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Metabolite profiling identifies pathways associated with metabolic risk in humans.
Cheng S, Rhee EP, Larson MG, Lewis GD, McCabe EL, Shen D, Palma MJ, Roberts LD, Dejam A, Souza AL, Deik AA, Magnusson M, Fox CS, O'Donnell CJ, Vasan RS, Melander O, Clish CB, Gerszten RE, Wang TJ
(2012) Circulation 125: 2222-31
MeSH Terms: Aged, Amino Acids, Animals, Body Mass Index, Cardiovascular Diseases, Diabetes Mellitus, Dyslipidemias, Female, Glutamine, Humans, Hypertension, Insulin Resistance, Male, Metabolic Networks and Pathways, Metabolome, Mice, Mice, Inbred C57BL, Middle Aged, Nucleotides, Obesity, Risk, Waist Circumference
Show Abstract · Added April 15, 2014
BACKGROUND - Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes mellitus and cardiovascular disease, the underlying biological mechanisms remain poorly understood.
METHODS AND RESULTS - To identify pathways associated with cardiometabolic risk, we used liquid chromatography/mass spectrometry to determine the plasma concentrations of 45 distinct metabolites and to examine their relation to cardiometabolic risk in the Framingham Heart Study (FHS; n=1015) and the Malmö Diet and Cancer Study (MDC; n=746). We then interrogated significant findings in experimental models of cardiovascular and metabolic disease. We observed that metabolic risk factors (obesity, insulin resistance, high blood pressure, and dyslipidemia) were associated with multiple metabolites, including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. We observed strong associations of insulin resistance traits with glutamine (standardized regression coefficients, -0.04 to -0.22 per 1-SD change in log-glutamine; P<0.001), glutamate (0.05 to 0.14; P<0.001), and the glutamine-to-glutamate ratio (-0.05 to -0.20; P<0.001) in the discovery sample (FHS); similar associations were observed in the replication sample (MDC). High glutamine-to-glutamate ratio was associated with lower risk of incident diabetes mellitus in FHS (odds ratio, 0.79; adjusted P=0.03) but not in MDC. In experimental models, administration of glutamine in mice led to both increased glucose tolerance (P=0.01) and decreased blood pressure (P<0.05).
CONCLUSIONS - Biochemical profiling identified circulating metabolites not previously associated with metabolic traits. Experimentally interrogating one of these pathways demonstrated that excess glutamine relative to glutamate, resulting from exogenous administration, is associated with reduced metabolic risk in mice.
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22 MeSH Terms
Adropin deficiency is associated with increased adiposity and insulin resistance.
Ganesh Kumar K, Zhang J, Gao S, Rossi J, McGuinness OP, Halem HH, Culler MD, Mynatt RL, Butler AA
(2012) Obesity (Silver Spring) 20: 1394-402
MeSH Terms: Adiposity, Animals, Axonemal Dyneins, Blood Glucose, Dietary Carbohydrates, Dietary Fats, Dyslipidemias, Eating, Energy Metabolism, Fasting, Fatty Liver, Female, Glucose Clamp Technique, Insulin Resistance, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Proteins
Show Abstract · Added July 21, 2014
Adropin is a secreted peptide that improves hepatic steatosis and glucose homeostasis when administered to diet-induced obese mice. It is not clear if adropin is a peptide hormone regulated by signals of metabolic state. Moreover, the significance of a decline in adropin expression with obesity with respect to metabolic disease is also not clear. We investigated the regulation of serum adropin by metabolic status and diet. Serum adropin levels were high in chow-fed conditions and were suppressed by fasting and diet-induced obesity (DIO). High adropin levels were observed in mice fed a high-fat low carbohydrate diet, whereas lower levels were observed in mice fed a low-fat high carbohydrate diet. To investigate the role of adropin deficiency in metabolic homeostasis, we generated adropin knockout mice (AdrKO) on the C57BL/6J background. AdrKO displayed a 50%-increase in increase in adiposity, although food intake and energy expenditure were normal. AdrKO also exhibited dyslipidemia and impaired suppression of endogenous glucose production (EndoR(a)) in hyperinsulinemic-euglycemic clamp conditions, suggesting insulin resistance. While homo- and heterozygous carriers of the null adropin allele exhibited normal DIO relative to controls, impaired glucose tolerance associated with weight gain was more severe in both groups. In summary, adropin is a peptide hormone regulated by fasting and feeding. In fed conditions, adropin levels are regulated dietary macronutrients, and increase with dietary fat content. Adropin is not required for regulating food intake, however, its functions impact on adiposity and are involved in preventing insulin resistance, dyslipidemia, and impaired glucose tolerance.
1 Communities
1 Members
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19 MeSH Terms
Dyslipidemias in children.
Lilley JS, Linton MF, Fazio S
(2012) Pediatr Ann 41: e1-7
MeSH Terms: Child, Child, Preschool, Cholesterol, LDL, Dyslipidemias, Humans, Mass Screening, Referral and Consultation, Risk Factors, Triglycerides
Added December 10, 2013
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2 Members
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9 MeSH Terms
Long-term management of the kidney transplant recipient.
Schaefer HM
(2012) Blood Purif 33: 205-11
MeSH Terms: Cardiovascular Diseases, Dyslipidemias, Graft Rejection, Humans, Hypertension, Infection, Kidney Failure, Chronic, Kidney Transplantation, Neoplasms
Show Abstract · Added February 25, 2014
Due to the successes of kidney transplantation, patients with allografts are enjoying long-term survival. In addition to care of the allograft with lifelong administration of immunosuppressive medications, common medical conditions must be recognized and managed appropriately. With constraints on the transplant centers and patient considerations of finance and geography, it is recognized that community providers will play an ever increasing role in the care of the kidney transplant recipient. Guidelines for understanding and managing some of the more important common general medical problems, including care as it relates to cardiovascular disease, chronic kidney disease, transplant-related issues, and general health maintenance, are reviewed in this article.
Copyright © 2012 S. Karger AG, Basel.
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9 MeSH Terms
A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers.
Albaugh VL, Singareddy R, Mauger D, Lynch CJ
(2011) PLoS One 6: e22662
MeSH Terms: Adolescent, Adult, Antipsychotic Agents, Benzodiazepines, Body Mass Index, Body Weight, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, Cross-Over Studies, Double-Blind Method, Dyslipidemias, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Glucose Tolerance Test, Humans, Leptin, Male, Olanzapine, Triglycerides, Young Adult
Show Abstract · Added August 26, 2015
BACKGROUND AND RATIONALE - Atypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans.
METHODOLOGY/PRINCIPAL FINDINGS - A double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18-30 years old, BMI 18.5-25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged.
CONCLUSIONS/SIGNIFICANCE - Olanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics.
TRIAL REGISTRATION - ClinicalTrials.gov NCT00741026.
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22 MeSH Terms
The association of bone density and calcified atherosclerosis is stronger in women without dyslipidemia: the multi-ethnic study of atherosclerosis.
Jensky NE, Hyder JA, Allison MA, Wong N, Aboyans V, Blumenthal RS, Schreiner P, Carr JJ, Wassel CL, Ix JH, Criqui MH
(2011) J Bone Miner Res 26: 2702-9
MeSH Terms: Aged, Aged, 80 and over, Aging, Atherosclerosis, Bone Density, Calcinosis, Calcium, Cholesterol, HDL, Dyslipidemias, Female, Humans, Male, Middle Aged, Sex Characteristics
Show Abstract · Added February 15, 2014
We tested whether the association between bone mineral density (BMD) and coronary artery calcification (CAC) varies according to dyslipidemia in community-living individuals. Between 2002 and 2005, 305 women and 631 men (mean age of 64 years), who were not taking lipid-lowering medications or estrogen were assessed for spine BMD, CAC, and total (TC), HDL- and LDL-cholesterol and triglycerides. Participants were a random sample from the Multi-Ethnic Study of Atherosclerosis (MESA) without clinical cardiovascular disease. Spine BMD at the L3 vertebrate was performed by computer tomography (CT). CAC prevalence was measured by CT. The total cholesterol to HDL ratio (TC:HDL) ≥ 5.0 was used as the primary marker of hyperlipidemia. The association of BMD with CAC differed in women with TC:HDL < 5.0 versus higher (p-interaction = 0.01). In age- and race-adjusted models, among women with TC:HDL < 5.0, each SD (43.4 mg/cc) greater BMD was associated with a 25% lower prevalence of CAC (prevalence ratio [PR] 0.75, 95% confidence interval [CI] 0.63-0.89), whereas among women with higher TC:HDL, higher BMD was not significantly associated with CAC (PR 1.22, 95% CI 0.82-1.82). Results were similar using other definitions of hyperlipidemia. In contrast, no consistent association was observed between BMD and CAC in men, irrespective of the TC:HDL ratio (p interaction 0.54). The inverse association of BMD with CAC is stronger in women without dyslipidemia. These data argue against the hypothesis that dyslipidemia is the key factor responsible for the inverse association of BMD with atherosclerosis.
Copyright © 2011 American Society for Bone and Mineral Research.
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14 MeSH Terms
Basal insulin: beyond glycemia.
Niswender KD
(2011) Postgrad Med 123: 27-37
MeSH Terms: Affect, Appetite, Blood Glucose, Cardiovascular System, Cognition, Diabetes Mellitus, Type 2, Dyslipidemias, Humans, Inflammation, Insulin, Insulin Resistance, Lipid Metabolism, Obesity
Show Abstract · Added February 15, 2016
Insulin is a pleiotropic hormone with numerous effects at the cellular, tissue, and organismal levels. Clinicians are familiar with physiological effects of insulin on carbohydrate metabolism, including stimulation of glucose uptake in skeletal muscle and the suppression of glucose production from the liver. Other metabolic effects of insulin include inhibiting the release of free fatty acids from adipose tissue and stimulating the incorporation of amino acids into proteins. Indeed, every organ in the body, including the brain, is a target for insulin action. Insulin resistance, typically defined with respect to glucose metabolism, is a condition in which normal levels of insulin do not trigger the signal for glucose disposition. The effects of insulin resistance and impaired insulin signaling have profound pathophysiologic effects, such as hyperglycemia-induced tissue damage, hypertension, dyslipidemia, metabolic syndrome, and cardiovascular and renal disease. An integrated view of insulin action in all of these tissues may yield improved therapeutic insight and possibly even illuminate new therapeutic opportunities. With the increase in the number of patients diagnosed with prediabetes and diabetes, an updated understanding of the disease and the pharmacologic armamentarium used to treat it is needed to improve outcomes. To help expand the clinical care provider's perspective, this article will provide a provocative discussion about the pathophysiology of diabetes, the role of insulin and insulin resistance, and the clinical efficacy potential of insulin. Understanding the cellular and molecular mechanisms underlying the effects of insulin and how these translate into clinical consequences beyond glycemia will assist primary care physicians in the care of their patients with diabetes and metabolic syndrome.
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13 MeSH Terms
PPARγ: a molecular link between systemic metabolic disease and benign prostate hyperplasia.
Jiang M, Strand DW, Franco OE, Clark PE, Hayward SW
(2011) Differentiation 82: 220-36
MeSH Terms: Animals, Diabetes Mellitus, Type 2, Disease Models, Animal, Dyslipidemias, Humans, Inflammation, Lower Urinary Tract Symptoms, Male, Mice, Molecular Targeted Therapy, PPAR gamma, Prostate, Prostatic Hyperplasia, Signal Transduction
Show Abstract · Added December 10, 2013
The emergent epidemic of metabolic syndrome and its complex list of sequelae mandate a more thorough understanding of benign prostatic hyperplasia and lower urinary tract symptoms (BPH/LUTS) in the context of systemic metabolic disease. Here we discuss the nature and origins of BPH, examine its role as a component of LUTS and review retrospective clinical studies that have drawn associations between BPH/LUTS and type II diabetes, inflammation and dyslipidemia. PPARγ signaling, which sits at the nexus of systemic metabolic disease and BPH/LUTS through its regulation of inflammation and insulin resistance, is proposed as a candidate for molecular manipulation in regard to BPH/LUTS. Finally, we introduce new cell and animal models that are being used to study the consequences of obesity, diabetes and inflammation on benign prostatic growth.
Copyright © 2011 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.
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14 MeSH Terms
Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans.
Rhee EP, Cheng S, Larson MG, Walford GA, Lewis GD, McCabe E, Yang E, Farrell L, Fox CS, O'Donnell CJ, Carr SA, Vasan RS, Florez JC, Clish CB, Wang TJ, Gerszten RE
(2011) J Clin Invest 121: 1402-11
MeSH Terms: Adult, Aged, Biomarkers, Case-Control Studies, Diabetes Mellitus, Type 2, Dyslipidemias, Exercise Test, Female, Glucose Tolerance Test, Humans, Insulin, Insulin Resistance, Lipids, Male, Middle Aged, Molecular Structure, Predictive Value of Tests, Risk Factors, Triglycerides
Show Abstract · Added April 15, 2014
Dyslipidemia is an independent risk factor for type 2 diabetes, although exactly which of the many plasma lipids contribute to this remains unclear. We therefore investigated whether lipid profiling can inform diabetes prediction by performing liquid chromatography/mass spectrometry-based lipid profiling in 189 individuals who developed type 2 diabetes and 189 matched disease-free individuals, with over 12 years of follow up in the Framingham Heart Study. We found that lipids of lower carbon number and double bond content were associated with an increased risk of diabetes, whereas lipids of higher carbon number and double bond content were associated with decreased risk. This pattern was strongest for triacylglycerols (TAGs) and persisted after multivariable adjustment for age, sex, BMI, fasting glucose, fasting insulin, total triglycerides, and HDL cholesterol. A combination of 2 TAGs further improved diabetes prediction. To explore potential mechanisms that modulate the distribution of plasma lipids, we performed lipid profiling during oral glucose tolerance testing, pharmacologic interventions, and acute exercise testing. Levels of TAGs associated with increased risk for diabetes decreased in response to insulin action and were elevated in the setting of insulin resistance. Conversely, levels of TAGs associated with decreased diabetes risk rose in response to insulin and were poorly correlated with insulin resistance. These studies identify a relationship between lipid acyl chain content and diabetes risk and demonstrate how lipid profiling could aid in clinical risk assessment.
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19 MeSH Terms
A common CNR1 (cannabinoid receptor 1) haplotype attenuates the decrease in HDL cholesterol that typically accompanies weight gain.
Feng Q, Jiang L, Berg RL, Antonik M, MacKinney E, Gunnell-Santoro J, McCarty CA, Wilke RA
(2010) PLoS One 5: e15779
MeSH Terms: Adult, Body Mass Index, Cholesterol, HDL, Chromosome Mapping, Dyslipidemias, Female, Haplotypes, Humans, Male, Middle Aged, Obesity, Phenotype, Receptor, Cannabinoid, CB1, Triglycerides, Weight Gain
Show Abstract · Added February 12, 2015
We have previously shown that genetic variability in CNR1 is associated with low HDL dyslipidemia in a multigenerational obesity study cohort of Northern European descent (209 families, median  = 10 individuals per pedigree). In order to assess the impact of CNR1 variability on the development of dyslipidemia in the community, we genotyped this locus in all subjects with class III obesity (body mass index >40 kg/m(2)) participating in a population-based biobank of similar ancestry. Twenty-two haplotype tagging SNPs, capturing the entire CNR1 gene locus plus 15 kb upstream and 5 kb downstream, were genotyped and tested for association with clinical lipid data. This biobank contains data from 645 morbidly obese study subjects. In these subjects, a common CNR1 haplotype (H3, frequency 21.1%) is associated with fasting TG and HDL cholesterol levels (p = 0.031 for logTG; p = 0.038 for HDL-C; p = 0.00376 for log[TG/HDL-C]). The strength of this relationship increases when the data are adjusted for age, gender, body mass index, diet and physical activity. Mean TG levels were 160±70, 155±70, and 120±60 mg/dL for subjects with 0, 1, and 2 copies of the H3 haplotype. Mean HDL-C levels were 45±10, 47±10, and 48±9 mg/dL, respectively. The H3 CNR1 haplotype appears to exert a protective effect against development of obesity-related dyslipidemia.
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15 MeSH Terms