scholarly journals Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences

2021 ◽  
Vol 14 (3) ◽  
pp. 238
Author(s):  
Marco Carli ◽  
Shivakumar Kolachalam ◽  
Biancamaria Longoni ◽  
Anna Pintaudi ◽  
Marco Baldini ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Weight Gain ◽  
Atypical Antipsychotics ◽  
Molecular Mechanisms ◽  
Psychotic Disorders ◽  
Partial Agonist ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Therapeutic Drug ◽  
Metabolic Disturbances

Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophrenia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their actions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5′AMP-activated protein kinase (AMPK) activity, thus producing a supraphysiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olanzapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasidone and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP’s higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well.

scholarly journals The Hormetic Effect of Metformin: “Less Is More”?

2021 ◽  
Vol 22 (12) ◽  
pp. 6297
Author(s):  
Isabella Panfoli ◽  
Alessandra Puddu ◽  
Nadia Bertola ◽  
Silvia Ravera ◽  
Davide Maggi
Keyword(s):  
Complex I ◽  
Molecular Mechanisms ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Target Tissue ◽  
Atp Production ◽  
Less Is More ◽  
First Line Therapy ◽  
Hormetic Effect ◽  
Intracellular Content

Metformin (MTF) is the first-line therapy for type 2 diabetes (T2DM). The euglycemic effect of MTF is due to the inhibition of hepatic glucose production. Literature reports that the principal molecular mechanism of MTF is the activation of 5′-AMP-activated protein kinase (AMPK) due to the decrement of ATP intracellular content consequent to the inhibition of Complex I, although this effect is obtained only at millimolar concentrations. Conversely, micromolar MTF seems to activate the mitochondrial electron transport chain, increasing ATP production and limiting oxidative stress. This evidence sustains the idea that MTF exerts a hormetic effect based on its concentration in the target tissue. Therefore, in this review we describe the effects of MTF on T2DM on the principal target organs, such as liver, gut, adipose tissue, endothelium, heart, and skeletal muscle. In particular, data indicate that all organs, except the gut, accumulate MTF in the micromolar range when administered in therapeutic doses, unmasking molecular mechanisms that do not depend on Complex I inhibition.

scholarly journals Statins Stimulate Hepatic Glucose Production via the miR-183/96/182 Cluster

2019 ◽  
Author(s):  
Tyler J. Marquart ◽  
Ryan M. Allen ◽  
Mary R. Chen ◽  
Gerald W. Dorn ◽  
Scot J. Matkovich ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Association Studies ◽  
Hepatic Glucose Production ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Hepatic Clearance ◽  
Glucose Production ◽  
Genome Wide Association Studies ◽  
Medical Advance

Statins are the most common pharmacologic intervention in hypercholesterolemic patients, and their use is recognized as a key medical advance leading to a 50% decrease in deaths from heart attack or stroke over the past 30 years. The atheroprotective outcomes of statins are largely attributable to the accelerated hepatic clearance of low-density lipoprotein (LDL)-cholesterol from circulation, following the induction of the LDL receptor. However, multiple studies suggest that these drugs exert additional LDL–independent effects. The molecular mechanisms behind these so-called pleiotropic effects of statins, either beneficial or undesired, remain largely unknown. Here we determined the coding transcriptome, miRNome, and RISCome of livers from mice dosed with saline or atorvastatin to define a novel in vivo epitranscriptional regulatory pathway that links statins to hepatic gluconeogenesis, via the SREBP2–miR-183/96/182–TCF7L2 axis. Notably, multiple genome-wide association studies identified TCF7L2 (transcription factor 7 like 2) as a candidate gene for type 2 diabetes, independent of ethnicity. Conclusion: our data reveal an unexpected link between cholesterol and glucose metabolism, provides a mechanistic explanation to the elevated risk of diabetes recently observed in patients taking statins, and identifies the miR-183/96/182 cluster as an attractive pharmacological candidate to modulate non-canonical effects of statins.

scholarly journals Metabolic syndrome in the population of psychiatric patients in Novi Sad

2020 ◽  
Vol 45 (4) ◽  
pp. 145-152
Author(s):  
Dušan Kuljančić
Keyword(s):  
Metabolic Syndrome ◽  
Atypical Antipsychotics ◽  
Psychotic Disorders ◽  
Psychiatric Patients ◽  
Study Data ◽  
Hospitalized Patients ◽  
Male Dominance ◽  
Psychiatric Clinic ◽  
The Metabolic Syndrome ◽  
Novi Sad

OBJECTIVES: The aim of this study is to determine the prevalence of metabolic syndrome (MetS) in a sample of hospitalized patients and to relate it to socio-demographic characteristics, psychiatric diagnosis and psycho-pharmacotherapy. METHODS: The study was conceived as a retrospective cohort study. Data of interest for this research were collected from the medical history of hospitalized patients at the Clinic for Psychiatry KCV in the period from January 2018 to January 2020. RESULTS: Out of a total of 2409 patients hospitalized at the Psychiatric Clinic, 1327 patients had criteria for metabolic syndrome, with a high prevalence of 55.1% among this population. Although there are more respondents in the sample (55.7%), males with a diagnosis of MetS (58.1%) dominate. The data show that the prevalence of metabolic syndrome increases statistically significantly with the age of psychiatric patients. However, the prevalence of metabolic syndrome in the study population younger than 30 years is about 33%. Among patients with incomplete primary school, 67% have a diagnosis of metabolic syndrome, which is statistically significantly higher than other compulsory profiles (p <0.001). The study sample shows a statistically significantly higher prevalence of metabolic syndrome among patients treated for psychotic disorders, with as much as 67% prevalence. Therapy with atypical antipsychotics was most associated with metabolic syndrome in 67.5% of patients, followed by a combination of 2 or more antipsychotics with 60.7% (x²=26.99, p<0.0019). Abdominal obesity is the strongest predictor of the response that the subjects will suffer from the metabolic syndrome, the quotient of which is 1.34 by logistic regression. Another important predictor refers to triglyceridemia, whose probability quotient is 1.12. CONCLUSION: The prevalence of metabolic syndrome in psychiatric patients in Novi Sad is alarmingly high, in more than half of patients, especially those treated for psychotic and mood disorders and using atypical antipsychotics and combinations of antipsychotics. In a patient with metabolic syndrome there is male dominance, low educational profile and the prevalence increases statistically significantly with increasing age of psychiatric patients.

scholarly journals Glucocorticoid Receptor Signaling in Diabetes

2021 ◽  
Vol 22 (20) ◽  
pp. 11173
Author(s):  
Ioanna Kokkinopoulou ◽  
Andriana Diakoumi ◽  
Paraskevi Moutsatsou
Keyword(s):  
Glucocorticoid Receptor ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Glucose Production ◽  
Metabolic Disturbances ◽  
Peripheral Blood Mononuclear ◽  
Peripheral Tissues ◽  
Micro Rnas ◽  
A Cell ◽  
Context Specific

Stress and depression increase the risk of Type 2 Diabetes (T2D) development. Evidence demonstrates that the Glucocorticoid (GC) negative feedback is impaired (GC resistance) in T2D patients resulting in Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivity and hypercortisolism. High GCs, in turn, activate multiple aspects of glucose homeostasis in peripheral tissues leading to hyperglycemia. Elucidation of the underlying molecular mechanisms revealed that Glucocorticoid Receptor (GR) mediates the GC-induced dysregulation of glucose production, uptake and insulin signaling in GC-sensitive peripheral tissues, such as liver, skeletal muscle, adipose tissue, and pancreas. In contrast to increased GR peripheral sensitivity, an impaired GR signaling in Peripheral Blood Mononuclear Cells (PBMCs) of T2D patients, associated with hyperglycemia, hyperlipidemia, and increased inflammation, has been shown. Given that GR changes in immune cells parallel those in brain, the above data implicate that a reduced brain GR function may be the biological link among stress, HPA hyperactivity, hypercortisolism and hyperglycemia. GR polymorphisms have also been associated with metabolic disturbances in T2D while dysregulation of micro-RNAs—known to target GR mRNA—has been described. Collectively, GR has a crucial role in T2D, acting in a cell-type and context-specific manner, leading to either GC sensitivity or GC resistance. Selective modulation of GR signaling in T2D therapy warrants further investigation.

scholarly journals Metabolic flexibility

2004 ◽  
Vol 63 (2) ◽  
pp. 363-368 ◽  
Author(s):  
Len Storlien ◽  
Nick D. Oakes ◽  
David E. Kelley
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Insulin Secretion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Metabolic Flexibility ◽  
Disease States ◽  
The Metabolic Syndrome ◽  
Cephalic Phase ◽  
Metabolic Inflexibility

Human physiology needs to be well adapted to cope with major discontinuities in both the supply of and demand for energy. This adaptability requires ‘a clear capacity to utilize lipid and carbohydrate fuels and to transition between them’ ( Kelley et al. 2002b). Such capacities characterize the healthy state and can be termed ‘metabolic flexibility’. However, increasing evidence points to metabolic inflexibility as a key dysfunction of the cluster of disease states encompassed by the term ‘metabolic syndrome’. In obese and diabetic individuals this inflexibility is manifest in a range of metabolic pathways and tissues including: (1) failure of cephalic-phase insulin secretion (impaired early-phase prandial insulin secretion concomitant with failure to suppress hepatic glucose production and NEFA efflux from adipose tissue); (2) failure of skeletal muscle to appropriately move between use of lipid in the fasting state and use of carbohydrate in the insulin-stimulated prandial state; (3) impaired transition from fatty acid efflux to storage in response to a meal. Finally, it is increasingly clear that reduced capacity for fuel usage in, for example, skeletal muscle, as indicated by reduced mitochondrial size and density, is characteristic of the metabolic syndrome state and a fundamental component of metabolic inflexibility. Key questions that remain are how metabolic flexibility is lost in obese and diabetic individuals and by what means it may be regained.

scholarly journals Mechanisms of the components of the metabolic syndrome that predispose to diabetes and atherosclerotic CVD

2007 ◽  
Vol 66 (1) ◽  
pp. 82-95 ◽  
Author(s):  
Robert H. Eckel
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Fatty Acid ◽  
Inflammatory Cytokines ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
The Metabolic Syndrome ◽  
Pro Inflammatory Cytokines

The metabolic syndrome represents a summation of obesity-driven risk factors for atherosclerotic CVD and type 2 diabetes. Definitions of the syndrome vary but in general agree closely in identifying subjects. The relationships between the metabolic syndrome and atherosclerotic CVD and diabetes also vary, with relative risks of approximately 1·5–3·0 and approximately 3·0–5·0 respectively. Insulin resistance appears to explain much of the pathophysiology of the syndrome. Both increased fatty acid flux and an excess of circulating pro-inflammatory cytokines are likely mediators. With increased waist circumference, increases in fatty acid delivery to the liver result in higher rates of hepatic glucose production and increases in the secretion of apoB-containing lipoproteins. Concomitant changes in HDL ensue, including a replacement of the cholesterol content with TAG, an accelerated clearance from the plasma and thus a reduced number of HDL particles. Typically also present are increases in small dense LDL. Hypertension in part relates to the insulin resistance, but may involve other mechanisms. Impaired fasting glucose often relates to defects in insulin secretion in addition to insulin resistance, and probably more than any other component of the syndrome predicts the increased incidence of type 2 diabetes. Although not included in the diagnostic criteria, increases in pro-inflammatory cytokines and pro-thrombotic factors, in addition to decreases in plasma adiponectin, may also contribute to the increased incidence of atherosclerotic CVD and diabetes. In general, the greater the number of metabolic syndrome components, the greater the risk for these outcomes. The cytokines and pro-thrombotic factors also appear to contribute.

The impact of weight gain associated with atypical antipsychotic use in schizophrenia

2004 ◽  
Vol 16 (3) ◽  
pp. 113-123 ◽  
Author(s):  
Pierre Chue ◽  
Raphael Cheung
Keyword(s):  
Weight Gain ◽  
Weight Management ◽  
Atypical Antipsychotic ◽  
Atypical Antipsychotics ◽  
Current Data ◽  
Antipsychotic Treatment ◽  
Metabolic Disturbances ◽  
Obesity And Diabetes ◽  
The Impact ◽  
Selection Of

Background:Atypical antipsychotics offer clear advantages in the management of schizophrenia, compared with conventional neuroleptics, but weight gain is a significant adverse effect with some of these agents.Objective:To review the literature on weight gain associated with atypical antipsychotic treatment in schizophrenia.Methods:Relevant sources were identified from Medline searches to February 2003 using combinations of keywords including ‘schizophrenia’, ‘antipsychotics’, ‘weight gain’, ‘adverse events’, ‘obesity’, and ‘diabetes’.Results:Most atypical antipsychotics induce some weight gain, but the magnitude of the effect varies markedly. The greatest increases are seen with clozapine and olanzapine: risperidone has a slight effect, comparable with that of conventional neuroleptics, while ziprasidone and aripiprazole appear from current data to have little effect. In addition, atypical antipsychotics have been associated with metabolic disturbances, particularly glucose dysregulation and dyslipidemia. These effects tend to be more marked with olanzapine and clozapine than with other agents. Weight gain associated with atypical antipsychotics imposes substantial morbidity, in addition to that associated with schizophrenia itself. Furthermore, weight gain can significantly impair patients' quality of life, and leads to non-adherence with treatment. Effective weight management should include the selection of an appropriate atypical antipsychotic and for effective weight management, as well both diet and exercise, formal weight management programs tailored to the needs of schizophrenic patients may be useful, and some patients may benefit from weight-reducing drugs.Conclusions:Weight gain associated with atypical antipsychotics is a common problem that requires effective management. The selection of an agent with a low risk of weight gain, such as risperidone or ziprasidone, is central to such management.

scholarly journals Metformin Targets Foxo1 to Control Glucose Homeostasis

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 873
Author(s):  
Xiaoqin Guo ◽  
Xiaopeng Li ◽  
Wanbao Yang ◽  
Wang Liao ◽  
James Zheng Shen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Blood Glucose ◽  
Signaling Pathway ◽  
Glucose Homeostasis ◽  
Molecular Mechanisms ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Suppressive Effect ◽  
Dependent Manner ◽  
Glucose Lowering Effect

Metformin is the first-line pharmacotherapy for type 2 diabetes mellitus (T2D). Metformin exerts its glucose-lowering effect primarily through decreasing hepatic glucose production (HGP). However, the precise molecular mechanisms of metformin remain unclear due to supra-pharmacological concentration of metformin used in the study. Here, we investigated the role of Foxo1 in metformin action in control of glucose homeostasis and its mechanism via the transcription factor Foxo1 in mice, as well as the clinical relevance with co-treatment of aspirin. We showed that metformin inhibits HGP and blood glucose in a Foxo1-dependent manner. Furthermore, we identified that metformin suppresses glucagon-induced HGP through inhibiting the PKA→Foxo1 signaling pathway. In both cells and mice, Foxo1-S273D or A mutation abolished the suppressive effect of metformin on glucagon or fasting-induced HGP. We further showed that metformin attenuates PKA activity, decreases Foxo1-S273 phosphorylation, and improves glucose homeostasis in diet-induced obese mice. We also provided evidence that salicylate suppresses HGP and blood glucose through the PKA→Foxo1 signaling pathway, but it has no further additive improvement with metformin in control of glucose homeostasis. Our study demonstrates that metformin inhibits HGP through PKA-regulated transcription factor Foxo1 and its S273 phosphorylation.

scholarly journals Atypical Antipsychotic Induced Weight Gain in Schizophrenic Patients

2021 ◽  
Vol 10 (1) ◽  
pp. 57
Author(s):  
Tetie Herlina ◽  
Dyah A. Perwitasari ◽  
Haafizah Dania ◽  
Santi Yuliani ◽  
Melisa I. Barliana
Keyword(s):  
Metabolic Syndrome ◽  
Body Weight ◽  
Weight Gain ◽  
Side Effects ◽  
Atypical Antipsychotic ◽  
Atypical Antipsychotics ◽  
Consecutive Sampling ◽  
Retrospective Design ◽  
Schizophrenic Patients ◽  
The Mean

Atypical antipsychotics are widely prescribed and have the potential to cause weight gain, which may result in the development of metabolic syndrome. Also, it is important to monitor the use of atypical antipsychotic for metabolic disturbance. The purpose of this study is to determine the side effects of atypical antipsychotics in increasing body weight in schizophrenia patients after 4 weeks of use. Furthermore, a retrospective design was conducted and data were collected based on consecutive sampling in 80 adult psychiatric inpatients (20 women and 60 men) with initial diagnoses of schizophrenia and with the same daily nutrition. The patients were hospitalized from January to March 2019, within the term (over 4 weeks) of initiation atypical antipsychotic. The patient body weight was collected before and 4 weeks after the treatment of atypical antipsychotic. The results showed that patients (20 women and 60 men) receiving atypical antipsychotic had a mean age of 35.6 years and a percentage of 70% women and 56% men had a weight gain of 1–5 kg over 4 weeks. The mean weight observed among our subjects increased from 57.55±10.743 kg to 59.83±12.205 kg after initiating treatment (p=0.001). However, the dual combination of atypical antipsychotics risperidone and clozapine are the most widely atypical antipsychotic used with a percentage equal to 91.25%, 3.75% clozapine, and 5% risperidone. Furthermore, it can be concluded that atypical antipsychotics use for at least 4 weeks can cause weight gain in schizophrenic patients. Pharmacist and doctors are recommended to monitor the metabolic side effects due to the atypical antipsychotic use. Keywords: Atypical antipsycotic, schizophrenia, weight gain  Antipsikotik Atipikal Menginduksi Peningkatan Berat Badan pada Pasien Skizofrenia AbstrakAntipsikotik atipikal banyak diresepkan dan berpotensi menyebabkan kenaikan berat badan yang dapat menyebabkan sindrom metabolik. Ada kebutuhan klinis yang mendesak untuk memantau penggunaan antipsikotik atipikal terhadap gangguan metabolisme. Penelitian ini bertujuan untuk mengetahui efek samping antipsikotik atipikal dalam meningkatkan berat badan pada pasien skizofrenia setelah pemakaian 4 minggu. Melalui desain retrospektif, data dikumpulkan dengan consecutive sampling pada 80 pasien rawat inap psikiatri dewasa (20 wanita dan 60 pria) dengan diagnosis awal skizofrenia dan dengan pengaturan nutrisi harian yang sama. Pasien dirawat di rumah sakit sejak Januari 2019 sampai dengan Maret 2019, dalam jangka menengah (lebih dari 4 minggu) pemberian antipsikotik atipikal. Data berat badan pasien dicatat sebelum dan 4 minggu sesudah pemakaian antipsikotik atipikal. Pasien (20 wanita dan 60 pria) yang menerima antipsikotik atipikal memiliki usia rata-rata 35,6 tahun, semua pasien dengan persentase 70% wanita dan 56% pria memiliki kenaikan berat badan 1–5 kg selama periode 4 minggu. Berat rata-rata yang diamati di antara subyek meningkat dari 57,55±10,743 kg menjadi 59,83±12,205 kg setelah memulai pengobatan (p=0,001). Antipsikotik atipikal yang paling banyak digunakan adalah kombinasi antipsikotik atipikal risperidon clozapin dengan persentase sebesar 91,25%, clozapin 3,75%, risperidon 5%. Kami menyimpulkan bahwa penggunaan antipsikotik atipikal selama setidaknya 4 minggu dapat menyebabkan penambahan berat badan pada pasien skizofrenia. Apoteker dan dokter direkomendasikan untuk memantau efek samping metabolik akibat penggunaan antipsikotik atipikal.Kata kunci: Antipsikotik atipikal, peningkatan berat badan, skizofrenia

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