Portal infusion of escitalopram enhances hepatic glucose disposal in conscious dogs
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.European journal of pharmacology (Impact Factor: 2.53). 02/2009; 607(1-3). DOI: 10.1016/j.ejphar.2009.01.042
To examine whether escitalopram enhances net hepatic glucose uptake during a hyperinsulinemic hyperglycemic clamp, studies were performed in conscious 42-h-fasted dogs. The experimental period was divided into P1 (0-90 min) and P2 (90-270 min). During P1 and P2 somatostatin (to inhibit insulin and glucagon secretion), 4X basal intraportal insulin, basal intraportal glucagon, and peripheral glucose (2X hepatic glucose load) were infused. Saline was infused intraportally during P1 in all groups. In one group saline infusion was continued in P2 (SAL, n=11), while escitalopram was infused intraportally at 2 mug/kg/min (L-ESC, n=6) or 8 mug/kg/min (H-ESC, n=7) during P2 in two other groups. The arterial insulin concentrations rose ~four fold (to 123+/-8, 146+/-13 and 148+/-15 pmol/L) while glucagon concentrations remained basal (41+/-3, 44+/-9 and 40+/-3 ng/L) in all groups. The hepatic glucose load averaged 216+/-13, 223+/-19 and 202+/-12 mumol/kg/min during the entire experimental period (P1 and P2) in the SAL, L-ESC and H-ESC groups, respectively. Net hepatic glucose uptake was 11.6+/-1.4, 10.1+/-0.9 and 10.4+/-2.3 mumol/kg/min in P1 and averaged 16.9+/-1.5, 15.7+/-1.3 and 22.6+/-3.7 (P<0.05) in the SAL, L-ESC and H-ESC groups, respectively during the last hour of P2 (210-270 min). Net hepatic carbon retention (glycogen storage) was 15.4+/-1.3, 14.9+/-0.6 and 20.9+/-2.6 (P<0.05) mumol/kg/min in SAL, L-ESC and H-ESC respectively during the last hour of P2. Escitalopram enhanced net hepatic glucose uptake and hepatic glycogen deposition, showing that it can improve hepatic glucose clearance under hyperinsulinemic hyperglycemic conditions. Its use in individuals with diabetes may, therefore, result in improved glycemic control.
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ABSTRACT: Low birth weight (LBW) is associated with type 2 diabetes and depression, which may be related to prenatal stress and insulin resistance as a result of chronic hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We examined whether treatment with a selective serotonin reuptake inhibitor [escitalopram (ESC)] could downregulate HPA axis activity and restore insulin sensitivity in LBW rats. After 4-5 wk of treatment, ESC-exposed LBW (SSRI-LBW) and saline-treated control and LBW rats (Cx and LBW) underwent an oral glucose tolerance test or a hyperinsulinemic euglycemic clamp to assess whole body insulin sensitivity. Hepatic phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression and red skeletal muscle PKB Ser(473) phosphorylation were used to assess tissue-specific insulin sensitivity. mRNA expression of the hypothalamic mineralocorticoid receptor was fivefold upregulated in LBW (P < 0.05 vs. Cx), accompanied by increased corticosterone release during restraint stress and total 24-h urinary excretion (P < 0.05 vs. Cx), whole body insulin resistance (P < 0.001 vs. Cx), and impaired insulin suppression of hepatic PEPCK mRNA expression (P < 0.05 vs. Cx). Additionally, there was a tendency for reduced red muscle PKB Ser(473) phosphorylation. The ESC treatment normalized corticosterone secretion (P < 0.05 vs. LBW), whole body insulin sensitivity (P < 0.01) as well as postprandial suppression of hepatic mRNA PEPCK expression (P < 0.05), and red muscle PKB Ser(473) phosphorylation (P < 0.01 vs. LBW). We conclude that these data suggest that the insulin resistance and chronic HPA axis hyperactivity in LBW rats can be reversed by treatment with an ESC, which downregulates HPA axis activity, lowers glucocorticoid exposure, and restores insulin sensitivity in LBW rats.AJP Endocrinology and Metabolism 05/2010; 298(5):E920-9. DOI:10.1152/ajpendo.00606.2009 · 3.79 Impact Factor
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ABSTRACT: The objective of this study was to determine how increasing the hepatic glycogen content would affect the liver's ability to take up and metabolize glucose. During the first 4 h of the study, liver glycogen deposition was stimulated by intraportal fructose infusion in the presence of hyperglycemic-normoinsulinemia. This was followed by a 2-h hyperglycemic-normoinsulinemic control period, during which the fructose infusion was stopped, and a 2-h experimental period in which net hepatic glucose uptake (NHGU) and disposition (glycogen, lactate, and CO(2)) were measured in the absence of fructose but in the presence of a hyperglycemic-hyperinsulinemic challenge including portal vein glucose infusion. Fructose infusion increased net hepatic glycogen synthesis (0.7 ± 0.5 vs. 6.4 ± 0.4 mg/kg/min; P < 0.001), causing a large difference in hepatic glycogen content (62 ± 9 vs. 100 ± 3 mg/g; P < 0.001). Hepatic glycogen supercompensation (fructose infusion group) did not alter NHGU, but it reduced the percent of NHGU directed to glycogen (79 ± 4 vs. 55 ± 6; P < 0.01) and increased the percent directed to lactate (12 ± 3 vs. 29 ± 5; P = 0.01) and oxidation (9 ± 3 vs. 16 ± 3; P = NS). This change was associated with increased AMP-activated protein kinase phosphorylation, diminished insulin signaling, and a shift in glycogenic enzyme activity toward a state discouraging glycogen accumulation. These data indicate that increases in hepatic glycogen can generate a state of hepatic insulin resistance, which is characterized by impaired glycogen synthesis despite preserved NHGU.Diabetes 02/2011; 60(2):398-407. DOI:10.2337/db10-0592 · 8.10 Impact Factor
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ABSTRACT: The aim of the present study was to investigate the effect of several drugs acting on serotonergic neurotransmission on the development of hepatocellular injury caused by carbon tetrachloride (CCl4) in rats. Liver damage was induced in rats by administration of CCl4 (2.8 ml/kg in olive oil, orally). Sertraline, citalopram, or fluvoxamine were administered orally once daily in association with CCl4 and for 1 week thereafter. Sibutramine was administered 1 week prior to the toxic agent and for 3 days thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. In CCl4-treated rats, sertraline (10, 20 mg/kg) reduced serum alanine aminotransferase (ALT) levels by 41.8% and 53.4%, respectively, compared to controls. Serum aspartate aminotransferase (AST) levels decreased by 37.4% and 58.2%, respectively, while alkaline phosphatase (ALP) decreased by 40.5% and 59.3%, respectively. Treatment with citalopram (5, 10, 20 mg/kg) reduced serum ALT levels by 29.8%, 35.6%, and 43.8%, AST levels by 24.2%, 29.9%, and 43%, and ALP by 17.8%, 35%, and 48.9%, respectively. Fluvoxamine (5, 10, 20 mg/kg) dose-dependently reduced the elevation of ALT levels by 42.6%, 49.9%, and 51.9%, AST levels by 40.2%, 44.6%, and 61.6%, and ALP by 8.3%, 46.8%, and 52.7%, respectively. Given as a pretreatment, sibutramine (5, 10, 20 mg/kg) reduced serum ALT levels by 52.1%, 52.2%, and 57.5%, AST levels by 53.6%, 58.4%, and 59.4%, and ALP by 46.8%, 67.6%, and 72.2%, respectively. Histopathological and histochemical examinations also indicated that CCl4-induced liver injury was less severe after treatment with the test drugs than in the CCl4 control groups. It is concluded that the administration of drugs with serotonin reuptake inhibitory properties is associated with a reduction in experimental liver injury induced by CCl4.Comparative Clinical Pathology 02/2012; 19(3). DOI:10.1007/s00580-010-1067-5 · 0.37 Impact Factor
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