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 11␤-hydroxysteroid dehydrogenase-1 (11␤-HSD1) inhibition on basal and hormone-stimulated glucose metabolism in fasted conscious dogs. For 7 days prior to study, either an 11␤-HSD1 inhibitor (HSD1-I; n ϭ 6) or placebo (PBO; n ϭ 6) was administered. After the basal period, a 4-h metabolic challenge followed, where glucagon (3ϫ-basal), epinephrine (5ϫ-basal), and insulin (2ϫ-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 Ͻ 0.05) to match the glycemia between groups. Net hepatic glucose output and endogenous glucose production were decreased by 11␤-HSD1 inhibition (P Ͻ 0.05) due to a reduction in net hepatic glycogenolysis (P Ͻ 0.05), with no effect on gluconeogenic flux compared with PBO. In addition, glucose utilization (P Ͻ 0.05) and the suppression of lipolysis were increased (P Ͻ 0.05) in HSD-I compared with PBO. These data suggest that inhibition of 11␤-HSD1 may be of therapeutic value in the treatment of diseases characterized by insulin resistance and excessive hepatic glucose production.11␤-hydroxysteroid dehydrogenase-1; cortisol; hepatic glucose production; glycogenolysis; gluconeogenesis CORTISOL IS A STEROID HORMONE with many physiological effects, including the regulation of carbohydrate, protein, and fat metabolism. At pathological concentrations, cortisol produces metabolic abnormalities similar to the metabolic syndrome, including obesity, insulin resistance, fasting hyperglycemia, hypertension, and dyslipidemia (2,42,56,58). In vivo cortisol action can be modified by 11␤-hydroxysteroid dehydrogenase-1 (11␤-HSD1), an enzyme that converts intracellular cortisone into active cortisol without necessarily modifying plasma cortisol concentrations (4, 6, 59). Liver (55, 57) and adipose (30, 33) 11␤-HSD1 activity has been shown to be elevated in obese humans with type 2 diabetes mellitus and the metabolic syndrome, and an intracellular Cushings-like state may contribute to these abnormalities (28, 32). In mice, hepatic 11␤-HSD1 overexpression can increase hepatic lipid flux, thereby causing dyslipidemia and insulin resistance (46), whereas overexpression in adipose tissue causes obesity, impaired glucose tolerance, and hypertension (35, 36). Conversely, when the enzyme is knocked out or acutely inhibited, mouse models of diabetes are protected against the manifestations of the metabolic syndrome (1, 31, 43). Together, these data demonstrate an overarching ability of dysregulated cortisol metabolism to generate a phenotype similar to that of type 2 diabetes and illustrate the potential therapeutic value of 11␤-HSD1 inhibition in the treatment of insulin resistance.Cortisol has potent effects on the glucoregulatory actions of hormones that regulate hepatic glucose production (HGP). For example, cortisol has been...

Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis

“…As noted above, previous studies have demonstrated that AMPK activation in the VMH is capable of generating a counterregulatory response to hypoglycemia (31,32). We have shown that increased hepatic glycogen content is associated with an increase in hepatic AMPK phosphorylation at the Thr172 site (35,36), an event that is most likely triggered by the enzyme becoming more susceptible to phosphorylation as a result of binding to intracellular glycogen (37). Future studies will be required to determine the event or events that trigger the afferent neural signal and the area or areas of the brain that coordinate altered hormone secretion.…”

“…Future studies will be required to determine the event or events that trigger the afferent neural signal and the area or areas of the brain that coordinate altered hormone secretion. To increase liver glycogen content, we infused fructose intraportally on the background of hyperglycemia and euinsulinemia as we have previously described (35,36,38). This was then followed by a 2-hour control period during which fructose was not infused and thereafter by a 2-hour hypoglycemic/hyperinsulinemic clamp.…”

“…Because of our study design (a 4-hour period of hepatic glycogen manipulation), we were unable to use 3-3 H glucose to measure whole body glucose turnover; instead we assessed net hepatic glucose balance (NHGB) as described previously (50). Net hepatic gluconeogenesis and glycogenolysis were calculated as previously described (35) and liver glycogen content just prior to the hypoglycemic experimental period was calculated as the postexperimental glycogen content (which was measured via biopsy) plus the amount of glycogen mobilized during the experimental period. The sinusoidal insulin and glucagon levels were calculated as described previously (50), and plasma glucose levels were seen in the Gly++ group relative to the Gly group, we studied a group of animals with livers that were completely denervated during the surgery for catheter placement (Gly++DEN; n = 6).…”

Longitudinal changes in glucocorticoid metabolism are associated with later development of adverse metabolic phenotype

“…animal models (9,33), and clinical studies using selective 11b-HSD1 inhibitors have now shown improvement in glycemic control in patients with type 2 diabetes mellitus, as well as reductions in BP and weight (10,11,34). However, in this study, 11b-HSD1 activity did not predict development of metabolic disease.…”

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

“…Inevitably, some agents have off-target effects when used at high drug exposure in preclinical studies [83], but in our view this does not undermine the consistency of beneficial effects in preclinical studies of inhibitors with a variety of chemical structures. Both short-and long-term selective inhibition of 11βHSD1 in dogs decreases hepatic glucose production mainly by suppressing glycogenolysis [84,85]. Have these encouraging results translated to humans?…”