Christos Zavos, Jannis

Deretzi, Georgia

Kountouras, Jannis

Polyzos, Stergios A.

English

Cadernos Espinosanos (E-Journal)

LETTER TO THE EDITORThe potentially dual-faceted nature of fetuin-A inHelicobacter pylori infection and insulin resistanceStergios A. Polyzos, Jannis Kountouras, Christos Zavos, Georgia DeretziDepartment of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece.Email: stergios@endo.grTel.: 302310424710We read with interest the study by Kebapcilar et al.1 onthe effect of Helicobacter pylori (HP) eradication on serumfetuin-A concentrations. Specifically, baseline serum fetuin-A was lower in HP-positive participants than in HP-negative matched participants. Furthermore, fetuin-A levelssignificantly increased after successful HP eradicationtreatment.1 To our knowledge, this is the first report onthe effect of HP eradication on serum fetuin-A.Recently, Manolakis et al. proposed serum fetuin-A as amediator linking HP infection and insulin resistance (IR).2This is also an interesting concept with therapeutic potentialbecause it suggests that HP eradication might decrease IRand IR-related morbidity, including type II diabetes mellitus(T2DM), nonalcoholic fatty liver disease (NAFLD) andcardiovascular disease (CVD),3 although the effect on CVDis highly debatable.4 We have recently performed asystematic review on the association between HP infectionand IR.5 Existing data indicate a potential associationbetween HP infection and IR, as assessed by homeostaticmodel assessment IR (HOMA-IR). However, althoughhistology is considered the gold standard diagnostic testfor HP, some studies used other methods to determine HPstatus. The serum anti-HP-specific IgG antibody level maybe of diagnostic value, but it does not discriminate betweenpast and current infections. Furthermore, given that serumremains positive for anti-HP-specific IgG even after eradica-tion of HP, it is unclear whether HP infection is the induceror the promoter of IR.5However, in the study by Manolakis et al., baseline fetuin-A was higher in HP-positive participants than in HP-negative participants.2 The reason for this discrepancybetween the two studies1,2 is largely unknown. Both studiesrecruited non-diabetic patients with dyspeptic symptoms,and their exclusion criteria were similar. However, themean age and BMI of the HP-positive group were higher inthe Manolakis et al. study2 than in the Kebapcilar et al.study1 (57.3¡16.1 versus 29.1¡7.5 years and 25.8¡12.7versus 22.9¡4.5 kg/m2, respectively, after converting SEMto SD in the first study), and these two differences couldhave affected IR. There were also ethnic differences, whichmight have affected IR and possibly serum fetuin-A. Finally,in the two studies, serum fetuin-A was measured bydifferent commercial ELISA kits.Fetuin-A is an acute-phase glycoprotein synthesized andsecreted almost exclusively by the liver that plays a role inbone mineralization and insulin-signaling regulation.6Fetuin-A binds a form of insoluble calcium phosphate,inhibiting pathological extraosseous calcification andthereby playing a protective role in the evolution of arterialcalcification. However, when dysregulated, fetuin-A canlead to ectopic calcification of soft tissues in the vasculature,thereby contributing to atherosclerosis. Likewise, by bind-ing the extracellular portion of the b-subunit of the insulinreceptor, fetuin-A inhibits insulin-receptor tyrosine kinase,thereby attenuating, under normal conditions, excessiveinsulin signaling. However, when dysregulated, fetuin-Aresults in excessive inhibition of insulin signaling in theliver and in skeletal muscle, thereby triggering IR.Subsequently, increased serum fetuin-A has been associatedwith IR-related morbidity, including T2DM, visceral obe-sity, NAFLD, CVD and ischemic stroke.6,7 Fetuin-A alsoseems to play a role in inflammation by downregulating thepro-inflammatory cytokines produced by macrophages.1Fetuin-A is regarded as an anti-inflammatory mediator thatcontributes to macrophage deactivation, and moreover, itpossesses anti-fibrotic activity and inhibits apoptosis invascular smooth muscle cells. Nonetheless, fetuin-A down-regulates adiponectin, an anti-inflammatory and insulin-sensitizing adipokine. Finally, although fetuin-A induceslipid accumulation in the liver, it may attenuate hepaticfibrosis by modifying the effects of transforming growthfactor-b signaling in hepatocytes.7 Summarizing all theabove-mentioned data, fetuin-A may possess a dual-facetednature in the metabolic and inflammatory milieu. It may beprotective by inhibiting extraosseous calcification or exces-sive insulin signaling in lean, metabolically healthy indivi-duals, but, in other situations, it may also be harmful,especially if its action is persistently elevated and pro-longed. This dual-faceted nature may also apply to mostcytokines and adipocytokines.8In the Kebapcilar et al. study,1 serum fetuin-A was low inyoung, HP-positive individuals with a negative history ofdiabetes, obesity and known cardiovascular risk factors.Furthermore, successful HP eradication was associatedwith a fetuin-A increase and a simultaneous decrease inboth C-reactive protein and macrophage migration inhibi-tory factor. This result seems rational for this specificpopulation, in whom the counteracting mechanisms,including fetuin-A, are beneficial. In the Manolakis et al.study,2 serum fetuin-A was increased in non-diabetic, HP-positive individuals with established IR, who generallywere older and had a higher BMI than the HP-positiveindividuals of the Kebapcilar et al. study.1 This finding alsoCopyright  2011 CLINICS – This is an Open Access article distributed underthe terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided theoriginal work is properly cited.CLINICS 2011;66(5):911-912 DOI:10.1590/S1807-59322011000500031911seems rational for this specific population, in whom thecounteracting mechanisms may no longer be beneficial,and thus fetuin-A may contribute, at least in part, to IR. Inconclusion, serum fetuin-A may represent a promisingindex for assessing the HP-related contributions to inflam-mation, IR and IR-related conditions, including T2DM,NAFLD and CVD; however, further clinical trials arenecessary to confirm its diagnostic efficacy.REFERENCES1. Kebapcilar L, Bilgir O, Cetinkaya E, Akyol M, Bilgir F, Bozkaya G. Theeffect of Helicobacter pylori eradication on macrophage migrationinhibitory factor, C-reactive protein and fetuin-a levels. Clinics.2010;65:799-802, doi: 10.1590/S1807-59322010000800010.2. Manolakis AC, Tiaka EK, Kapsoritakis AN, Georgoulias P, Tsiopoulos F,Valotassiou V, et al. Increased fetuin A levels in Helicobacter pyloriinfection: a missing link between H. pylori and insulin resistance?Diabetologia. 2011;54:472-4, doi: 10.1007/s00125-010-1995-2.3. Gen R, Demir M, Ataseven H. Effect of Helicobacter pylori eradicationon insulin resistance, serum lipids and low-grade inflammation. SouthMed J. 2010;103:190-6, doi: 10.1097/SMJ.0b013e3181cf373f.4. Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, et al. Helicobacterpylori eradication has no effect on metabolic and inflammatoryparameters. J Natl Med Assoc. 2005;97:508-13.5. Polyzos SA, Kountouras J, Zavos C, Deretzi G. The association betweenHelicobacter pylori infection and insulin resistance: A systematic review.Helicobacter. 2011;16:79–88, doi: 10.1111/j.1523–5348. 2011.00822.6.6. Goustin AS, bou-Samra AB. The ‘‘thrifty’’ gene encoding Ahsg/Fetuin-Ameets the insulin receptor: Insights into the mechanism of insulinresistance. Cell Signal. 2011;23:980–90; doi: 10.1016/j.cellsig.2010.11.003.7. Tonjes A, Bluher M, Stumvoll M. Retinol-binding protein 4 and newadipocytokines in nonalcoholic fatty liver disease. Curr Pharm Des.2010;16:1921-8, doi: 10.2174/138161210791208938.8. Polyzos SA, Kountouras J, Zavos C, Stergiopoulos C. Adipocytokines ininsulin resistance and non-alcoholic fatty liver disease: The two sides ofthe same coin. Med Hypotheses. 2010;74:1089-90, doi: 10.1016/j.mehy.2009.12.028.Fetuin-A, H. Pylori and insulin resistancePolyzos SACLINICS 2011;66(5):911-912912

The potentially dual-faceted nature of fetuin-A in Helicobacter pylori infection and insulin resistance

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The potentially dual-faceted nature of fetuin-A in Helicobacter pylori infection and insulin resistance

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