scholarly journals The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice

Diabetologia ◽  
2021 ◽  
Author(s):  
Diana Grajales ◽  
Patricia Vázquez ◽  
Mónica Ruíz-Rosario ◽  
Eva Tudurí ◽  
Mercedes Mirasierra ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Beta Cell Dysfunction ◽  
Chow Diet ◽  
Islet Function ◽  
Female Mice ◽  
Cell Dysfunction ◽  
The Metabolic Syndrome ◽  
Second Generation Antipsychotic

Abstract Aims/hypothesis Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. Methods We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5–6.0 mg kg−1 day−1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. Results Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction. Conclusions/interpretation Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes. Graphical abstract

scholarly journals Circadian Regulation of the Pancreatic Beta Cell

Endocrinology ◽  
2021 ◽  
Author(s):  
Nivedita Seshadri ◽  
Christine A Doucette
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Cell Biology ◽  
Pancreatic Beta Cell ◽  
Glucose Sensing ◽  
Beta Cell Dysfunction ◽  
Circadian Timing ◽  
Cell Dysfunction ◽  
Timing System ◽  
Circadian Timing System

Abstract Beta cell dysfunction is central to the development of type 2 diabetes (T2D). In T2D, environmental and genetic influences can manifest beta cell dysfunction in many ways, including impaired glucose-sensing and secretion coupling mechanisms, insufficient adaptative responses to stress and aberrant beta cell loss through increased cell death and/or beta cell de-differentiation. In recent years, circadian disruption has emerged as an important environmental risk factor for T2D. In support of this, genetic disruption of the circadian timing system in rodents impairs insulin secretion and triggers diabetes development, lending important evidence that the circadian timing system is intimately connected to, and essential for the regulation of pancreatic beta cell function; however, the role of the circadian timing system in the regulation of beta cell biology is only beginning to be unravelled. Here, we review the recent literature that explores the importance of the pancreatic islet/beta cell circadian clock in the regulation of various aspects of beta cell biology, including transcriptional and functional control of daily cycles of insulin secretion capacity, regulation of postnatal beta cell maturation, and control of the adaptive responses of the beta cell to metabolic stress and acute injury.

scholarly journals Inherent Beta Cell Dysfunction Contributes to Autoimmune Susceptibility

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 512
Author(s):  
Yong Kyung Kim ◽  
Lori Sussel ◽  
Howard W. Davidson
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cell ◽  
Cell Loss ◽  
The Body ◽  
Beta Cell Dysfunction ◽  
Metabolic Characteristics ◽  
Cell Dysfunction ◽  
Glucose Stimulated Insulin Secretion

The pancreatic beta cell is a highly specialized cell type whose primary function is to secrete insulin in response to nutrients to maintain glucose homeostasis in the body. As such, the beta cell has developed unique metabolic characteristics to achieve functionality; in healthy beta cells, the majority of glucose-derived carbons are oxidized and enter the mitochondria in the form of pyruvate. The pyruvate is subsequently metabolized to induce mitochondrial ATP and trigger the downstream insulin secretion response. Thus, in beta cells, mitochondria play a pivotal role in regulating glucose stimulated insulin secretion (GSIS). In type 2 diabetes (T2D), mitochondrial impairment has been shown to play an important role in beta cell dysfunction and loss. In type 1 diabetes (T1D), autoimmunity is the primary trigger of beta cell loss; however, there is accumulating evidence that intrinsic mitochondrial defects could contribute to beta cell susceptibility during proinflammatory conditions. Furthermore, there is speculation that dysfunctional mitochondrial responses could contribute to the formation of autoantigens. In this review, we provide an overview of mitochondrial function in the beta cells, and discuss potential mechanisms by which mitochondrial dysfunction may contribute to T1D pathogenesis.

scholarly journals Reduced islet function contributes to impaired glucose homeostasis in fructose-fed mice

2017 ◽  
Vol 312 (2) ◽  
pp. E109-E116 ◽  
Author(s):  
Zeenat A. Asghar ◽  
Andrew Cusumano ◽  
Zihan Yan ◽  
Maria S. Remedi ◽  
Kelle H. Moley
Keyword(s):  
Metabolic Syndrome ◽  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glucagon Secretion ◽  
Islet Function ◽  
Sugar Consumption ◽  
Sweetened Beverages ◽  
The Metabolic Syndrome ◽  
High Fructose ◽  
Glucose Stimulated Insulin Secretion

Increased sugar consumption, particularly fructose, in the form of sweetened beverages and sweeteners in our diet adversely affects metabolic health. Because these effects are associated with features of the metabolic syndrome in humans, the direct effect of fructose on pancreatic islet function is unknown. Therefore, we examined the islet phenotype of mice fed excess fructose. Fructose-fed mice exhibited fasting hyperglycemia and glucose intolerance but not hyperinsulinemia, dyslipidemia, or hyperuricemia. Islet function was impaired, with decreased glucose-stimulated insulin secretion and increased glucagon secretion and high fructose consumption leading to α-cell proliferation and upregulation of the fructose transporter GLUT5, which was localized only in α-cells. Our studies demonstrate that excess fructose consumption contributes to hyperglycemia by affecting both β- and α-cells of islets in mice.

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