Novel biomarkers for prediabetes, diabetes, and associated complications

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Abstract

The number of individuals with prediabetes is expected to grow substantially and estimated to globally affect 482 million people by 2040. Therefore, effective methods for diagnosing prediabetes will be required to reduce the risk of progressing to diabetes and its complications. The current biomarkers, glycated hemoglobin (HbA1c), fructosamine, and glycated albumin have limitations including moderate sensitivity and specificity and are inaccurate in certain clinical conditions. Therefore, identification of additional biomarkers is being explored recognizing that any single biomarker will also likely have inherent limitations. Therefore, combining several biomarkers may more precisely identify those at high risk for developing prediabetes and subsequent progression to diabetes. This review describes recently identified biomarkers and their potential utility for addressing the burgeoning epidemic of dysglycemic disorders.

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Most cited references 118

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The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes.

S E Kahn (2003)

The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes have been debated extensively. The concept that a feedback loop governs the interaction of the insulin-sensitive tissues and the beta cell as well as the elucidation of the hyperbolic relationship between insulin sensitivity and insulin secretion explains why insulin-resistant subjects exhibit markedly increased insulin responses while those who are insulin-sensitive have low responses. Consideration of this hyperbolic relationship has helped identify the critical role of beta-cell dysfunction in the development of Type 2 diabetes and the demonstration of reduced beta-cell function in high risk subjects. Furthermore, assessments in a number of ethnic groups emphasise that beta-cell function is a major determinant of oral glucose tolerance in subjects with normal and reduced glucose tolerance and that in all populations the progression from normal to impaired glucose tolerance and subsequently to Type 2 diabetes is associated with declining insulin sensitivity and beta-cell function. The genetic and molecular basis for these reductions in insulin sensitivity and beta-cell function are not fully understood but it does seem that body-fat distribution and especially intra-abdominal fat are major determinants of insulin resistance while reductions in beta-cell mass contribute to beta-cell dysfunction. Based on our greater understanding of the relative roles of insulin resistance and beta-cell dysfunction in Type 2 diabetes, we can anticipate advances in the identification of genes contributing to the development of the disease as well as approaches to the treatment and prevention of Type 2 diabetes.

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Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis

Marta Guasch-Ferré, Adela Hruby, Estefanía Toledo … (2016)

OBJECTIVE To conduct a systematic review of cross-sectional and prospective human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on prediabetes and type 2 diabetes. RESEARCH DESIGN AND METHODS We searched MEDLINE and EMBASE databases through August 2015. We conducted a qualitative review of cross-sectional and prospective studies. Additionally, meta-analyses of metabolite markers, with data estimates from at least three prospective studies, and type 2 diabetes risk were conducted, and multivariable-adjusted relative risks of type 2 diabetes were calculated per study-specific SD difference in a given metabolite. RESULTS We identified 27 cross-sectional and 19 prospective publications reporting associations of metabolites and prediabetes and/or type 2 diabetes. Carbohydrate (glucose and fructose), lipid (phospholipids, sphingomyelins, and triglycerides), and amino acid (branched-chain amino acids, aromatic amino acids, glycine, and glutamine) metabolites were higher in individuals with type 2 diabetes compared with control subjects. Prospective studies provided evidence that blood concentrations of several metabolites, including hexoses, branched-chain amino acids, aromatic amino acids, phospholipids, and triglycerides, were associated with the incidence of prediabetes and type 2 diabetes. We meta-analyzed results from eight prospective studies that reported risk estimates for metabolites and type 2 diabetes, including 8,000 individuals of whom 1,940 had type 2 diabetes. We found 36% higher risk of type 2 diabetes per study-specific SD difference for isoleucine (pooled relative risk 1.36 [1.24–1.48]; I 2 = 9.5%), 36% for leucine (1.36 [1.17–1.58]; I 2 = 37.4%), 35% for valine (1.35 [1.19–1.53]; I 2 = 45.8%), 36% for tyrosine (1.36 [1.19–1.55]; I 2 = 51.6%), and 26% for phenylalanine (1.26 [1.10–1.44]; I 2 = 56%). Glycine and glutamine were inversely associated with type 2 diabetes risk (0.89 [0.81–0.96] and 0.85 [0.82–0.89], respectively; both I 2 = 0.0%). CONCLUSIONS In studies using high-throughput metabolomics, several blood amino acids appear to be consistently associated with the risk of developing type 2 diabetes.

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Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance.

Durba Pal, Suman Dasgupta, Rakesh Kundu … (2012)

Toll-like receptor 4 (TLR4) has a key role in innate immunity by activating an inflammatory signaling pathway. Free fatty acids (FFAs) stimulate adipose tissue inflammation through the TLR4 pathway, resulting in insulin resistance. However, current evidence suggests that FFAs do not directly bind to TLR4, but an endogenous ligand for TLR4 remains to be identified. Here we show that fetuin-A (FetA) could be this endogenous ligand and that it has a crucial role in regulating insulin sensitivity via Tlr4 signaling in mice. FetA (officially known as Ahsg) knockdown in mice with insulin resistance caused by a high-fat diet (HFD) resulted in downregulation of Tlr4-mediated inflammatory signaling in adipose tissue, whereas selective administration of FetA induced inflammatory signaling and insulin resistance. FFA-induced proinflammatory cytokine expression in adipocytes occurred only in the presence of both FetA and Tlr4; removing either of them prevented FFA-induced insulin resistance. We further found that FetA, through its terminal galactoside moiety, directly binds the residues of Leu100-Gly123 and Thr493-Thr516 in Tlr4. FFAs did not produce insulin resistance in adipocytes with mutated Tlr4 or galactoside-cleaved FetA. Taken together, our results suggest that FetA fulfills the requirement of an endogenous ligand for TLR4 through which lipids induce insulin resistance. This may position FetA as a new therapeutic target for managing insulin resistance and type 2 diabetes.

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Author and article information

Journal

Journal ID (nlm-ta): Diabetes Metab Syndr Obes

Journal ID (iso-abbrev): Diabetes Metab Syndr Obes

Journal ID (publisher-id): Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy

Title: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy

Publisher: Dove Medical Press

ISSN (Electronic): 1178-7007

Publication date Collection: 2017

Publication date (Electronic): 14 August 2017

Volume: 10

Pages: 345-361

Affiliations

[1 ]New York University School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Medical Center, New York, NY

[2 ]Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA

Author notes

Correspondence: Michael Bergman, New York University School of Medicine, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Medical Center, 550 1st Avenue, Suite 5E, New York, NY 10016, USA, Tel +1 212 481 1350, Fax +1 212 481 1355, Email michael.bergman@ 123456nyumc.org

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Publisher ID: dmso-10-345

DOI: 10.2147/DMSO.S100074

PMC ID: 5565252

PubMed ID: 28860833

SO-VID: b8bbaa0e-c760-4662-a135-74cd32f66c76

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The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

Novel biomarkers for prediabetes, diabetes, and associated complications

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Bioscientifica Open Endocrinology

Most cited references 118

The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes.

Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis

Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance.

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