) and the suppression of lipolysis were increased (P < 0.05) in HSD-I compared with PBO. These data suggest that inhibition of 11β-HSD1 may be of therapeutic value in the treatment of diseases characterized by insulin resistance and excessive hepatic glucose production.

Fig. 1.

Twelve dogs were dosed daily with either an 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitor (compound 392) or placebo for 8 days, after which they were studied during the basal fasted state and during hormone infusion.

Fig. 2.

Whole body, liver, and visceral (gut) d₃-cortisol production rates and arterial plasma cortisol levels in conscious dogs during the basal (−40 to 0 min) and experimental (0–240 min) periods treated with a placebo (PBO; ○) or an 11β-HSD1 inhibitor (HSD1-Inh; ●). Data are means ± SE; n = 6/group. *P < 0.05, HSD1-Inh vs. PBO.

Fig. 3.

Hepatic sinusoidal glucagon and insulin and arterial epinephrine levels in conscious dogs during the basal (−40 to 0 min) and experimental (0–240 min) periods treated with a PBO (○) or an HSD1-Inh (●). Data are means ± SE; n = 6/group.

Fig. 4.

Arterial plasma glucose level and glucose infusion rates in conscious dogs during the basal (−40 to 0 min) and experimental (0–240 min) periods treated with a PBO (○) or an HSD1-Inh (●). Data are means ± SE; n = 6/group. *P < 0.05, HSD1-Inh vs. PBO.

Fig. 5.

Net hepatic glucose output, endogenous glucose production, net hepatic glycogenolysis, and gluconeogenic flux rates in conscious dogs during the basal (−40 to 0 min) and experimental (0–240 min) periods treated with a PBO (○) or an HSD1-Inh (●). Data are means ± SE; n = 6/group. *P < 0.05, HSD1-Inh vs. PBO.

Fig. 6.

Nonhepatic and whole body glucose uptake and arterial glucose clearance rates in conscious dogs during the basal (−40 to 0 min) and experimental (0–240 min) periods treated with a PBO (○) or an HSD1-Inh (●). Data are means ± SE; n = 6/group. *P < 0.05, HSD1-Inh vs. PBO; #P < 0.05, HSD1-Inh vs. PBO area under the curve.

Fig. 7.

Change from basal arterial blood glycerol and plasma nonesterified free fatty acid (NEFA) levels in conscious dogs during the basal (−40 to 0 min) and experimental (0–240 min) periods treated with a PBO (○) or an HSD1-Inh (●). Data are means ± SE; n = 6/group. *P < 0.05, HSD1-Inh vs. PBO. Average basal glycerol levels were 77 ± 5 and 97 ± 9 μmol/l, and basal NEFA levels were 695 ± 65 and 779 ± 87 μmol/l in PBO and HSD1-Inh, respectively.