Antipsychotics impair regulation of glucose metabolism by central glucose

Castellani, L; Pereira, Sandra; Kowalchuk, Chantel; Asgariroozbehani, Roshanak; Singh, Raghunath; Wu, Sally P. W.; Hamel, Laurie; Alganem, Khaled; Ryan, William G.; Zhang, Xiaolu; Au, Emily; Chintoh, Araba; Remington, Gary; Agarwal, Sri Mahavir; Giacca, Adria; McCullumsmith, Robert E.; Hahn, Margaret

doi:10.1038/s41380-022-01798-y

Cited by 11 publications

(14 citation statements)

References 76 publications

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“…The cannula was secured in place with stainless steel screws (McCray Optical Supply Inc., Scarborough, ON, Canada) and dental cement, and kept patent with a steel stylet. Following approximately 1 week of recovery, rats underwent blood vessel cannulation for future blood sampling as earlier 20 . Rats were monitored closely after surgeries with behavior and body weight recorded daily to ensure successful recovery.…”

Section: Methodsmentioning

confidence: 99%

“…Male Sprague-Dawley rats underwent intracerebroventricular (i.c.v. ; 3 rd ventricle) surgeries as described previously 20,151 . A cannula was stereotaxically placed into the third cerebral ventricle under isoflurane anesthesia (coordinates from bregma: anteroposterior, -2.5 mm; mediolateral, 0.0 mm; dorsoventral, -8.0 mm).…”

Section: Methodsmentioning

confidence: 99%

“…Until now, most studies examining dopaminergic modulation of metabolism have primarily focused on DA D2-like receptors (D2, D3 and D4 receptors) in brain regions associated with metabolic regulation including striatum and hypothalamus 3,10,[14][15][16] . For example, hypothalamic dopamine D2 (D2R) and D3 (D3R) receptors mediate appetite and feeding behaviors, while blockade of these receptors with antipsychotic drugs (APDs) impairs central glucose sensing [17][18][19][20][21][22] . Changes in the expression of striatal D2-like receptors are also associated with overeating and obesity 23,24 .…”

Section: Introductionmentioning

confidence: 99%

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Development of novel tools for dissection of central versus peripheral dopamine D₂-like receptor signaling in dysglycemia

Bonifazi,

Ellenberger,

Farino

et al. 2024

Preprint

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Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D2-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D2-like receptors including D2(D2R) and D3(D3R) receptors remain poorly understood. To address this, we developed new pharmacological tools, D2-like receptor agonists with diminished and delayed blood-brain barrier capability, to selectively manipulate D2R/D3R signaling in the periphery. We designated bromocriptine methiodide (BrMeI), a quaternary methiodide analogue of D2/3R agonist and diabetes drug bromocriptine, as our lead compound based on preservation of D2R/D3R binding and functional efficacy. We then used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral D2R/D3R signaling in treating dysglycemia. Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic micein vivo. In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI. Our findings demonstrate that the coordinated actions of both CNS and peripheral D2-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development of novel tools for dissection of central versus peripheral dopamine D₂-like receptor signaling in dysglycemia

Bonifazi,

Ellenberger,

Farino

et al. 2024

Preprint

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“…Although triple treatment did not protect against olanzapine induced increases in blood glucose a caveat to this initial experiment was that it was completed in the absence of an additional homeostatic challenge. There is evidence that a nutrient stimulus may be necessary to observe acute AP-induced glucose dysregulation (Castellani et al, 2022), (Albaugh et al, 2011b). This is likely an important consideration given the impact of carbohydrate consumption on GLP1 secretion and the fact that individuals prescribed olanzapine could be consuming carbohydrate after taking their medication.…”

Section: Triple Treatment During Ogtt Improved Acute Olanzapine-induc...mentioning

confidence: 99%

“…Our group has provided evidence that increases in glucagon mediate acute olanzapine-induced hyperglycemia. In support of this, our group and others have shown that 1) acute treatment with olanzapine increases circulating glucagon (Townsend et al, 2018), (Shamshoum et al, 2019), (Shamshoum et al, 2022), (Shamshoum et al, 2021a), 2) the hyperglycemic effects of olanzapine are absent in glucagon receptor knockout mice (Castellani et al, 2017), 3) protection against olanzapine-induced hyperglycemia is often paralleled by reductions in glucagon and/or the glucagon:insulin ratio (Medak et al, 2019), (Shamshoum et al, 2019), and 4) suppressing pancreatic secretions with somatostatin blocked olanzapine-induced hyperglycemia (Castellani et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Enhancing endogenous levels of GLP1 dampens acute olanzapine induced perturbations in lipid and glucose metabolism

Medak

Weber²,

Shamshoum³

et al. 2023

Front. Pharmacol.

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Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and several on- and off-label conditions. While effective in reducing psychoses, acute olanzapine treatment causes rapid hyperglycemia, insulin resistance, and dyslipidemia and these perturbations are linked to an increased risk of developing cardiometabolic disease. Pharmacological agonists of the glucagon-like peptide-1 (GLP1) receptor have been shown to offset weight-gain associated with chronic SGA administration and mitigate the acute metabolic side effects of SGAs. The purpose of this study was to determine if increasing endogenous GLP1 is sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis. Male C57BL/6J mice were treated with olanzapine, in the absence or presence of an oral glucose tolerance test (OGTT), and a combination of compounds to increase endogenous GLP1. These include the non-nutritive sweetener allulose which acts to induce GLP1 secretion but not other incretins, the DPPiv inhibitor sitagliptin which prevents degradation of active GLP1, and an SSTR5 antagonist which relieves inhibition on GLP1 secretion. We hypothesized that this cocktail of agents would increase circulating GLP1 to supraphysiological concentrations and would protect against olanzapine-induced perturbations in glucose and lipid homeostasis. We found that ‘triple treatment’ increased both active and total GLP1 and protected against olanzapine-induced perturbations in lipid and glucose metabolism under glucose stimulated conditions and this was paralleled by an attenuation in the olanzapine induced increase in the glucagon:insulin ratio. Our findings provide evidence that pharmacological approaches to increase endogenous GLP1 could be a useful adjunct approach to reduce acute olanzapine-induced perturbations in lipid and glucose metabolism.

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Increased Metabolic Potential, Efficacy, and Safety of Emerging Treatments in Schizophrenia

Meyer

Correll

2023

CNS Drugs

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Patients with schizophrenia experience a broad range of detrimental health outcomes resulting from illness severity, heterogeneity of disease, lifestyle behaviors, and adverse effects of antipsychotics. Because of these various factors, patients with schizophrenia have a much higher risk of cardiometabolic abnormalities than people without psychiatric illness. Although exposure to many antipsychotics increases cardiometabolic risk factors, mortality is higher in patients who are not treated versus those who are treated with antipsychotics. This indicates both direct and indirect benefits of adequately treated illness, as well as the need for beneficial medications that result in fewer cardiometabolic risk factors and comorbidities. The aim of the current narrative review was to outline the association between cardiometabolic dysfunction and schizophrenia, as well as discuss the confluence of factors that increase cardiometabolic risk in this patient population. An increased understanding of the pathophysiology of schizophrenia has guided discovery of novel treatments that do not directly target dopamine and that not only do not add, but may potentially minimize relevant cardiometabolic burden for these patients. Key discoveries that have advanced the understanding of the neural circuitry and pathophysiology of schizophrenia now provide possible pathways toward the development of new and effective treatments that may mitigate the risk of metabolic dysfunction in these patients. Novel targets and preclinical and clinical data on emerging treatments, such as glycine transport inhibitors, nicotinic and muscarinic receptor agonists, and trace amine-associated receptor-1 agonists, offer promise toward relevant therapeutic advancements. Numerous areas of investigation currently exist with the potential to considerably progress our knowledge and treatment of schizophrenia.

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Antipsychotics impair regulation of glucose metabolism by central glucose

Cited by 11 publications

References 76 publications

Development of novel tools for dissection of central versus peripheral dopamine D₂-like receptor signaling in dysglycemia

Development of novel tools for dissection of central versus peripheral dopamine D₂-like receptor signaling in dysglycemia

Enhancing endogenous levels of GLP1 dampens acute olanzapine induced perturbations in lipid and glucose metabolism

Increased Metabolic Potential, Efficacy, and Safety of Emerging Treatments in Schizophrenia

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Antipsychotics impair regulation of glucose metabolism by central glucose

Cited by 11 publications

References 76 publications

Development of novel tools for dissection of central versus peripheral dopamine D2-like receptor signaling in dysglycemia

Development of novel tools for dissection of central versus peripheral dopamine D2-like receptor signaling in dysglycemia

Enhancing endogenous levels of GLP1 dampens acute olanzapine induced perturbations in lipid and glucose metabolism

Increased Metabolic Potential, Efficacy, and Safety of Emerging Treatments in Schizophrenia

Contact Info

Product

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Development of novel tools for dissection of central versus peripheral dopamine D₂-like receptor signaling in dysglycemia

Development of novel tools for dissection of central versus peripheral dopamine D₂-like receptor signaling in dysglycemia