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Cited by 186Diet, Metabolism, and DiseaseLiver Disease Diagnosis and TreatmentDiabetes, Cardiovascular Risks, and Lipoproteins

Toward a unifying hypothesis of metabolic syndrome

Open access
Bremer, Andrew A., Mietus-Snyder, Michele, Lustig, Robert H.·2012·PEDIATRICS
DOI 10.1542/peds.2011-2912PMC PMC3289531
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Abstract

Despite a lack of consistent diagnostic criteria, the metabolic syndrome (MetS) is increasingly evident in children and adolescents, portending a tsunami of chronic disease and mortality as this generation ages. The diagnostic criteria for MetS apply absolute cutoffs to continuous variables and fail to take into account aging, pubertal changes, and race/ethnicity. We attempt to define MetS mechanistically to determine its specific etiologies and to identify targets for therapy. Whereas the majority of studies document a relationship of visceral fat to insulin resistance, ectopic liver fat correlates better with dysfunctional insulin dynamics from which the rest of MetS derives. In contrast to the systemic metabolism of glucose, the liver is the primary metabolic clearinghouse for 4 specific foodstuffs that have been associated with the development of MetS: trans-fats, branched-chain amino acids, ethanol, and fructose. These 4 substrates (1) are not insulin regulated and (2) deliver metabolic intermediates to hepatic mitochondria without an appropriate "pop-off" mechanism for excess substrate, enhancing lipogenesis and ectopic adipose storage. Excessive fatty acid derivatives interfere with hepatic insulin signal transduction. Reactive oxygen species accumulate, which cannot be quenched by adjacent peroxisomes; these reactive oxygen species reach the endoplasmic reticulum, leading to a compensatory process termed the "unfolded protein response," driving further insulin resistance and eventually insulin deficiency. No obvious drug target exists in this pathway; thus, the only rational therapeutic approaches remain (1) altering hepatic substrate availability (dietary modification), (2) reducing hepatic substrate flux (high fiber), or (3) increasing mitochondrial efficiency (exercise).

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  • Liver fructose metabolism in the fed state generates lipogenic substrates in an unregulated fashion, driving hepatic de novo lipogenesis and reduced fatty acid oxidation, forming excessive liver fat and inflammation that inactivates insulin signaling, leading to hepatic insulin resistance.

    “For example, liver fructose metabolism in the fed state generates lipogenic substrates in an unregulated fashion, which drives hepatic de novo lipogenesis and reduced fatty acid oxidation, forming excessive liver fat and inflammation that inactivates the insulin signaling pathway, leading to hepatic insulin resistance [16], [17].”

    From The relationship of sugar to population-level diabetes prevalence: an econometric analysis of repeated cross-sectional data (2013) · cites this paper as [16]

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Research works printed but not linked: 1

  1. [16]Kylin E. Studien uber das Hypertonie-Hyperglyka “mie-Hyperurika” miesyndrom. Zentralbl Inn Med. 1923;44:105–127 [Google Scholar]

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Authors
Bremer, A. A., Mietus-Snyder, M., & Lustig, R. H.
Affiliations
  • Vanderbilt University (US)
  • Department of Pediatrics and Children’s National Obesity Institute, Children’s National Medical Center, Washington, District of Columbia; and
  • University of California, San Francisco (US)
ORCID
Venue
PEDIATRICS
Publisher
American Academy of Pediatrics (AAP)
Published
2012-03-01
Volume
129
Issue
3
Pages
557-570
ISSN
  • 0031-4005 (ISSN-L)
  • 1098-4275
DOI
10.1542/peds.2011-2912
PMC
PMC3289531
OpenAlex
W2111313276
Cited by
186
References
180
Citations by year
2026: 2 · 2025: 4 · 2024: 5 · 2023: 9 · 2022: 6 · 2021: 14 · 2020: 5 · 2019: 13 · 2018: 8 · 2017: 8 · 2016: 18 · 2015: 14 · 2014: 27 · 2013: 40 · 2012: 13
FWCI
4.13
Type
journal article
Language
en
Open access
Locations
  • PEDIATRICS (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
metabolic syndrome, pediatric metabolic syndrome, insulin resistance, visceral fat, hepatic insulin signaling, trans fatty acids, branched-chain amino acids, ethanol, fructose, lipogenesis, reactive oxygen species, unfolded protein response, mitochondrial dysfunction, physical activity, dietary change, children with chronic illness
MeSH terms
Adolescent, Child, Combined Modality Therapy, Diet, Female, Humans, Hypertension, Insulin Resistance, Life Style, Male, Obesity, Prognosis, Severity of Illness Index, United States, Prevalence, Survival Analysis, Age Distribution, Sex Distribution, Risk Assessment, Metabolic Syndrome, Dyslipidemias

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