Antipsychotic drugs affect glucose uptake and the expression of glucose transporters in PC12 cells

Dwyer, Donard S.; Pinkofsky, Harold B.; Liu, Ye; Bradley, Ronald J.

doi:10.1016/s0278-5846(98)00092-x

Cited by 80 publications

(53 citation statements)

References 28 publications

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“…These facts suggest that administration of these clinical drugs inhibits glucose transport at a cellular level as a common effect and that this increases blood glucose levels in animals. In addition, the apparent inhibition of glucose uptake is observed in human erythrocytes and brain during administration of volatile anesthetics (Salah et al 1982;Alkire et al 1997), as well as in PC12 cells following treatment with phenothiazines (Dwyer et al 1999). With our findings, these facts suggest that anesthetics and antipsychotic phenothiazines inhibit the function of Hxts in animals in a similar manner irrespective of the structural difference of the drugs.…”

Section: Inhibitory Effects Of Clinical Drugs On Glucose Transport Insupporting

confidence: 76%

Local Anesthetics and Antipsychotic Phenothiazines Interact Nonspecifically with Membranes and Inhibit Hexose Transporters in Yeast

et al. 2016

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Action mechanisms of anesthetics remain unclear because of difficulty in explaining how structurally different anesthetics cause similar effects. In Saccharomyces cerevisiae, local anesthetics and antipsychotic phenothiazines induced responses similar to those caused by glucose starvation, and they eventually inhibited cell growth. These drugs inhibited glucose uptake, but additional glucose conferred resistance to their effects; hence, the primary action of the drugs is to cause glucose starvation. In hxt 0 strains with all hexose transporter (HXT) genes deleted, a strain harboring a single copy of HXT1 (HXT1s) was more sensitive to tetracaine than a strain harboring multiple copies (HXT1m), which indicates that quantitative reduction of HXT1 increases tetracaine sensitivity. However, additional glucose rather than the overexpression of HXT1/2 conferred tetracaine resistance to wild-type yeast; therefore, Hxts that actively transport hexoses apparently confer tetracaine resistance. Additional glucose alleviated sensitivity to local anesthetics and phenothiazines in the HXT1m strain but not the HXT1s strain; thus, the glucose-induced effects required a certain amount of Hxt1. At low concentrations, fluorescent phenothiazines were distributed in various membranes. At higher concentrations, they destroyed the membranes and thereby delocalized Hxt1-GFP from the plasma membrane, similar to local anesthetics. These results suggest that the aforementioned drugs affect various membrane targets via nonspecific interactions with membranes. However, the drugs preferentially inhibit the function of abundant Hxts, resulting in glucose starvation. When Hxts are scarce, this preference is lost, thereby mitigating the alleviation by additional glucose. These results provide a mechanism that explains how different compounds induce similar effects based on lipid theory.

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Section: Inhibitory Effects Of Clinical Drugs On Glucose Transport Insupporting

confidence: 76%

Local Anesthetics and Antipsychotic Phenothiazines Interact Nonspecifically with Membranes and Inhibit Hexose Transporters in Yeast

et al. 2016

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“…In humans, as the use of SGAs is associated with weight gain, the assumption has been made that these drugs are causing the development of severe insulin resistance in the major insulin-sensitive tissues, inducing compensatory increases in insulin secretion [3]. Indeed, some previous studies have claimed SGAs induce insulin resistance in cell culture models, albeit using the drugs at supra-therapeutic concentrations [6][7][8]11]. …”

Section: Discussionmentioning

confidence: 99%

“…However, a major side effect of SGAs is the development of symptoms similar to type 2 diabetes [1][2][3][4][5]. It is widely assumed that this is caused by peripheral insulin resistance following excessive weight gain observed with people prescribed these drugs [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Atypical antipsychotic drugs induce derangements in glucose homeostasis by acutely increasing glucagon secretion and hepatic glucose output in the rat

et al. 2008

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Aims/hypothesis Use of the second-generation antipsychotic drugs (SGAs) results in the development of obesity and a type 2 diabetes-like syndrome. We hypothesised that, in addition to the insulin resistance associated with the obesity, the SGAs might have acute effects on glucose metabolism that could contribute to the derangements in glucose metabolism. Methods We investigated the effects of therapeutically relevant levels of three different antipsychotic medications (haloperidol, quetiapine and clozapine) on glucose tolerance, measures of insulin resistance and hepatic glucose production, and on insulin and glucagon secretion in rats.Results We found that these drugs induce impaired glucose tolerance in rats that is associated with increased insulin secretion (clozapine>quetiapine>haloperidol) but is independent of weight gain. However, Akt/protein kinase B activation is normal, and at these levels of drug there was no effect on insulin action in fat cells or soleus muscle, and no effect on insulin sensitivity as evaluated by insulin tolerance tests. We show that clozapine induces increased glucose levels following pyruvate and glycerol challenges, indicating an increase in hepatic glucose output (HGO). Increased HGO would in turn increase insulin release and would explain the apparent phenotype mimicking insulin resistance. We provide evidence that this effect could at least in part be mediated by a stimulation of glucagon secretion. Conclusions/interpretation Our findings indicate that SGAs can cause acute derangements in glucose metabolism that are not caused by a direct induction of insulin resistance but act via an increase in glucagon secretion and thus stimulation of hepatic glucose production.

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“…The molecular mechanisms responsible for these side effects are not known, however, in vitro studies of the drugs have provided some insight into the problem. Antipsychotic drugs adversely affect cell growth [16], energy metabolism [17] and glucose transport [18,19] in cultured cell lines. The major pharmacological actions of the antipsychotic drugs on dopamine and serotonin receptors do not appear to explain the effects of the drugs on cell cultures.…”

Section: Introductionmentioning

confidence: 99%

Antipsychotic drugs disrupt normal development in Caenorhabditis elegans via additional mechanisms besides dopamine and serotonin receptors

Donohoe¹,

Aamodt²,

Osborn³

et al. 2006

Pharmacological Research

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Antipsychotic drugs may produce adverse effects during development in humans and rodents. However, the extent of these effects has not been systematically characterized nor have molecular mechanisms been identified. Consequently, we sought to evaluate the effects of an extensive panel of antipsychotic drugs in a model organism, C. elegans, whose development is well characterized, and which offers the possibility of identifying novel molecular targets. For these studies, animals were grown from hatching in the presence of vehicle (control) or antipsychotic drugs over a range of concentrations (20-160 μM) and growth was analyzed by measuring head-to-tail length at various intervals. First-generation antipsychotics (e.g., fluphenazine) generally slowed growth and maturation more than second-generation drugs such as quetiapine, and olanzapine. This is consistent with in vitro effects on human neuronal cell lines. Clozapine, a second-generation drug, produced similar growth deficits as haloperidol. Converging lines of evidence, including the failure to rescue growth with high concentrations of agonists, suggested that the drug-induced delay in development was not mediated by the major neurotransmitter receptors recognized by the antipsychotic drugs. Moreover, in serotonin-deficient tph-1 mutants, the drugs dramatically slowed development and led to larval arrest (including dauer formation), and neuronal abnormalities. Evaluation of alternative targets of the antipsychotics revealed a potential role for calmodulin and underscored the significance of Ca 2+ -calmodulin signaling in development. These findings suggest that antipsychotic drugs may interfere with normal developmental processes, and provide a tool for investigating the key signaling pathways involved.

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Antipsychotic drugs affect glucose uptake and the expression of glucose transporters in PC12 cells

Cited by 80 publications

References 28 publications

Local Anesthetics and Antipsychotic Phenothiazines Interact Nonspecifically with Membranes and Inhibit Hexose Transporters in Yeast

Local Anesthetics and Antipsychotic Phenothiazines Interact Nonspecifically with Membranes and Inhibit Hexose Transporters in Yeast

Atypical antipsychotic drugs induce derangements in glucose homeostasis by acutely increasing glucagon secretion and hepatic glucose output in the rat

Antipsychotic drugs disrupt normal development in Caenorhabditis elegans via additional mechanisms besides dopamine and serotonin receptors

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