Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine

Ardizzone, Timothy D.; Bradley, Ronald J.; Freeman, Arthur M.; Dwyer, Donard S.

doi:10.1016/s0006-8993(01)03026-8

Cited by 98 publications

(71 citation statements)

References 35 publications

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“…The decreased glucose oxidation with unchanged glucose utilisation indicates impairment of the tricarboxylic acid (TCA) cycle in the mitochondria, although we did not study how clozapine inhibits enzymes of the TCA cycle. It has been reported that clozapine inhibited complex I in the respiratory chain of rat brain mitochondria at 100 μmol/l [32], and that, at pharmacological concentrations, it suppressed glucose transport in rat pheochromocytoma cells with a half-maximal inhibitory concentration (IC 50 ) of 20 μmol/l [33]; it also inhibited activation of voltage-dependent Ca 2+ channels with IC 50 of 55 μmol/l in bovine adrenal chromaffin cells [34].…”

Section: Discussionmentioning

confidence: 99%

The atypical antipsychotic clozapine impairs insulin secretion by inhibiting glucose metabolism and distal steps in rat pancreatic islets

et al. 2006

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Aims/hypothesis Diabetogenic effects of some atypical antipsychotic drugs have been reported, although the mechanisms are not fully understood. We investigated the long-term effects of culturing isolated rat pancreatic islets with atypical antipsychotic clozapine. Methods Glucose-and non-glucose-stimulated insulin secretion, glucose metabolism and intracellular Ca 2+ concentration ([Ca 2+ ] i ) were measured in islets cultured with or without clozapine. Results Although acute incubation or 3-day culture with clozapine did not affect glucose-stimulated insulin secretion, clozapine suppressed glucose-stimulated insulin secretion by 53.2% at 1.0 μmol/l (therapeutic concentration) after 7 days of culture. Islet glucose oxidation and [Ca 2+ ] i elevation by high glucose were not affected after 3 days of culture, but clozapine significantly inhibited islet glucose oxidation, ATP production, and [Ca 2+ ] i elevation by high glucose after 7 days of culture. Moreover, 7 days of culture with clozapine inhibited insulin secretion stimulated by: (1) membrane depolarisation induced by high K + ; (2) protein kinase C activation; and (3) mastoparan at 16.7 mmol/l glucose under stringent Ca 2+ -free conditions. Elevation of [Ca 2+ ] i by high K + -induced membrane depolarisation was similar in control and clozapine-treated islets. Clozapine, a muscarinic blocker, acutely inhibited carbachol-induced insulin secretion, as did atropine, whereas after 7 days of culture atropine did not have the inhibitory effect shown by clozapine after 7 days. The impairment of glucose-stimulated insulin secretion recovered 3 days after the removal of clozapine treatment. Conclusions/interpretationThe present study demonstrated that the atypical antipsychotic drug clozapine directly impaired insulin secretion via multiple sites including glucose metabolism and the distal step in insulin exocytosis in a long-term culture condition. These mechanisms may be involved in the form of diabetes mellitus associated with atypical antipsychotic drugs.

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Section: Discussionmentioning

confidence: 99%

The atypical antipsychotic clozapine impairs insulin secretion by inhibiting glucose metabolism and distal steps in rat pancreatic islets

et al. 2006

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“…In animal models, researchers have been able to elucidate a mechanism by which the antipsychotic drugs markedly decreased glucose transport into target cells. 7 This animal study suggests that the antipsychotic drugs might block glucose accumulation directly at the level of the glucose transporter (GLUT) protein in both peripheral and brain tissue, leading to hyperglycemia. Another possibility is a derangement of pancreas function, more specifically beta cell function.…”

Section: Discussionmentioning

confidence: 99%

“…Another possibility is a derangement of pancreas function, more specifically beta cell function. 7,9 Pancreatic function might become depressed in the presence of the newer atypical antipsychotics. 7 Compared with phenothiazine medications, the atypical antipsychotic drugs interact with greater affinities at the 5HT receptors (5HT 2A and 5HT 2C ) in the pancreatic beta cells, which might in turn decrease pancreatic beta cell response to elevations in blood glucose.…”

Section: Discussionmentioning

confidence: 99%

“…4 -6 Other studies suggest that these agents affect glucose transport metabolism peripherally in patients, possibly increasing the potential for hyperinsulinemia and peripheral insulin resistance. 7,8 Further hypotheses point to the activity of atypical antipsychotic drugs at the serotonin receptors of the beta cells in the pancreas, more specifically 5HT 1A and 5HT 2 receptors. This activity might lead to derangement of beta cell function, with resulting increases in glucose levels in patients.…”

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Type 2 Diabetes Mellitus Induced by an Atypical Antipsychotic Medication

Sneed¹,

Gonzalez²

2003

The Journal of the American Board of Family Medicine

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“…tem. 25 Clozapine was noted to inhibit glucose uptake into the rat skeletal muscle cell line L6 in a dose dependent manner. However, the authors of this particular study did not investigate the mechanism of this action by quantifying GLUT4 expression or translocation.…”

Section: Mechanism Of Association Of Atypical Antipsychotic Drugs Witmentioning

confidence: 98%

Atypical antipsychotic drugs and diabetes

Livingstone¹,

Rampes

2003

Pract Diab Int

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Atypical antipsychotic drugsSchizophrenia is a syndrome characterised by a broad range of cognitive, emotional and behavioural problems, the prevalence of which is estimated at 0.2-1.0% in the general population. Its symptoms are classified into positive (hallucinations, delusions, formal thought disorder and bizarre behaviour) and negative (flattening of mood, emotional apathy, social withdrawal, lack of motivation and loss of pleasure). Schizophrenia has been treated largely using conventional antipsychotic drugs. However, over the last 10 years, the atypical, also known as novel or secondgeneration, antipsychotics have increasingly been used. The British National Formulary currently lists amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole and zotepine as atypical antipsychotic drugs. From a pharmacological perspective, they are distinguished by their dual action of serotonin 2A receptor and dopamine D2 receptor antagonism as compared to the conventional antipsychotic drugs, which have an antagonistic action mainly on the D2 receptor.The atypical antipsychotics are indicated both for the treatment of schizophrenia and related disorders in which psychosis is a defining feature. However, they can also be used to quieten patients whatever the underlying psychopathology, e.g. brain damage, severe anxiety, toxic delirium or agitated depression. From a clinical perspective, atypical antipsychotic drugs have a lower incidence of extrapyramidal adverse effects than the conventional antipsychotic drugs and are more efficacious in the treatment of negative symptoms of schizophrenia. Recently, the National Institute Clinical Excellence has published guidance on the use of atypical antipsychotic drugs for the treatment of schizophrenia. 1 It is recommended that they are used as firstline treatments for individuals with newly diagnosed schizophrenia and should also be used for those patients whose management has been unsatisfactory on conventional drugs or who have experienced unacceptable adverse effects. The following two prescribing restrictions should be noted. Sertindole is available on a named patient supply only due to its cardiac adverse effects and clozapine is restricted to individuals who are intolerant or unresponsive to conventional antipsychotic drugs. The association between atypical antipsychotic drugs and diabetesIt has long been recognised that hyperglycaemia and type 2 diabetes mellitus are more common in patients with schizophrenia than in the general population. In one recent study the prevalence of diabetes in a sample population of patients with schizophrenia was 15.8% as opposed to 3.2% in the general population. 2 Type 2 diabetes is itself becoming a commoner condition in the population as a whole.Since the introduction of the atypical antipsychotic drugs it has become apparent that their use is associated with metabolic adverse effects (Table 1) diabetes. 4 In another study, patients who already had diabetes required to be switched from an oral hypoglycaemic agent to insulin o...

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Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine

Cited by 98 publications

References 35 publications

The atypical antipsychotic clozapine impairs insulin secretion by inhibiting glucose metabolism and distal steps in rat pancreatic islets

The atypical antipsychotic clozapine impairs insulin secretion by inhibiting glucose metabolism and distal steps in rat pancreatic islets

Type 2 Diabetes Mellitus Induced by an Atypical Antipsychotic Medication

Atypical antipsychotic drugs and diabetes

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