Pharmacogenomics of Metabolic Effects of Rosiglitazone

Šeda, Ondřej; Šedová, Lucie; Oliyarnyk, Olena; Kazdová, Ludmila; Křenová, D; Corbeil, Gilles; Hamet, Pavel; Tremblay, Johanne; Křen,

doi:10.2217/14622416.9.2.141

Cited by 19 publications

(14 citation statements)

References 65 publications

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“…Because the model is derived from basic principles and physiology, it can be applied to other rat strains, perhaps a modified version can also be applied to humans, and it can be used for translational research. Drug effects on leptin and food intake may be incorporated, such as down-regulation of the leptin gene by rosiglitazone (Kallen and Lazar, 1996;Seda et al, 2008). Increasing leptin availability in the hypothalamus by gene therapy enforced euglycemia in mice because of increased glucose metabolism throughout 7 weeks despite persisting severe insulinopenia (Ueno et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Mechanism-Based Modeling of Nutritional and Leptin Influences on Growth in Normal and Type 2 Diabetic Rats

Landersdorfer¹,

DuBois²,

Almon³

et al. 2008

J Pharmacol Exp Ther

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Influences of genetic and nutritional factors on body weight, fat mass, and leptin production and effects of leptin were assessed in normal [Wistar-Kyoto (WKY)] and diabetic [GotoKakizaki (GK)] rats by mechanism-based modeling. The study included 60 WKY and 60 GK rats; half received high-fat diet (HF), and the others received normal rat chow (N). Body weights and food consumption were measured twice weekly. Six rats per group were sacrificed at 4, 8, 12, 16, and 20 weeks. Abdominal fat was weighed, and plasma leptin was measured by enzyme-linked immunosorbent assay. All data were comodeled using NONMEM version VI level 1.1 (first-order conditional estimation with interaction) (Beal SL, Boeckmann AJ, Sheiner LB, and NONMEM Project Group, NONMEM Users Guides, University of California, San Francisco, CA, 2007). Weight gain was modeled as differences between energy intake and metabolic rate based on allometrically scaled lean body mass (LBM).The GK had higher metabolic rates (1.15 kcal/day/g LBM 0.75 ) than WKY-N (0.92) and WKY-HF (1.02) rats and higher efficiency in transforming energy into body weight. Leptin effect was modeled as inhibition of food consumption. Total body fat was estimated from abdominal fat. Leptin production from fat was 4.7-fold higher for GK (3.03 ng/ml/day/g) than WKY (0.66 ng/ml/day/g). Leptin production rate from LBM was 0.53 ng/ ml/day/g for all groups. The IC 50 for inhibition of food intake by leptin was approximately 3-fold higher in GK versus WKY, indicating leptin resistance for the effect on food consumption in GK. The GK had similar intake of kilocalories but lower body weights and fat mass than WKY, possibly because of higher metabolic rates. Our mechanism-based model explains intrinsic reasons for differences in growth, food intake, and leptin concentrations among these two strains of rats.Type 2 diabetes (T2DM) is a major health risk in many countries and the number of diabetic patients and associated costs for health systems are increasing. More than 180 million people are diabetic worldwide, and this number was estimated to more than double by 2030 (Centers for Disease Control and Prevention, http://www.cdc.gov/diabetes/pubs/ factsheets.htm). In 2005, an estimated 1.1 million people died from diabetes, and such deaths were predicted to increase by more than 50% over the next 10 years (Centers for Disease Control and Prevention, http://www.cdc.gov/ diabetes/pubs/factsheets.htm).

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Section: Discussionmentioning

confidence: 99%

Mechanism-Based Modeling of Nutritional and Leptin Influences on Growth in Normal and Type 2 Diabetic Rats

Landersdorfer¹,

DuBois²,

Almon³

et al. 2008

J Pharmacol Exp Ther

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“…AQP9 was also reported to be present at mitochondria of glia [61], which may also be an artifact due to poor quality of the antibody as AQP9 is not expressed in the brain [8]. The AQP9 expression was stimulated in rat white adipose tissues by one of thiazolidinediones, which are increasingly used drugs for the treatment of type 2 diabetes [62], although AQP9 expression in fat tissues is controversial.…”

Section: Characteristics Of Mammalian Aqpsmentioning

confidence: 99%

Aquaporin water channels in mammals

2009

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Water channels, aquaporins (AQPs), are a family of small integral plasma membrane proteins that primarily transport water across the plasma membrane. There are 13 members (AQP0-12) in humans. This number is final as the human genome project has been completed. They are divided into three subgroups based on the primary sequences: water selective AQPs (AQP0, 1, 2, 4, 5, 6, 8), aquaglyceroporins (AQP3, 7, 9, 10), and superaquaporins (AQP11, 12). Since no specific inhibitors are yet available, functional roles of AQPs are suggested by AQP null mice and humans. Abnormal water metabolism was shown with AQP1, 2, 3, 4, 5 null mice, especially with AQP2 null mice: fatal at neonate due to diabetes insipidus. Abnormal glycerol transport was shown with AQP3, 7, 9 null mice, although they appeared normal. AQP0 null mice suffer from cataracts, although the pathogenesis is not clear. Unexpectedly, AQP11 null mice die from uremia as a result of polycystic kidneys. Interestingly, AQP6, 8, 10, 12 null mice are almost normal. AQP null humans have been reported with AQP0, 1, 2, 3, 7: only AQP2 null humans show an outstanding phenotype, diabetes insipidus. This review summarizes the current knowledge on all mammalian AQPs and hopefully will stimulate future research in both clinical and basic fields.

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“…One of the mechanisms responsible may lie in the fact that human islets express Cd36 in the plasma membrane as well as in the insulinsecretory granules, and Cd36 activity was deemed important for uptake of fatty acids into b-cells as well as for mediating their modulatory effects on insulin secretion (Noushmehr et al, 2005) . Altogether, it is apparent that the eventual metabolic effect of Cd36 deficiency is tightly linked to a particular setting of both genomic background (for example, PD.SHR4 vs BN.SHR4 (Seda et al, 2002(Seda et al, , 2003b; Table 5 and Supplementary Figure 3) and environmental factors, particularly diet (Febbraio et al, 1999;Hajri et al, 2002;Koonen et al, 2007;Kennedy et al, 2011) or medication (Qi et al, 2002;Seda et al, 2003a;Seda et al, 2008;Krupkova et al, 2010). Therefore, the apparently controversial issue of causal relation between level of Cd36 expression and metabolic outcome may be resolved by adoption of broader conceptual framework incorporating other (eco)genomic factors.…”

Section: Discussionmentioning

confidence: 99%

“…Of those, only Cd36 was found to be differentially expressed between PD and PD.SHR4a. Further studies are needed to assess the effect of Cd36 and the whole differential segment under distinct nutritional and pharmacological challenges, especially given our previous extensive documentation of nutrigenetic and pharmacogenetic interactions of a similar genomic region in the BN.SHR4 congenic strain (Seda et al, 2003a(Seda et al, , 2008Krupkova et al, 2010). In sum, the introduction of mutated Cd36 into the genomic background of an inbred model of metabolic syndrome resulted in disconnected shifts of metabolic profile along with distinct changes in hepatic transcriptome.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we have found this limited portion of genome to be crucial for several pharmacogenetic interactions involving the insulin sensitizer rosiglitazone (Seda et al, 2003a(Seda et al, , 2008 and glucocorticoid dexamethasone (Krupkova et al, 2010). In SHR, Cd36 was established as a key determinant of the insulin-sensitizing actions of thiazolidinediones using SHR transgenic and congenic strains expressing wild-type Cd36 (Qi et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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CD36-deficient congenic strains show improved glucose tolerance and distinct shifts in metabolic and transcriptomic profiles

et al. 2012

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Pharmacogenomics of Metabolic Effects of Rosiglitazone

Abstract: Rosiglitazone's effects on lipid deposition and insulin sensitivity of peripheral tissues are largely dependent on the genetic background it acts upon.

Cited by 19 publications

References 65 publications

Mechanism-Based Modeling of Nutritional and Leptin Influences on Growth in Normal and Type 2 Diabetic Rats

Mechanism-Based Modeling of Nutritional and Leptin Influences on Growth in Normal and Type 2 Diabetic Rats

Aquaporin water channels in mammals

CD36-deficient congenic strains show improved glucose tolerance and distinct shifts in metabolic and transcriptomic profiles

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