Serotonin-mediated acute insulin resistance in the perfused rat hindlimb but not in incubated muscle: A role for the vascular system

Rattigan, Stephen; Dora, K A; Colquhoun, Eric Q.; Clark, Michael G.

doi:10.1016/0024-3205(93)90563-i

Cited by 43 publications

(41 citation statements)

References 21 publications

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“…This intervention was based on experiments using the isolated pumpperfused rat hindleg in which the vasoconstrictors ␣-methyl serotonin or serotonin were found to redirect flow from the nutritive to the nonnutritive route (41). Indirect evidence that serotoninergic agonist-mediated insulin resistance did not result from a direct effect on muscle glucose uptake and metabolism was obtained using isolated incubated muscle preparations (42), where the vascular distribution of insulin and glucose is not involved. In that preparation, serotonin had no effect on IMGU (42).…”

Section: Discussionmentioning

confidence: 99%

“…Indirect evidence that serotoninergic agonist-mediated insulin resistance did not result from a direct effect on muscle glucose uptake and metabolism was obtained using isolated incubated muscle preparations (42), where the vascular distribution of insulin and glucose is not involved. In that preparation, serotonin had no effect on IMGU (42). Thus, it would appear likely that IMGU becomes partly inhibited by denying access for insulin and glucose to regions of the muscles of the perfused hindleg or the hindleg in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Lipid Infusion Impairs Physiologic Insulin-Mediated Capillary Recruitment and Muscle Glucose Uptake In Vivo

2002

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Infusion of triglycerides and heparin causes insulin resistance in muscle. Because the vascular actions of insulin, particularly capillary recruitment, may contribute to the increase in glucose uptake by skeletal muscle, we investigated the effects of Intralipid/heparin infusion on the hemodynamic actions of insulin during clamp conditions. Saline or 10% Intralipid/heparin (33 U/ml) was infused into anesthetized rats at 20 l/min for 6 h. At 4 h into the saline infusion, a 2-h hyperinsulinemic (3 mU ⅐ min ؊1 ⅐ kg ؊1 )-euglycemic clamp was conducted (Ins group). At 4 h into the lipid infusion, a 2-h saline control (Lip group) or 2-h hyperinsulinemiceuglycemic clamp (Lip ؉ Ins group) was conducted. Arterial blood pressure, heart rate, femoral blood flow (FBF), hindleg vascular resistance, glucose infusion rate (GIR), hindleg glucose uptake (HGU), and muscle 2-deoxyglucose uptake (Rg) were measured. Capillary recruitment, as measured by metabolism of infused 1-methylxanthine (1-MX), was also assessed. When compared with either Lip or Lip ؉ Ins, Ins had no effect on arterial blood pressure, heart rate, FBF, or vascular resistance but increased GIR, HGU, and Rg of soleus, plantaris, extensor digitorum longus, and gastrocnemius red muscles and hindlimb 1-MX metabolism. GIR, HGU, and Rg of soleus, plantaris, gastrocnemius red, and the combined muscles and 1-MX metabolism were less in Lip ؉ Ins than in Ins rats. HGU correlated closely with hindleg capillary recruitment (r ‫؍‬ 0.86, P < 0.001) but not total hindleg blood flow. In conclusion, acute elevation of plasma free fatty acids blocks insulinmediated glucose uptake and capillary recruitment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lipid Infusion Impairs Physiologic Insulin-Mediated Capillary Recruitment and Muscle Glucose Uptake In Vivo

2002

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“…Circulating concentrations of 5-HT did not rise, but it is conceivable that local concentrations in the skeletal muscle were elevated secondary to a centrally mediated reflex. 5-HT is reported to have either no effect (30) or a stimulatory effect (14) on glucose uptake in isolated skeletal muscle. However, it has vasoactive effects in skeletal muscle in vivo, causing the channeling of blood away from the vessels supplying oxygen and nutrients to skeletal muscle ("nutritive flow") and into other vessels (those supplying connective tissue and associated adipocytes, creating "nonnutritive flow") and reducing muscle and hindlimb nutrient uptake (8,30).…”

Section: Discussionmentioning

confidence: 99%

“…5-HT is reported to have either no effect (30) or a stimulatory effect (14) on glucose uptake in isolated skeletal muscle. However, it has vasoactive effects in skeletal muscle in vivo, causing the channeling of blood away from the vessels supplying oxygen and nutrients to skeletal muscle ("nutritive flow") and into other vessels (those supplying connective tissue and associated adipocytes, creating "nonnutritive flow") and reducing muscle and hindlimb nutrient uptake (8,30). Finally, it is worth noting that our laboratory (1,17,18) has previously observed a reciprocal relationship between hepatic and peripheral glucose uptake, such that when NHGU is stimulated by the presence of the "portal signal," there is a concomitant decrease in non-HGU.…”

Section: Discussionmentioning

confidence: 99%

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

Moore

DiCostanzo

Dardevet

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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Portal infusion of a selective serotonin reuptake inhibitor enhances hepatic glucose disposal in conscious dogs. Am J Physiol Endocrinol Metab 287: E1057-E1063, 2004. First published August 17, 2004 doi:10.1152/ajpendo.00313.2004.-Intraportal delivery of serotonin enhanced net hepatic glucose uptake (NHGU) during a hyperinsulinemic hyperglycemic clamp, but serotonin elevated catecholamines and can cause gastrointestinal distress. We hypothesized that the selective serotonin reuptake inhibitor (SSRI) fluvoxamine would enhance NHGU without side effects. Arteriovenous difference and tracer ([3-3 H]glucose) techniques were used in conscious 42-h-fasted dogs. Experiments consisted of equilibration (Ϫ120 to Ϫ30 min), basal (Ϫ30 to 0 min), and experimental (EXP; 0 -270 min) periods. During EXP, somatostatin, fourfold basal intraportal insulin, basal intraportal glucagon, and peripheral glucose (to double the hepatic glucose load) were infused. Saline (SAL) was infused intraportally during 0 -90 min (P1), and fluvoxamine was infused intraportally at 0.5, 1, and 2 g ⅐ kg Ϫ1 ⅐ min Ϫ1 from 90 to 150 (P2), 150 to 210 (P3), and 210 to 270 (P4) min, respectively, in the FLUV group (n ϭ 8). The SAL group (n ϭ 9) received intraportal saline during 0 -270 min. NHGU in SAL was 13.9 Ϯ 1.7 and 17.0 Ϯ 2.0 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 in P3-P4, respectively, while NHGU in FLUV averaged 19.7 Ϯ 2.8 and 26.6 Ϯ 3.0 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 (P Ͻ 0.05 vs. SAL). Net hepatic carbon retention was greater (P Ͻ 0.05) in FLUV than in SAL (17.6 Ϯ 2.6 vs. 13.9 Ϯ 2.7 and 23.8 Ϯ 3.0 vs. 14.4 Ϯ 3.3 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 in P3-P4, respectively), and final hepatic glycogen concentrations were 50% greater in FLUV (P Ͻ 0.005). Nonhepatic glucose uptake was greater in SAL than in FLUV at 270 min (P Ͻ 0.05). Catecholamine concentrations remained basal, and the animals evidenced no distress. Thus fluvoxamine enhanced NHGU and hepatic carbon storage without raising circulating serotonin concentrations or causing stress, suggesting that hepatic-targeted SSRIs might be effective in reducing postprandial hyperglycemia in individuals with diabetes or impaired glucose tolerance. glycemia; liver; portal vein; hepatic glucose uptake; nonhepatic glucose uptake INTRAPORTAL INFUSION OF SEROTONIN (5-hydroxytryptamine, or 5-HT) enhanced net hepatic glucose uptake (NHGU) in conscious dogs during a hyperinsulinemic hyperglycemic clamp (22). These findings suggest that 5-HT might play a role in limiting postprandial glycemic excursions in individuals with type 2 diabetes or impaired glucose tolerance. Good control of glycemia has been documented to reduce the risk of diabetesrelated complications (35); because diabetes is a progressive disease, there is a need for a variety of pharmacological tools for diabetes treatment. Thus the effects of 5-HT on hepatic and whole body glucose metabolism are intriguing and invite further study.Plasma concentrations of catecholamines and cortisol increased during the portal 5-HT infusion (22), and high concentrations of 5-HT in humans are well known...

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“…However, the mechanisms that account for hypoglycaemia [6,7] or improved glucose tolerance in diabetes after treatment with selective 5-HT reuptake inhibitors [9] are not fully understood. In skeletal muscle 5-HT has been found to either stimulate or to have no effect on glucose uptake [10,11]. However, in the liver, intraportal infusion of 5-HT or its precursor, 5-hydroxytryptophan, stimulated glucose uptake during a hyperinsulinaemic clamp [12,13].…”

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confidence: 99%

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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Serotonin-mediated acute insulin resistance in the perfused rat hindlimb but not in incubated muscle: A role for the vascular system

Cited by 43 publications

References 21 publications

Lipid Infusion Impairs Physiologic Insulin-Mediated Capillary Recruitment and Muscle Glucose Uptake In Vivo

Lipid Infusion Impairs Physiologic Insulin-Mediated Capillary Recruitment and Muscle Glucose Uptake In Vivo

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

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

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