Intrahepatic Fat Accumulation and Alterations in Lipoprotein Composition in Obese Adolescents
A perfect proatherogenic state
Anna M.G. Cali , MD 1 ,
Tosca L. Zern , PHD 1 ,
Sara E. Taksali , MPH 1 ,
...Ana Mayra de Oliveira , MD 2 ,
Sylvie Dufour , PHD 3 ,
James D. Otvos , PHD 4 and
Sonia Caprio , MD 1
1 Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut
2 Department of Health, State University of Feira de Santana, Feira De Santana, Brazil
3 Department of Internal Medicine and the Howard Hughes Institute, Yale University School of Medicine, New Haven, Connecticut
4 LipoScience, Raleigh, North Carolina
Address correspondence and reprint requests to Sonia Caprio, MD, Yale University School of Medicine, Department of Pediatrics,
330 Cedar St., P.O. Box 208064, New Haven, CT 06520. E-mail: sonia.caprio{at}yale.edu
Abstract
OBJECTIVE —Among other metabolic consequences, a dyslipidemic profile often accompanies childhood obesity. In adults, type 2 diabetes
and hepatic steatosis have been shown to alter lipoprotein subclass distribution and size; however, these alterations have
not yet been shown in children or adolescents. Therefore, our objective was to determine the effect of hepatic steatosis on
lipoprotein concentration and size in obese adolescents.
RESEARCH DESIGN AND METHODS —Using fast magnetic resonance imaging, we measured intrahepatic fat content in 49 obese adolescents with normal glucose tolerance.
The presence or absence of hepatic steatosis was determined by a threshold value for hepatic fat fraction (HFF) of 5.5%; therefore,
the cohort was divided into two groups (HFF > or <5.5%). Fasting lipoprotein subclasses were determined using nuclear magnetic
resonance spectroscopy.
RESULTS —Overall, the high-HFF group had 88% higher concentrations of large VLDL compared with the low-HFF group ( P < 0.001). Likewise, the high-HFF group had significantly higher concentrations of small dense LDL ( P < 0.007); however, the low-HFF group had significantly higher concentrations of large HDL ( P < 0.001). Stepwise multiple regression analysis revealed that high HFF was the strongest single correlate, accounting for
32.6% of the variance in large VLDL concentrations ( P < 0.002).
CONCLUSIONS —The presence of fatty liver was associated with a pronounced dyslipidemic profile characterized by large VLDL, small dense
LDL, and decreased large HDL concentrations. This proatherogenic phenotype was strongly related to the intrahepatic lipid
content.
EMCL, extramyocellular triglyceride content
HFF, hepatic fat fraction
IMCL, intramyocellular triglyceride content
MRI, magnetic resonance imaging
NMR, nuclear magnetic resonance
WBISI, whole-body insulin sensitivity index
Footnotes
Published ahead of print at http://care.diabetesjournals.org on 23 August 2007. DOI: 10.2337/dc07-1088.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.
Accepted August 17, 2007.
Received June 7, 2007.
DIABETES CARE
β-Cell Function Across the Spectrum of Glucose Tolerance in Obese Youth
Ram Weiss 1 ,
Sonia Caprio 1 ,
Maddalena Trombetta 2 ,
Sara E. Taksali 1 ,
William V. Tamborlane 1 3 and
Riccardo Bonadonna 2
1 ...Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut
2 Department of Biomedical & Surgical Sciences, Section of Endocrinology & Metabolic Diseases, University of Verona and Azienda
Ospedaliera di Verona, Verona, Italy
3 General Clinical Research Center of the Yale University School of Medicine, New Haven, Connecticut
Address correspondence and reprint requests to Dr. Ram Weiss, Department of Pediatrics, Yale University School of Medicine,
333 Cedar St., P.O. Box 208064, New Haven, CT, 06520. E-mail: ram.weiss{at}yale.edu
Abstract
The profile of insulin secretion and the role of proinsulin processing across the spectrum of glucose tolerance in obese youth
have not been studied. The aims of this study were to define the role of insulin secretion and proinsulin processing in glucose
regulation in obese youth. We performed hyperglycemic clamps to assess insulin secretion, applying a model of glucose-stimulated
insulin secretion to the glucose and C-peptide concentration data. Thirty obese youth with normal glucose tolerance (NGT),
22 with impaired glucose tolerance (IGT), and 10 with type 2 diabetes were studied. The three groups had comparable anthropometric
measures and insulin sensitivity. The glucose sensitivity of first-phase secretion showed a significant stepwise decline from
NGT to IGT and from IGT to type 2 diabetes. The glucose sensitivity of second-phase secretion was similar in NGT and IGT subjects
yet was significantly lower in subjects with type 2 diabetes. Proinsulin-to-insulin ratios were comparable during first- and
second-phase secretion between subjects with NGT and IGT and were significantly increased in type 2 diabetes. Obese youth
with IGT have a significant defect in first-phase insulin secretion, while a defect in second-phase secretion and proinsulin
processing is specific for type 2 diabetes in this age-group.
IGT, impaired glucose tolerance
NGT, normal glucose tolerance
OGTT, oral glucose tolerance test
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted March 14, 2005.
Received November 29, 2004.
DIABETES
We used fast-gradient magnetic resonance imaging (MRI) to determine the longitudinal associations between the hepatic fat content (HFF), glucose homeostasis, and a biomarker of hepatocellular ...apoptosis in obese youth.
Baseline and longitudinal liver and abdominal MRI were performed with an oral glucose tolerance test in 76 obese youth followed for an average of 1.9 years. Cytokeratin-18 (CK-18) was measured at baseline and follow-up as a biomarker of hepatic apoptosis. The relationship between baseline HFF and metabolic parameters and circulating levels of CK-18 at follow-up were assessed using a bivariate correlation.
At baseline, 38% had hepatic steatosis based on %HFF ≥5.5% with alterations in indices of insulin sensitivity and secretion. At follow-up, BMI increased in both groups and baseline %HFF correlated strongly with the follow-up %HFF (r = 0.81, P < 0.001). Over time, markers of insulin sensitivity and 2-h glucose improved significantly in the group without fatty liver, in contrast with the persistence of the insulin resistance and associated correlates in the fatty liver group. Baseline HFF correlated with 2-h glucose (r = 0.38, P = 0.001), whole-body insulin sensitivity (r = -0.405, P = 0.001), adiponectin (r = -0.44, P < 0.001), CK-18 levels, (r = 0.63, P < 0.001), and disposition index (r = -0.272, P = 0.021) at follow-up. In a multivariate analysis, we showed that baseline HFF is an independent predictor of 2-h glucose and whole-body insulin sensitivity.
In obese youth, the phenotype of MRI-measured hepatic steatosis is persistent. Baseline HFF strongly modulates longitudinally 2-h blood glucose, biomarkers of insulin resistance, and hepatocellular apoptosis.
The worldwide epidemic of childhood obesity in the last decades is responsible for the occurrence in pediatrics of disorders once mainly found in adults, such as the metabolic syndrome. A key factor ...in the pathogenesis of metabolic syndrome is insulin resistance, a phenomenon occurring mainly in obese subjects with a general resistance to the insulin effect only on carbohydrates metabolism. Given that the metabolic syndrome is driven by obesity, the prevalence of the latter will strongly influence the prevalence of metabolic syndrome. This article addresses the causes of metabolic syndrome and the relevance of obesity in the pediatric population.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children, but diagnosis is challenging due to limited availability of noninvasive biomarkers. Machine learning ...applied to high‐resolution metabolomics and clinical phenotype data offers a novel framework for developing a NAFLD screening panel in youth. Here, untargeted metabolomics by liquid chromatography–mass spectrometry was performed on plasma samples from a combined cross‐sectional sample of children and adolescents ages 2‐25 years old with NAFLD (n = 222) and without NAFLD (n = 337), confirmed by liver biopsy or magnetic resonance imaging. Anthropometrics, blood lipids, liver enzymes, and glucose and insulin metabolism were also assessed. A machine learning approach was applied to the metabolomics and clinical phenotype data sets, which were split into training and test sets, and included dimension reduction, feature selection, and classification model development. The selected metabolite features were the amino acids serine, leucine/isoleucine, and tryptophan; three putatively annotated compounds (dihydrothymine and two phospholipids); and two unknowns. The selected clinical phenotype variables were waist circumference, whole‐body insulin sensitivity index (WBISI) based on the oral glucose tolerance test, and blood triglycerides. The highest performing classification model was random forest, which had an area under the receiver operating characteristic curve (AUROC) of 0.94, sensitivity of 73%, and specificity of 97% for detecting NAFLD cases. A second classification model was developed using the homeostasis model assessment of insulin resistance substituted for the WBISI. Similarly, the highest performing classification model was random forest, which had an AUROC of 0.92, sensitivity of 73%, and specificity of 94%. Conclusion: The identified screening panel consisting of both metabolomics and clinical features has promising potential for screening for NAFLD in youth. Further development of this panel and independent validation testing in other cohorts are warranted.
Currently, pediatric NAFLD is a diagnosis of exclusion and there is a need for cost‐effective screening tests to facilitate early detection. Here, we aimed to develop a pediatric NAFLD screening panel by applying machine learning to metabolomics and clinical data from a cross‐sectional cohort of 559 children and adolescents (2‐25 yrs). The resulting model consisted of 11 metabolite features and 3 clinical variables and achieved an AUROC of 0.94, sensitivity of 73% and specificity of 97% in the highest performing classification model.
Insulin Clearance in Health and Disease Najjar, Sonia M; Caprio, Sonia; Gastaldelli, Amalia
Annual review of physiology,
02/2023, Letnik:
85
Journal Article
Recenzirano
Odprti dostop
Insulin action is impaired in type 2 diabetes. The functions of the hormone are an integrated product of insulin secretion from pancreatic β-cells and insulin clearance by receptor-mediated ...endocytosis and degradation, mostly in liver (hepatocytes) and, to a lower extent, in extrahepatic peripheral tissues. Substantial evidence indicates that genetic or acquired abnormalities of insulin secretion or action predispose to type 2 diabetes. In recent years, along with the discovery of the molecular foundation of receptor-mediated insulin clearance, such as through the membrane glycoprotein CEACAM1, a consensus has begun to emerge that reduction of insulin clearance contributes to the disease process. In this review, we consider the evidence suggesting a pathogenic role for reduced insulin clearance in insulin resistance, obesity, hepatic steatosis, and type 2 diabetes.
The prevalence of insulin resistance and type 2 diabetes (T2D) in obese youth is rapidly increasing, especially in Hispanics and African Americans compared to Caucasians. Insulin resistance is known ...to be associated with increases in intramyocellular (IMCL) and hepatic fat content. We determined if there are ethnic differences in IMCL and hepatic fat content in a multiethnic cohort of 55 obese adolescents. We used (1)H magnetic resonance spectroscopy (MRS) to quantify IMCL levels in the soleus muscle, oral glucose tolerance testing to estimate insulin sensitivity, magnetic resonance imaging (MRI) to measure abdominal fat distribution. Liver fat content was measured by fast-MRI. Despite similar age and % total body fat among the groups, IMCL was significantly higher in the Hispanics (1.71% 1.43%, 2.0%) than in the African-Americans (1.04% 0.75%, 1.34%, p = 0.013) and the Caucasians (1.2% 0.94%, 1.5%, p = 0.04). Liver fat content was undetectable in the African Americans whereas it was two fold higher than normal in both Caucasians and Hispanics. Visceral fat was significantly lower in African Americans (41.5 cm(2) 34.6, 49.6) and was similar in Caucasians (65.2 cm(2) 55.9, 76.0) and Hispanics (70.5 cm(2) 59.9, 83.1). In a multiple regression analysis, we found that ethnicity independent of age, gender and % body fat accounts for 10% of the difference in IMCL. Our study indicates that obese Hispanic adolescents have a greater IMCL lipid content than both Caucasians and African Americans, of comparable weight, age and gender. Excessive accumulation of fat in the liver was found in both Caucasian and Hispanic groups as opposed to virtually undetectable levels in the African Americans. Thus, irrespective of obesity, there seem to be some clear ethnic differences in the amount of lipid accumulated in skeletal muscle, liver and abdominal cavity.
The Padova Chart for Health in Children (PCHC) aims to gather the evidence of healthcare promotion and protection for chidren and adolescents (i.e., aged <18 y) into a single document in order to ...guide families, healthcare providers and social actors on healthy choices. No more than 2% of Europeans and North Americans aged <30 y have a healthy lifestyle. This, together with metabolic and brain plasticity during childhood, creates the ideal opportunity to implement preventive strategies. Guided interventions promoting healthy lifestyle in children and families therefore have a key role in abating the unprecedented pandemic of non-communicable diseases (NCDs) in adulthood.
The PCHC is divided into four sections: nutrition, cardiovascular health, respiratory health, and mental and social health. Each section is structured in an ALICE approach (assessment, lobbying, intervention, call-for-action, evaluation): assessment of necessity, describing relevance to healthcare; lobbying to identify those who can effect the proposed interventions; interventions involving family, school and peers; a call-for-action to define priorities among the proposed interventions; and objective evaluation measures that can be applied on a population basis.
Interventions promoting health in childhood require joint action from multiple institutional, local and family representatives, with the shared goal of promoting health across the entire age group. These lifestyle interventions have the potential to change the lifetime risk trajectory for NCDs.
To describe the metabolic phenotype of type 2 diabetes mellitus in youth and possible metabolic defects leading to its development with particular emphasis on fatty liver.
We present data gathered ...from studies performed in obese adolescents across the spectrum of glucose tolerance to assess both alterations in insulin sensitivity and secretion. Discussion regarding treatment options is presented using the data from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.
As the number of children with obesity continues to grow, the health implications of the condition are becoming increasingly evident. An unprecedented phenomenon rarely seen before has emerged: type 2 diabetes mellitus. At the time of diabetes diagnosis, cardiovascular disease may already be present, even in young adults. The progression from normal glucose tolerance to type 2 diabetes in adults occurs through an intermediate phase of altered glucose metabolism known as impaired glucose tolerance or prediabetes. Previous studies from our group and others reported a high prevalence of impaired glucose tolerance among children and adolescents with marked obesity. Cross-sectional studies demonstrate that impaired glucose tolerance in obese youth is associated with severe insulin resistance, β-cell dysfunction, and altered abdominal and muscle fat partitioning. We end briefly by discussing the current data available on treatment of this condition from the TODAY study, the largest clinical trial ever performed in youth with type 2 diabetes.
The observed rapid progression of the glucose homeostasis alterations in adolescents underlines the importance of focusing attention on the earliest stages of the disease before the onset of any alterations in glucose tolerance.
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