Portal infusion of a selective serotonin reuptake inhibitor enhances hepatic glucose disposal in conscious dogs

Moore, Mary Courtney; DiCostanzo, Catherine A.; Dardevet, Dominique; Lautz, Margaret; Farmer, Ben; Neal, Doss W.; Cherrington, Alan D.

doi:10.1152/ajpendo.00313.2004

Cited by 22 publications

(26 citation statements)

References 36 publications

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“…Studies were carried out in conscious 42-h-fasted dogs of either sex (20 -23 kg). This length of fast in the canine does not induce hypoglycemia, raise the plasma levels of stress hormones, or exhaust liver glycogen (38,39). In addition, after a 42-h fast approximately two-thirds of hepatic glucose production is accounted for by gluconeogenic flux (48), comparable with overnight-fasted humans.…”

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confidence: 99%

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

Winnick

Ramnanan

Saraswathi

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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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...

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confidence: 99%

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

Winnick

Ramnanan

Saraswathi

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Physiological studies by Moore and colleagues demonstrated increased hepatic glucose uptake after intraportal infusion of 5-HT or selective 5-HT uptake inhibitors [12][13][14][15]. This raised the question whether these effects are mediated by a direct effect of 5-HT on hepatocytes or by indirect mechanisms involving haemodynamic changes or altered transmission of afferent signals.…”

Section: Discussionmentioning

confidence: 99%

“…The final DMSO concentration in all incubations was 0.1% v/v. For the determination of glycogen synthesis, glycolysis and glucose phosphorylation the medium was supplemented with [U- 14 C]glucose, [3-3 H]glucose or [2-3 H]glucose (37-74 kBq/ml) respectively. Glycogen synthesis was determined from the incorporation of 14 C label into glycogen, determined by ethanol precipitation [23], and glycolysis and glucose phosphorylation were determined from the rate of formation of 3 H 2 O [24].…”

Section: Methodsmentioning

confidence: 99%

“…However, in the liver, intraportal infusion of 5-HT or its precursor, 5-hydroxytryptophan, stimulated glucose uptake during a hyperinsulinaemic clamp [12,13]. Stimulation of hepatic glucose uptake with concomitant glycogen storage also occurred during infusion of a selective 5-HT reuptake inhibitor during a hyperinsulinaemic clamp but not during euinsulinaemic clamps [14,15]. This could be due to a direct effect of 5-HT on hepatocytes or to indirect mechanisms involving either haemodynamic changes or decreased afferent signalling.…”

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confidence: 97%

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Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

2007

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Aims/hypothesis Intraportal infusion of serotonin (5-hydroxytryptamine, 5-HT) or inhibitors of its cellular uptake stimulate hepatic glucose uptake in vivo by either direct or indirect mechanisms. The aims of this study were to determine the direct effects of 5-HT in hepatocytes and to test the hypothesis that atypical antipsychotic drugs that predispose to type 2 diabetes counter-regulate the effects of 5-HT. Materials and methods Rat hepatocytes were studied in short-term primary culture. Results Serotonin (5-HT) stimulated glycogen synthesis at nanomolar concentrations but inhibited it at micromolar concentrations. The stimulatory effect was mimicked by α-methyl-5-HT, a mixed 5-HT1/5-HT2 receptor agonist, whereas the inhibition was counteracted by a 5-HT2B/2C receptor antagonist. α-Methyl-5-HT stimulated glycogen synthesis additively with insulin, but unlike insulin, did not stimulate glucose phosphorylation and glycolysis, nor did it cause Akt (protein kinase B) phosphorylation. Stimulation of glycogen synthesis by α-methyl-5-HT correlated with depletion of phosphorylase a. This effect could not be explained by elevated levels of glucose 6-phosphate, which causes inactivation of phosphorylase, but was explained, at least in part, by decreased phosphorylase kinase activity in situ. The antipsychotic drugs clozapine and olanzapine, which bind to 5-HT receptors, counteracted the effect of α-methyl-5-HT on phosphorylase inactivation. Conclusions/interpretation This study provides evidence for both stimulation and inhibition of glycogen synthesis in hepatocytes by serotonergic mechanisms. The former effects are associated with the inactivation of phosphorylase and are counteracted by atypical antipsychotic drugs that cause hepatic insulin resistance. Antagonism of hepatic serotonergic mechanisms may be a component of the hepatic dysregulation caused by antipsychotic drugs that predispose to type 2 diabetes.

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“…Experiments were conducted on twenty-one 42-h-fasted conscious mongrel dogs of either sex (18 -25 kg). This length of fast does not induce hypoglycemia, raise the plasma levels of stress hormones, or exhaust liver glycogen in the dog (42,43). Housing and diet have been described previously (21).…”

Section: Methodsmentioning

confidence: 99%

Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog

Edgerton

Johnson

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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-Incretins improve glucose metabolism through multiple mechanisms. It remains unclear whether direct hepatic effects are an important part of exenatide's (Ex-4) acute action. Therefore, the objective of this study was to determine the effect of intraportal delivery of Ex-4 on hepatic glucose production and uptake. Fasted conscious dogs were studied during a hyperglycemic clamp in which glucose was infused into the hepatic portal vein. At the same time, portal saline (control; n ϭ 8) or exenatide was infused at low (0.3 pmol·kg Ϫ1 ·min Ϫ1 , Ex-4-low; n ϭ 5) or high (0.9 pmol·kg Ϫ1 ·min Ϫ1 , Ex-4-high; n ϭ 8) rates. Arterial plasma glucose levels were maintained at 160 mg/dl during the experimental period. This required a greater rate of glucose infusion in the Ex-4-high group (1.5 Ϯ 0.4, 2.0 Ϯ 0.7, and 3.7 Ϯ 0.7 mg·kg Ϫ1 ·min Ϫ1 between 30 and 240 min in the control, Ex-4-low, and Ex-4-high groups, respectively). Plasma insulin levels were elevated by Ex-4 (arterial: 4,745 Ϯ 428, 5,710 Ϯ 355, and 7,262 Ϯ 1,053 U/ml; hepatic sinusoidal: 14,679 Ϯ 1,700, 15,341 Ϯ 2,208, and 20,445 Ϯ 4,020 U/ml, 240 min, area under the curve), whereas the suppression of glucagon was nearly maximal in all groups. Although glucose utilization was greater during Ex-4 infusion (5.92 Ϯ 0.53, 6.41 Ϯ 0.57, and 8.12 Ϯ 0.54 mg·kg Ϫ1 ·min Ϫ1 ), when indices of hepatic, muscle, and whole body glucose uptake were expressed relative to circulating insulin concentrations, there was no indication of insulin-independent effects of Ex-4. Thus, this study does not support the notion that Ex-4 generates acute changes in hepatic glucose metabolism through direct effects on the liver. exenatide; exendin-4; incretin; hepatic glucose metabolism; hepatic glucose uptake; hepatic glucose production GLUCAGON-LIKE PEPTIDE-1 (GLP-1) receptor agonists represent a new class of antidiabetic agent that has gained popularity in recent years. Exenatide [exendin-4 (Ex-4)] is a long-acting mimetic of GLP-1 that has been shown to increase glucosedependent insulin secretion, restore the first-phase insulin response, and reduce inappropriately high glucagon secretion in patients with type 2 diabetes mellitus (17,30,37). It has also been demonstrated to slow gastric emptying and reduce food intake in humans and to increase pancreatic ␤-cell proliferation and neogenesis in rodents (17,30). Compared with GLP-1, Ex-4 is a more potent stimulator of glucose-dependent insulin release, and it has greater potency for glucose lowering in vivo (23,30,52,66). This is due at least partly to Ex-4 resistance to degradation by dipeptidyl peptidase-4, which extends its plasma half-life and thereby increases its therapeutic potential (30).Although the effects of GLP-1 and Ex-4 are known to be related to their ability to alter pancreatic ␣-and ␤-cell hormone secretion (7, 9, 29), their direct effects on the liver are less clear (1,10,26). Although several groups have detected GLP-1 receptor expression in the liver of mice (6), rats (61, 64), and humans (24, 56), others have been unable to do...

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Portal infusion of a selective serotonin reuptake inhibitor enhances hepatic glucose disposal in conscious dogs

Cited by 22 publications

References 36 publications

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

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

Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog

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