Clozapine and quetiapine acutely reduce glucagon-like peptide-1 production and increase glucagon release in obese rats: Implications for glucose metabolism and food choice behaviour

Smith, Greg; Vickers, Mark H.; Cognard, Emmanuelle; Shepherd, Peter R.

doi:10.1016/j.schres.2009.07.011

Cited by 47 publications

(51 citation statements)

References 41 publications

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“…These reports differ from one another with respect to AP treatment dose and duration, as well methods of assessing glucose metabolism (e.g., stand-alone measures of fasting insulin and glucose, GTTs). In general, incretins (Lykkegaard et al 2008, Smith et al 2009) and Met (Adeneye et al 2011, Boyda et al 2012, 2014 appear to improve metabolic indices, whereas the data have been more variable for sulfonylureas and thiazolidinediones (Arulmozhi et al 2006, Boyda et al 2012, 2014.…”

Section: Discussionmentioning

confidence: 99%

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

Remington

Teo

Wilson

et al. 2015

Journal of Endocrinology

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Antipsychotics (APs) are linked to diabetes, even without weight gain. Whether anti-diabetic drugs are efficacious in reversing the direct effects of APs on glucose pathways is largely undetermined. We tested two metformin (Met) doses to prevent impairments seen following a dose of olanzapine (Ola) (3 mg/kg); glucokinetics were measured using the hyperinsulinemic-euglycemic clamp (HIEC). Met (150 mg/kg; nZ13, or 400 mg/kg; nZ11) or vehicle (Veh) (nZ11) was administered through gavage preceding an overnight fast, followed by a second dose prior to the HIEC. Eleven additional animals were gavaged with Veh and received a Veh injection during the HIEC (Veh/Veh); all others received Ola. Basal glucose was similar across treatment groups. The Met 400 group had significantly greater glucose appearance (R a ) in the basal period (i.e., before Ola, or hyperinsulinemia) vs other groups. During hyperinsulinemia, glucose infusion rate (GINF) to maintain euglycemia (reflective of whole-body insulin sensitivity) was higher in Veh/Veh vs other groups. Met 150/Ola animals demonstrated increased GINF relative to Veh/Ola during early time points of the HIEC. Glucose utilization during hyperinsulinemia, relative to basal conditions, was significantly higher in Veh/Veh vs other groups. The change in hepatic glucose production (HGP) from basal to hyperinsulinemia demonstrated significantly greater decreases in Veh/Veh and Met 150/Ola groups vs Veh/Ola. Given the increase in basal R a with Met 400, we measured serum lactate (substrate for HGP), finding increased levels in Met 400 vs Veh and Met 150. In conclusion, Met attenuates hepatic insulin resistance observed with acute Ola administration, but fails to improve peripheral insulin resistance. Use of supra-therapeutic doses of Met may mask metabolic benefits by increasing lactate.

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Section: Discussionmentioning

confidence: 99%

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

Remington

Teo

Wilson

et al. 2015

Journal of Endocrinology

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“…[55][56][57] Among other beneficial antidiabetic effects, GLP-1 suppresses the hyperglycemic action of glucagon, causing decreased HGO and lower circulating glucose levels. Recent studies by Smith and colleagues 41,58 demonstrated that olanzapine-, clozapine-and quetiapine-induced glucose dysregulation was associated with decreased GLP-1 production and enhanced glucagon secretion, leading to stimulated HGO. These studies, together with our present findings, suggest common targets for both metformin and antipsychotic drug action.…”

Section: Discussionmentioning

confidence: 99%

“…In a separate study, treatment with the GLP-1 receptor agonist exendin-4 decreased glucose levels in the GTT after treatment with an acute 10 mg/kg dose of clozapine. 58 Arulmozhi and colleagues 62 assessed the effects of 3 different PPARγ modulators (glimepiride, rosiglitazone and fenofibrate) on ziprasidone-, clozapine-and chlorpromazine-induced hyperglycemia and hyperinsulinemia in mice. Rosiglitazone and glimepiride reduced hyperglycemia in chlorpromazine-treated animals, whereas all 3 antidiabetics reduced clozapine-induced hyperglycemia, with the greatest effect attributed to rosiglitazone.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of 3 classes of antidiabetic drugs on olanzapine-induced glucose dysregulation and insulin resistance in female rats

Boyda

Procyshyn²,

Tse

et al. 2012

J Psychiatry Neurosci

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“…Although these experiments suggested olanzapine had no deleterious effect on glycemic control independent of weight gain, more sensitive measures of glycemic control, e.g., glucose or insulin challenge tests, were not performed. Several other SGAs, including risperidone, quetiepine, and clozapine, did not induce weight gain in male rats (Baptista et al 1998(Baptista et al , 2002aSmith et al 2008aSmith et al , 2009. Glucose tolerance tests revealed that repeated administration of sulpiride, quetiapine, or clozapine, but not risperidone, enhanced plasma glucose and insulin (Baptista et al 1998(Baptista et al , 2002aSmith et al 2008aSmith et al , 2009).…”

Section: Insights From Animal Models On the Effects Of Antipsychotic mentioning

confidence: 99%

“…Several other SGAs, including risperidone, quetiepine, and clozapine, did not induce weight gain in male rats (Baptista et al 1998(Baptista et al , 2002aSmith et al 2008aSmith et al , 2009. Glucose tolerance tests revealed that repeated administration of sulpiride, quetiapine, or clozapine, but not risperidone, enhanced plasma glucose and insulin (Baptista et al 1998(Baptista et al , 2002aSmith et al 2008aSmith et al , 2009). These results demonstrate that antipsychotic drugs impair glucose tolerance and decrease insulin action, consistent with clamp experiments (Chintoh et al 2008).…”

Section: Insights From Animal Models On the Effects Of Antipsychotic mentioning

confidence: 99%

Metabolic Consequences of Antipsychotic Therapy: Preclinical and Clinical Perspectives on Diabetes, Diabetic Ketoacidosis, and Obesity

Heal

Gosden

Jackson

et al. 2012

Current Antipsychotics

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Antipsychotic drugs, particularly second-generation antipsychotics (SGAs), have reduced the burden to society of schizophrenia, but many still produce excessive weight gain. A significant number of SGAs also act directly to impair glycemic control causing insulin resistance, impaired glucose tolerance and type 2 diabetes, and also rarely diabetic ketoacidosis (DKA). Schizophrenia itself is almost certainly causal in many endocrine and metabolic disturbances, making this population especially vulnerable to the adverse metabolic consequences of treatment with SGAs. Hence, there is an urgent need for a new generation of antipsychotic drugs that provide efficacy equal to the best of the SGAs without their liability to cause weight gain or type 2 diabetes. In the absence of such safe and effective alternatives to the SGAs, there is a substantial clinical need for the introduction of new antipsychotics without adverse metabolic effects and new antiobesity drugs to combat these metabolic side effects. We discuss the adverse metabolic consequences of schizophrenia, its exacerbation by a lack of social care, and the additional burden placed on patients by their medication. A critical evaluation of the animal models of antipsychotic-induced metabolic disturbances is provided with observations on their strengths and limitations. Finally, we discuss novel antipsychotic drugs with a lower propensity to increase metabolic risk and adjunctive medications to mitigate the adverse metabolic actions of the current generation of antipsychotics.

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Clozapine and quetiapine acutely reduce glucagon-like peptide-1 production and increase glucagon release in obese rats: Implications for glucose metabolism and food choice behaviour

Cited by 47 publications

References 41 publications

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

Differential effects of 3 classes of antidiabetic drugs on olanzapine-induced glucose dysregulation and insulin resistance in female rats

Metabolic Consequences of Antipsychotic Therapy: Preclinical and Clinical Perspectives on Diabetes, Diabetic Ketoacidosis, and Obesity

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