Wired on sugar: the role of the CNS in the regulation of glucose homeostasis

Grayson, Bernadette E.; Seeley, Randy J.; Sandoval, Darleen A.

doi:10.1038/nrn3409

Cited by 104 publications

(81 citation statements)

References 113 publications

(158 reference statements)

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“…It is well established that insulin can independently regulate HGP by both its direct or indirect hepatic effects (5, 43), yet considerable controversy remains regarding the relative importance of each mechanism. The central effects of insulin have been said to be required, necessary, crucial, or even essential for the suppression of HGP by insulin (17,18,(44)(45)(46)(47)(48)(49), and recently it was concluded that suppression of lipolysis is the major mechanism by which insulin inhibits HGP (11). To date, both the direct and indirect effects of insulin have been identified as being the dominant signal by which a rise in insulin reduces HGP in vivo (1,50), leaving the issue unresolved.…”

Section: Discussionmentioning

confidence: 99%

Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion

Edgerton¹,

Kraft²,

Smith³

et al. 2017

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion

Edgerton¹,

Kraft²,

Smith³

et al. 2017

JCI Insight

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“…Not surprisingly, most studies into the metabolic side effects of OLZ have also focused on the CNS (Weston-Green et al, 2012). Although the CNS clearly plays a key role in regulating food consumption, obesity, dyslipidemia, and diabetes (Sandoval et al, 2009;Grayson et al, 2013), peripheral organs also significantly contribute to metabolic dysregulation in the intact organism. To date, very little is understood about the potential effects of OLZ administration on the peripheral organs critical for metabolic homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Olanzapine Activates Hepatic Mammalian Target of Rapamycin: New Mechanistic Insight into Metabolic Dysregulation with Atypical Antipsychotic Drugs

Schmidt

Jokinen

Massey

et al. 2013

J Pharmacol Exp Ther

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Olanzapine (OLZ), an effective treatment of schizophrenia and other disorders, causes weight gain and metabolic syndrome. Most studies to date have focused on the potential effects of OLZ on the central nervous system's mediation of weight; however, peripheral changes in liver or other key metabolic organs may also play a role in the systemic effects of OLZ. Thus, the purpose of this study was to investigate the effects of OLZ on hepatic metabolism in a mouse model of OLZ exposure. Female C57Bl/6J mice were administered OLZ (8 mg/kg per day) or vehicle subcutaneously by osmotic minipumps for 28 days. Liver and plasma were taken at sacrifice for biochemical analyses and for comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics analysis. OLZ increased body weight, fat pad mass, and liver-to-body weight ratio without commensurate increase in food consumption, indicating that OLZ altered energy expenditure. Expression and biochemical analyses indicated that OLZ induced anaerobic glycolysis and caused a pseudo-fasted state, which depleted hepatic glycogen reserves. OLZ caused similar effects in cultured HepG2 cells, as determined by Seahorse analysis. Metabolomic analysis indicated that OLZ increased hepatic concentrations of amino acids that can alter metabolism via the mTOR pathway; indeed, hepatic mTOR signaling was robustly increased by OLZ. Interestingly, OLZ concomitantly activated AMP-activated protein kinase (AMPK) signaling. Taken together, these data suggest that disturbances in glucose and lipid metabolism caused by OLZ in liver may be mediated, at least in part, via simultaneous activation of both catabolic (AMPK) and anabolic (mammalian target of rapamycin) pathways, which yields new insight into the metabolic side effects of this drug.

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“…Although this model is a global knockout, the effects observed are probably due to the lack of functional GABA B receptors in the islets, as we have demonstrated the impact of these receptors on islet physiology in vitro (7,8). Nevertheless, we cannot discard effects derived from the CNS, where GABA B receptors are abundant, since it is involved in the control of glucose homeostasis (31).…”

Section: Discussionmentioning

confidence: 99%

Postnatal development of the endocrine pancreas in mice lacking functional GABA_Breceptors

Crivello

Bonaventura

Chamson-Reig

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Adult mice lacking functional GABAB receptors (GABAB1KO) have glucose metabolism alterations. Since GABAB receptors (GABABRs) are expressed in progenitor cells, we evaluated islet development in GABA B1KO mice. Postnatal day 4 (PND4) and adult, male and female, GABAB1KO, and wild-type littermates (WT) were weighed and euthanized, and serum insulin and glucagon was measured. Pancreatic glucagon and insulin content were assessed, and pancreas insulin, glucagon, PCNA, and GAD65/67 were determined by immunohistochemistry. RNA from PND4 pancreata and adult isolated islets was obtained, and Ins1, Ins2, Gcg, Sst, Ppy, Nes, Pdx1, and Gad1 transcription levels were determined by quantitative PCR. The main results were as follows: 1) insulin content was increased in PND4 GABAB1KO females and in both sexes in adult GABAB1KOs; 2) GABAB1KO females had more clusters (Ͻ500 m 2 ) and less islets than WT females; 3) cluster proliferation was decreased at PND4 and increased in adult GABAB1KO mice; 4) increased ␤-area at the expense of the ␣-cell area was present in GABAB1KO islets; 5) Ins2, Sst, and Ppy transcription were decreased in PND4 GABAB1KO pancreata, adult GABAB1KO female islets showed increased Ins1, Ins2, and Sst expression, Pdx1 was increased in male and female GABAB1KO islets; and 6) GAD65/67 was increased in adult GABA B1KO pancreata. We demonstrate that several islet parameters are altered in GABAB1KO mice, further pinpointing the importance of GABABRs in islet physiology. Some changes persist from neonatal ages to adulthood (e.g., insulin content in GABAB1KO females), whereas other features are differentially regulated according to age (e.g., Ins2 was reduced in PND4, whereas it was upregulated in adult GABAB1KO females). islet development; ␥-aminobutyrate acid B receptors; hormones; transcription factors BLOOD GLUCOSE LEVELS ARE MODULATED by circulating hormones and the autonomous nervous system. The glucagon-producing ␣-cells and insulin-producing ␤-cells in Langerhans islets are chemoreceptor cells, which act as an integrated system to control blood glucose homeostasis and are capable of extremely rapid responses to changes in circulating metabolites, such as glucose or amino-acids (27). In addition, hormone release from ␤-cells, as well as from the other islet cell types, is regulated by autocrine and paracrine interactions (3, 60) that include a variety of additional factors, such as ions (Zn 2ϩ , Ca 2ϩ

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Wired on sugar: the role of the CNS in the regulation of glucose homeostasis

Cited by 104 publications

References 113 publications

Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion

Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion

Olanzapine Activates Hepatic Mammalian Target of Rapamycin: New Mechanistic Insight into Metabolic Dysregulation with Atypical Antipsychotic Drugs

Postnatal development of the endocrine pancreas in mice lacking functional GABA_Breceptors

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Wired on sugar: the role of the CNS in the regulation of glucose homeostasis

Cited by 104 publications

References 113 publications

Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion

Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion

Olanzapine Activates Hepatic Mammalian Target of Rapamycin: New Mechanistic Insight into Metabolic Dysregulation with Atypical Antipsychotic Drugs

Postnatal development of the endocrine pancreas in mice lacking functional GABABreceptors

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Postnatal development of the endocrine pancreas in mice lacking functional GABA_Breceptors