Edgerton, Dale S.

These studies were conducted to assess the relationship between visceral adipose tissue free fatty acid (FFA) release and splanchnic FFA release. Steady-state splanchnic bed palmitate ([9,10-3H]palmitate) kinetics were determined from 14 sampling intervals from eight dogs with chronic indwelling arterial, portal vein, and hepatic vein catheters. We tested a model designed to predict the proportion of FFAs delivered to the liver from visceral fat by use of hepatic vein data. The model predicted that 15 ± 2% of hepatic palmitate delivery originated from visceral lipolysis, which was greater ( P = 0.004) than the 11 ± 2% actually observed. There was a good relationship ( r 2 = 0.63) between the predicted and observed hepatic palmitate delivery values, but the model overestimated visceral FFA release more at lower than at higher palmitate concentrations. The discrepancy could be due to differential uptake of FFAs arriving from the arterial vs. the portal vein or to release of FFAs in the hepatic circulatory bed. Splanchnic FFA release measured using hepatic vein samples was strongly related to visceral adipose tissue FFA release into the portal vein. This finding suggests that splanchnic FFA release is a good indicator of visceral adipose tissue lipolysis.

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.

Inactive cortisone is converted to active cortisol within the liver by 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), and impaired regulation of this process may be related to increased hepatic glucose production (HGP) in individuals with type 2 diabetes. The primary aim of this study was to investigate the effect of acute 11β-HSD1 inhibition on HGP and fat metabolism during insulin deficiency. Sixteen conscious, 42-h-fasted, lean, healthy dogs were studied. Somatostatin was infused to create insulin deficiency, and the animals were treated with a specific 11β-HSD1 inhibitor (compound 531) or placebo for 5 h. 11β-HSD1 inhibition completely suppressed hepatic cortisol production, and this attenuated the increase in HGP that occurred during insulin deficiency. PEPCK and glucose-6-phosphatase expression were decreased when 11β-HSD1 was inhibited, but gluconeogenic flux was unchanged, implying an effect on glycogenolysis. Since inhibition of hepatic cortisol production reduces HGP during insulin deficiency, 11β-HSD1 is a potential therapeutic target for the treatment of excess glucose production that occurs in diabetes.

The action of lipoprotein lipase on triglyceride-rich lipoproteins generates fatty acids that are either transported into tissues or mix with circulating free fatty acids (FFAs) via a process known as spillover. In the present study, arterial, portal vein, and hepatic vein sampling catheters were surgically placed in nine mongrel dogs. The animals were subsequently studied after a 42-h fast during infusion of [14C]oleate and a lipid emulsion containing [3H]triolein; the emulsion was used as a surrogate for the study of chylomicron metabolism. More than one-half of splanchnic [3H]triglyceride uptake occurred in the liver, and substantial fractional spillover of [3H]oleate was observed in both liver and nonhepatic tissues (∼50% each). There was a significant correlation between FFA release from nonhepatic tissues (presumably visceral fat) and nonhepatic fractional spillover (R = 0.81, P &lt; 0.01), consistent with a model in which the rate of intracellular lipolysis influences spillover by determining the direction of net fatty acid flow between the cell and the interstitium. There was a significant correlation between “true” and “net” splanchnic spillover (R = 0.84, P &lt; 0.005), the latter representing calculation of spillover between arterial and hepatic venous blood without portal venous data. Metabolism of chylomicron triglycerides in visceral fat may be an important source of portal venous FFAs.

Eight dogs underwent combined hepatic/portal vein catheterization and infusion of D4-cortisol in order to determine the relative contributions of the viscera and liver to splanchnic cortisol production. D4-cortisol concentrations progressively decreased from 2.6 ± 0.1 to 2.4 ± 0.1 to 1.7 ± 0.1 μg/dl (P &lt; 0.001 by ANOVA) from hepatic artery to portal vein to hepatic vein, respectively, indicating 8 ± 3 and 28 ± 3% extraction across the viscera and liver, respectively. On the other hand, hepatic artery, portal vein, and hepatic vein cortisol concentrations did not differ (0.31 ± 0.12 vs. 0.28 ± 0.11 vs. 0.27 ± 0.10 μg/dl, respectively), indicating zero net cortisol balance. This meant that 1.0 ± 0.1 μg/min of cortisol was produced within the splanchnic bed, all of which occurred within the liver (1.2 ± 0.1 μg/min). On the other hand, visceral cortisol production did not differ from zero (−0.2 ± 0.2 μg/min; P &lt; 0.001 vs. liver). Flux through the 11β hydroxysteroid dehydrogenase (HSD) type 1 pathway can be measured by determining the rate of conversion of D4-cortisol to D3-cortisol. D3-cortisol concentrations were lower in the portal vein than hepatic artery (0.45 ± 0.03 vs. 0.48 ± 0.02, respectively; P &lt; 0.01) but did not differ in the portal vein and hepatic vein, indicating net uptake across the viscera but zero balance across the liver. D3-cortisol production with the viscera and liver averaged 0.2 ± 0.1 μg/min (P = NS vs. zero production) and 0.6 ± 0.1 μg/min (P &lt; 0.001 vs. zero production; P &lt; 0.001 vs. viscera production), respectively. We conclude that most, if not all, of splanchnic cortisol production occurs within the liver. Taken together, these data suggest that the high local cortisol concentrations generated via the 11β HSD type 1 pathway within the liver likely contribute to the regulation of hepatic glucose, fat, and protein metabolism.