Cedars Sinai Diabetes and Obesity Research Institute

Los Angeles, CA, United States

Cedars Sinai Diabetes and Obesity Research Institute

Los Angeles, CA, United States

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PubMed | University of Pennsylvania, Endocrinology and Metabolism, Clinical Research Unit, Cedars Sinai Diabetes and Obesity Research Institute and 3 more.
Type: | Journal: Nutrition & metabolism | Year: 2016

[This corrects the article DOI: 10.1186/s12986-016-0062-5.].


PubMed | Eli Lilly and Company, University of Washington, ROI Biopharma Consulting, University of Padua and 11 more.
Type: Journal Article | Journal: Diabetes care | Year: 2016

Standardized, reproducible, and feasible quantification of -cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states.Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT).From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from 0.3 to 0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations.Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use.


Morselli E.,Bernardo O'Higgins University | Frank A.P.,Cedars Sinai Diabetes and Obesity Research Institute | Palmer B.F.,Southwestern University | Rodriguez-Navas C.,Southwestern University | And 2 more authors.
International Journal of Obesity | Year: 2016

In this review, we discuss the observations that, following chronic high-fat diet (HFD) exposure, male mice have higher levels of saturated fatty acids (FAs) and total sphingolipids, whereas lower amounts of polyunsaturated FAs in the central nervous system (CNS) than females. Furthermore, males, when compared with female mice, have higher levels of inflammatory markers in the hypothalamus following exposure to HFD. The increase in markers of inflammation in male mice is possibly due to the reductions in proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and estrogen receptor alpha (ERα), which is not recapitulated in female mice. Consistently, hypothalamic inflammation is induced both in male and female ERα total-body knockout mice when exposed to a HFD, thus confirming the key role of ERα in the regulation of HFD-induced hypothalamic inflammation. Finally, the HFD-induced depletion of hypothalamic ERα is associated with dysregulation in metabolic homeostasis, as evidenced by reductions in glucose tolerance and decrements in myocardial function. © 2016 Macmillan Publishers Limited.


PubMed | Cedars Sinai Diabetes and Obesity Research Institute, University of Chile, University of Santiago de Chile and University of Texas Southwestern Medical Center
Type: Journal Article | Journal: International journal of obesity (2005) | Year: 2016

In this review, we discuss the observations that, following chronic high-fat diet (HFD) exposure, male mice have higher levels of saturated fatty acids (FAs) and total sphingolipids, whereas lower amounts of polyunsaturated FAs in the central nervous system (CNS) than females. Furthermore, males, when compared with female mice, have higher levels of inflammatory markers in the hypothalamus following exposure to HFD. The increase in markers of inflammation in male mice is possibly due to the reductions in proliferator-activated receptor gamma coactivator 1 alpha (PGC-1) and estrogen receptor alpha (ER), which is not recapitulated in female mice. Consistently, hypothalamic inflammation is induced both in male and female ER total-body knockout mice when exposed to a HFD, thus confirming the key role of ER in the regulation of HFD-induced hypothalamic inflammation. Finally, the HFD-induced depletion of hypothalamic ER is associated with dysregulation in metabolic homeostasis, as evidenced by reductions in glucose tolerance and decrements in myocardial function.


PubMed | Cedars Sinai Diabetes and Obesity Research Institute, University of Texas Southwestern Medical Center, University of Santiago de Chile, University of Campinas and University of Sao Paulo
Type: Journal Article | Journal: Cell metabolism | Year: 2016

In this Essay, we discuss the critical need to incorporate sex and gender in pre-clinical and clinical research toenhance our understanding of the mechanisms by which metabolic processes differ by sex and gender. This knowledge will allow for development of personalized medicine which will optimize therapies specific for individuals.


Rowe M.W.,Tethys Bioscience Inc. | Bergman R.N.,Cedars Sinai Diabetes and Obesity Research Institute | Wagenknecht L.E.,Wake forest University | Kolberg J.A.,Tethys Bioscience Inc.
Diabetes/Metabolism Research and Reviews | Year: 2012

Background: This study compares a previously developed Diabetes Risk Score to commonly used clinical tools for type 2 diabetes risk evaluation in the Insulin Resistance Atherosclerosis Study (IRAS) cohort, a multi-ethnic US cohort. Available as a clinical test, the PreDx® Diabetes Risk Score uses fasting concentrations of adiponectin, C-reactive protein, ferritin, interleukin-2 receptor alpha, HbA1c, glucose and insulin, plus age and gender to predict 5-year risk of diabetes. It was developed in a Northern European population. Methods: The Diabetes Risk Score was measured using archived fasting plasma specimens from 722 non-diabetic IRAS participants, 17.6% of whom developed diabetes during 5.2years median follow-up (inter-quartile range: 5.1-5.4years). The study included non-Hispanic whites (41.8%), Hispanics (34.5%) and African Americans (23.7%). Performance of the algorithm was evaluated by area under the receiver operating characteristic curve (AROC) and risk reclassification against other tools. Results: The Diabetes Risk Score discriminates participants who developed diabetes from those who did not significantly better than fasting glucose (AROC=0.763 versus 0.710, p=0.003). The Diabetes Risk Score performed equally well in subpopulations defined by race/ethnicity or gender. The Diabetes Risk Score provided a significant net reclassification improvement of 0.24 (p=0.01) when comparing predefined low/moderate/high Diabetes Risk Score categories to metabolic syndrome risk factor counting. The Diabetes Risk Score complemented the use of the oral glucose tolerance test by identifying high risk patients with impaired fasting glucose but normal glucose tolerance, 33% of whom converted. Conclusions: Measuring the Diabetes Risk Score of elevated-risk US patients could help physicians decide which patients warrant more intensive intervention. The Diabetes Risk Score performed equally well across the ethnic subpopulations present in this cohort. © 2012 John Wiley & Sons, Ltd.


Kim J.S.,University of Otago | Rizwan M.Z.,University of Otago | Clegg D.J.,Cedars Sinai Diabetes and Obesity Research Institute | Anderson G.M.,University of Otago
Endocrinology | Year: 2016

Estradiol and leptin are critical hormones in the regulation of body weight. The aim of this study was to determine whether this cross talk between leptin receptor (LepRb) and estrogen receptor-(ER) signaling is critical for estradiol's anorexigenic effects. Leprb-Cre mice were crossed with Cre-dependent Tau-green fluorescent protein (GFP) reporter, Stat3-flox or Er-flox mice to generate female mice with GFP expression, signal transducer and activator of transcription 3 (STAT3) knockout (KO), or ER KO, specifically in LepRb-expressing cells. The proportion of Leprb-GFP cells colocalizing ER was high (80%) in the preoptic area but low (10%) in the mediobasal hypothalamus, suggesting that intracellular cross talk between these receptors is minimal for metabolic regulation. To test whether estradiol enhanced arcuate leptin sensitivity, ovarectomized mice received varying levels of estradiol replacement. Increasing estrogenic states did not increase the degree of leptin-induced STAT3 phosphorylation. LepRb-specific STAT3KOmice and controls were ovarectomized and given either chronic estradiol or vehicle treatment to test whether STAT3 is required for estrogen-induced body weight suppression. Both groups of estradiol-treated mice showed an equivalent reduction in body weight and fat content compared with vehicle controls. Finally, mice lacking ER specifically in LepRb-expressing neurons also showed no increase in body weight or impairments in metabolic function compared with controls, indicating that estradiol acts independently of leptin-responsive cells to regulate body weight. However, fecundity was impaired in in Leprb-ER KO females. Contrary to the current dogma, we report that estradiol has minimal direct actions on LepRb cells in the mediodasal hypothalamus and that its anorexigenic effects can occur entirely independently of LepRb-STAT3 signaling in female mice. Copyright © 2016 by the Endocrine Society.


Rodriguez-Navas C.,University of Texas Southwestern Medical Center | Morselli E.,Bernardo O'Higgins University | Clegg D.J.,Cedars Sinai Diabetes and Obesity Research Institute
Molecular Metabolism | Year: 2016

Objective In this study, we analyzed the fatty acid profile of brains and plasma from male and female mice fed chow or a western-style high fat diet (WD) for 16 weeks to determine if males and females process fatty acids differently. Based on the differences in fatty acids observed in vivo, we performed in vitro experiments on N43 hypothalamic neuronal cells to begin to elucidate how the fatty acid milieu may impact brain inflammation. Methods Using a comprehensive mass spectrometry fatty acid analysis, which includes a profile for 52 different fatty acid isomers, we assayed the plasma and brain fatty acid composition of age-matched male and female mice maintained on chow or a WD. Additionally, using the same techniques, we determined the fatty acid composition of N43 hypothalamic cells following exposure to palmitic and linoleic acid, alone or in combination. Results Our data demonstrate there is a sexual dimorphism in brain fatty acid content both following the consumption of the chow diet, as well as the WD, with males having an increased percentage of saturated fatty acids and reductions in ω6-polyunsaturated fatty acids when compared to females. Interestingly, we did not observe a sexual dimorphism in fatty acid content in the plasma of the same mice. Furthermore, exposure of N43 cells to the ω6-PUFA linoleic acid, which is higher in female brains when compared to males, reduces palmitic acid-induced inflammation. Conclusions Our data suggest male and female brains, and not plasma, differ in their fatty acid profile. This is the first time, to our knowledge, lipidomic analyses has been used to directly test the hypothesis there is a sexual dimorphism in brain and plasma fatty acid composition following consumption of the chow diet, as well as following exposure to the WD. © 2016 The Author(s)


Bergman R.N.,Cedars Sinai Diabetes and Obesity Research Institute | Stefanovski D.,Cedars Sinai Diabetes and Obesity Research Institute | Kim S.P.,Cedars Sinai Diabetes and Obesity Research Institute
Current Opinion in Biotechnology | Year: 2014

Prevalence of Type 2 diabetes has increased at an alarming rate, highlighting the need to correctly predict the development of this disease in order to allow intervention and thus, slow progression of the disease and resulting metabolic derangement. There have been many recent 'advances' geared toward the detection of pre-diabetes, including genome wide association studies and metabolomics. Although these approaches generate a large amount of data with a single blood sample, studies have indicated limited success using genetic and metabolomics information alone for identification of disease risk. Clinical assessment of the disposition index (DI), based on the hyperbolic law of glucose tolerance, is a powerful predictor of Type 2 diabetes, but is not easily assessed in the clinical setting. Thus, it is evident that combining genetic or metabolomic approaches for a more simple assessment of DI may provide a useful tool to identify those at highest risk for Type 2 diabetes, allowing for intervention and prevention. © 2014.


PubMed | Cedars Sinai Diabetes and Obesity Research Institute, Bernardo O'Higgins University and University of Texas Southwestern Medical Center
Type: Journal Article | Journal: Molecular metabolism | Year: 2016

In this study, we analyzed the fatty acid profile of brains and plasma from male and female mice fed chow or a western-style high fat diet (WD) for 16 weeks to determine if males and females process fatty acids differently. Based on the differences in fatty acids observed invivo, we performed invitro experiments on N43 hypothalamic neuronal cells to begin to elucidate how the fatty acid milieu may impact brain inflammation.Using a comprehensive mass spectrometry fatty acid analysis, which includes a profile for 52 different fatty acid isomers, we assayed the plasma and brain fatty acid composition of age-matched male and female mice maintained on chow or a WD. Additionally, using the same techniques, we determined the fatty acid composition of N43 hypothalamic cells following exposure to palmitic and linoleic acid, alone or in combination.Our data demonstrate there is a sexual dimorphism in brain fatty acid content both following the consumption of the chow diet, as well as the WD, with males having an increased percentage of saturated fatty acids and reductions in 6-polyunsaturated fatty acids when compared to females. Interestingly, we did not observe a sexual dimorphism in fatty acid content in the plasma of the same mice. Furthermore, exposure of N43 cells to the 6-PUFA linoleic acid, which is higher in female brains when compared to males, reduces palmitic acid-induced inflammation.Our data suggest male and female brains, and not plasma, differ in their fatty acid profile. This is the first time, to our knowledge, lipidomic analyses has been used to directly test the hypothesis there is a sexual dimorphism in brain and plasma fatty acid composition following consumption of the chow diet, as well as following exposure to the WD.

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