SINDROMUL METABOLIC DE LA

INFLAMAȚIE LA PATOLOGIE;
NECESITĂȚI DE PREVENȚIE

Prof. Dr. Evelina MORARU

Universitatea de Medicina si Farmacie “Gr. T. Popa” Iasi

Sef lucrari Dr Laura Bozomitu

ME TA BO LIC
 PLAN
1. Sindromul metabolic-repere copil
2. Cine da startul insulin-rezistentei?
-adipocitul?
-muschiul?
-ficatul?
3 Imunologia, inflamatia metabolica
4 Modificari imunologice in SM
5 Implicatii practice preventive si terapeutice in perioada copilariei.
SINDROMUL METABOLIC-REPERE

METABOLICE IMUNOLOGICE
Cand ne-am gandit?
Factori de risc in diabet-1920
Termenul de SM dateaza din 1950 si
devine foarte utilizat in 1970-comfirmat 1980.

1947-Jean Vaque remarca relatia stransa intre

obezitate, predispozitia la diabet, ateroscleroza si calculi
renali.
CORECT - DISMETABOLIC SI IMUN????
• Sindrom dismetabolic
• Hypertriglyceridemie
• Sindrom de Insulin resistenta
• Obesity syndrome
• Syndromul X
• Beer Belly sindrom
• Sindrom Reaven
ADIPOCITUL ESTE UN REZERVOR DE SEMNALE IMUNE PRO INFLAMATORII
 DEFINITIA SM REPERE PENTRU DG CLINIC IN SM

Circumferinta talie
-femei 80
Barbati 102

Insulino-rezistenta
T Arteriala
Grasime ectopica

UNDE ESTE RASPUNSUL IMUN ABERANT????

 Diagnostic criteria
Metabolic syndrome was diagnosed based on the International Diabetes
Federation's paediatric definition
namely waist circumference ≥ 90th percentile plus two or more of the
following indices for all boys and girls:

• a. Triglycerides ≥150 mg/dL (1.7 mmol/L)

• b. Blood pressure (Systolic ≥130 mmHg or Diastolic ≥85 mmHg)
• c. Fasting blood glucose ≥100 mg/dL (5.6 mmol/L)
• d. High-density lipoprotein cholesterol ≤40 mg/dL (1.03 mmol/L)
BMC Public Health. 2011; 11: 333.
2011 May 18. doi: 10.1186/1471-2458-11-333MCID: PMC3111384
Risk of metabolic syndrome among children
living in metropolitan Kuala Lumpur: A case control study
Bee S Wee,
1,2 Bee K Poh, 1 Awang Bulgiba, 3 Mohd N Ismail,1 Abdul T Ruzita,1 and Andrew P Hills4
• Prevalenta de 13% la copii scolari
PROVOCATOR
• Tineri
• J Cardiovasc Thorac Res. 2015;7(4):158-63. doi: 10.15171/jcvtr.2015.34. Epub 2015 Nov 29.
• Prevalence of Metabolic Syndrome in Elementary School Children in East of Iran.
• Zardast M1, Namakin K1, Chahkandi T1, Taheri F1, Kazemi T2, Bijari B1.
• Metabolic Syndrome (MS) in children and adolescents is becoming a global public health concern. MS tracks into adulthood increasing the risk for
type 2 diabetes mellitus and cardiovascular diseases. This study was designed to verify the rate of MS in elementary school students of Birjand, as
a representative sample of Iranian children to verify the best preventive measures in this age group.
• METHODS:
• This descriptive-analytical, cross-sectional study was performed on 1425 elementary school children through multiple-cluster sampling in 2013.
Height, weight, waist circumference and blood pressure of children were measured by standard methods. Blood glucose, triglycerides, cholesterol,
High-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) levels were also measured after 12 hours fasting. MS
was defined according to the Adult Treatment Panel III (ATP-III) based on the National Cholesterol Education Program. Data were analyzed by SPSS
using t test and chi-square test. Significance level was set at P < 0.05.
• RESULTS:
• The prevalence of MS was 5.3% which increased with age. 43.5% of the studied cases had one or more components of the MS. The most common
components were hypertension, abdominal obesity, hypertriglyceridemia, low HDL-cholesterol and impaired fasting glucose, respectively. MS
prevalence was 0.9% in normal weight, 11.3% in overweight and 36.2% in obese children.
• CONCLUSION:
• Regarding the high prevalence of MS in elementary school children in our region, screening for obesity is recommended to prevent adulthood
complications. Therapeutic lifestyle changes and maintenance of regular physical activity are the most important strategies for preventing
childhood obesity.
Sindrom metabolic
Acanthosis nigricans
9 ani, sindrom metabolic – insulinorezistenta; Hb glicozilata = 5,97% (N<6)
CINE DA STARTUL
INSULINO-REZISTENTEI ????

CELULE IMUNE SI METABOLICE

IN PROXIMITATE INTIMA
IMUNOLOGIE METABOLICA!
IMUNO-NUTRITIE
IN INFLAMATIA METABOLICA
ADIPOCITE-MACROFAGE-CITOKINE-INFLAMATIE
(METABOLICA)
TESUT ADIPOS-REZERVOR IMUN ACTIV
REPERE PATOGENICE
• Grasimea viscerala
• Acumulare abundenta de adipocyte
• Nivel plasmatic de: TNF alfa, adiponectina,
resistina, PAI-1,
• Interactiunea TNF alfa-Receptori
specifici=trigger pentru declansarea
mecanismului de INSULINOREZISTENTA
•A high-fat diet augments Th17 cell development and the
expression of Acaca
•ACC1 controls Th17 cell development in vitro and Th17 cell
pathogenicity in vivo
•ACC1 modulates RORγt function in developing Th17 cells
•Obesity in humans induces ACACA and IL-17A expression in
CD4 T cellsAcetyl-CoA carboxylase (ACC) is a biotin-
dependent enzyme that catalyzes the irreversible
carboxylation of acetyl-CoA to producemalonyl-
CoA through its two catalytic activities, biotin
carboxylase (BC) and carboxyltransferase (CT). ACC is a
multi-subunit enzyme in most prokaryotes and in
the chloroplasts of most plants and algae, whereas it is
a large, multi-domain enzyme in the endoplasmic
reticulum of most eukaryotes. The most important
function of ACC is to provide the malonyl-CoA substrate
for the biosynthesis of fatty acids.[1] The activity of ACC
can be controlled at the transcriptional level as well as
by small molecule modulators and covalent
modification. The human genome contains the genes
for two different ACCs[2] — ACACA[3] and ACACB.[4]
MANIFESTARI CLINICE IMUNE
ASOCIATE SM
 AFECTAREA CEREBRALA - IMPACT SOCIAL
• Numeroase dezordini cognitive s-au raportat concomitent cu prevalenta
mare a obezitatii si DZ.
• “ The blood–brain barrier (BBB)”-reprezinta interfata intre circulatia
periferica si creier si are rol protectiv major pt, aceste compartimente.
• Functia homeostatica a BBB se exercita si in cazul inflamatiei.
• Perturbari nutritionale si metabolice - important factor de risc pentru
declinul integritatii anatomo-functionala BBB.
• Consecintele etiologice apar pentru o varietate incredibila de patologii
cerebro-vasculare si neurodegenerative.
• Impactul social reprezinta un serios avertisment.
Metabolic syndrome and the immunological affair with the blood–brain barrier
Egle Solito *, 2016 1

•1William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
•2Istituto Per L’Endocrinologia e L’Oncologia Sperimentale ”G.Salvatore” – Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples, Italy Claudio Mauro ,
1†
 High-fat diet impact on peripheral versus central function. High-fat diet (A)induces
obesity (B) increasing peripheral chronic inflammation (cytokines release). This has
deleterious effects on brain functionality (e.g., alteration of BBB transporters,
neuroinflammation, and cognitive disorders such as AD). Peripheral inflammation and
increased BBB leakage (C) induce leukocytes migration into the brain (D), which exacerbates
neuroinflammation and neurodegenerative diseases.
 MORBIDITATI CURENTE
Acta Derm Venereol. 2013 Mar 27;93(2):156-60. doi: 10.2340/00015555-
1443.
Co-existence of chronic urticaria and metabolic syndrome: clinical implications.
Ye YM1, Jin HJ, Hwang EK, Nam YH, Kim JH, Shin YS, Park HS.

• Pacientii cu SM prezinta status procoagulant si urticarie cronica pe fondul

inflamatiei sistemice permanente.
• Urticaria prezinta scor de activitate crescut, concentratie mai mare de proteina
cationica majora a eozinofilului si teste cutanate negative.
• Raspuns nesatisfacator la terapia dupa ghiduri.
• SM - predictor independent de afirmare a lipsei de control a
urticariei cronice.
• Terapia cu doze mai mari de antihistaminice nu da satisfactii dar creste riscurile
comune( cardiovasculare).
 ASTMUL BRONSIC-NECONTROLAT
VENTILATOR SAU INFLAMATOR IN SM???
• Hiperinsulinemia poate predispune la astm bronsic
• IR este factor de risc independent pentru dezvoltarea
astmului bronsic.
• Insulina si I like GF sunt implicate in dezvoltarea si
functionalitatea pulmonara.
• Hiperinsulinemia produce cu certitudine directionare
prioritara spre diferentierea TH2 a limfocitelor
cu implicatii pulmonare directe
• Experimental s-a atestat efectul benefic al insulinei
inhalatorii asupra FEV1, raspunsul local TH2 si
bronhoconstrictiei!
• SM si comorbiditatile asociate acestuia sunt probleme grave de
sanatate publica;
• Excesul de nutrient si SM, induc un raspuns imun aberant si
rezistenta la insulina.
• Adipocitele din tesutul gras alb interactioneaza cu SI si determina RI
si un grad minim de inflamatie cronica .
• Tesutul adipos alb determina secretia de substante bioactive
complexe, adipokines, citokine și alți mediatori ai inflamatiei.
• Perturbarile microbiotei intestinale,adipokine si citokine vor modula
insulina si caile de semnalizare imunitare determinand IR.
• Citochinele și stimuli proinflamatori pregatesc R I
ulterioară - elementul central etiopatogenic al SM.
• Rezistența la insulină
(1)incapacitatea insulinei de a stimula stocarea glucozei în
mușchii scheletici
(2) intensifica neoglicogeneza
(3) accentuiaza lipoliza în adipocite.

• Progresia RI si CRP crescut , sunt criterii de inflamatie

metabolica.
PRODUCTIA ANORMALA DE ADIPOKINE
2016 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online) 2016
• increased flux of free fatty
acids into the circulation and
uptake by the myocyte or
hepatocyte.
Activated fatty acids (i.e., fatty
acyl-CoAs) are “metabolized”
primarily via one of two
pathways, oxidation or storage.
When fatty acid flux exceeds the
ability of these pathways to
dispose of fatty acyl-CoAs,
intermediaries of fatty acid
metabolism (e.g., DAG, PA, LPA,
ceramide) accumulate.
In turn, these fatty acid
intermediates can activate a
number of different serine
kinases that can negatively
regulate insulin action
INFLAMATIE TISULARA-MODIFICARI SISTEMICE!
MICROHIPOXIA SI STRESUL CELULAR (RE)
INFLAMATIE INSULINREZISTENTA
combination of microhypoxia and nutrient excess leads
to induction of HIF-1 and the downstream target genes as
well as ER stress within the adipocyte. This can lead to
the eventual death of the adipocyte as well as a
characteristic inflammatory response. The inflammatory
response includes increased production and release of
proinflammatory cytokines/chemokines and the
recruitment of bone marrow–derived macrophages (Mϕ).
These macrophages are of the M1 activation/polarization
state and are highly inflammatory in nature. Once
recruited, these macrophages release proinflammatory
cytokines, which work in a paracrine manner to activate
the intracellular proinflammatory pathways (e.g., JNK
and IKK) in neighboring cells and possibly through
endocrine mechanisms in distal tissues. In a feed-forward
cycle, activation of macrophages promotes the
recruitment and infiltration of additional macrophages
into adipose tissue. This results in cell autonomous
insulin resistance in adipocytes and liver, exacerbation of
the inflammatory state, and systemic insulin resistance.
With obesity, there is also increased fat accumulation
within skeletal muscle, and these intermuscular fat depots
becomes infiltrated with proinflammatory macrophages,
which may cause paracrine-like insulin resistance in
skeletal muscle. In parallel with these inflammation-
related changes, alterations in fatty acid metabolism can
lead to the accumulation of fatty acid intermediates with
the liver and skeletal muscle, which can cause insulin
resistance via mechanisms outlined in Figure ​Figure1.1.
In addition, fatty acids can serve as ligands to broadly
activate inflammatory pathways in Kupffer cells and
ATMs (e.g., via TLR2/TLR4 signaling pathways).
3
INFLAMATIA ADIPOCITARA - CERTITUDINE IN SM
 Fibrin deposition in adipose tissue in obesity.

Fibrin deposition
in adipose tissue
in obesity.
Immunohistochemic
al staining for fibrin
in paraffin sections
of adipose tissue,
showing increased
fibrin deposition
(reddish-brown
color) in obese mice
(A,B) compared with
lean mice (C). (D)
Negative control
staining without the
primary anti-fibrin
antibody.

Fahumiya Samad, and Wolfram Ruf Blood 2013;122:3415-

3422

©2013 by American Society of Hematology

IMUNOLOGIA-RELATII
METABOLICE
• Preocupări privind implicarea vaccinării în
producerea sindromului metabolic (prin
inflamatia activata imun).
• Microbiota intestinala cu viitoare posibilitati de
interventie .
• Potențiale oportunități terapeutice.
IMUNOMETABOLISM-IMUNOFUNCTII-NUTRIFUNCTII

Front. Immunol., 08 April 2015 |

Time and demand are two critical dimensions of
immunometabolism: the process of macrophage
activation and the pentose phosphate pathway
Plasminogen
Activator Inhibitor
dendritice, bogate în granule conținând perforin (perf-DC Dovezile sugereaza ca mecanismele imunologice stau la baza controlului metabolic al
țesutului adipos.
Se discuta reglementarea unei subpopulații rare de celule s).
Folosind transplantul de măduvă osoasă pentru a genera animale lipsite în mod selectiv perf-DCs, am constatat că acestea au câștigat în mod progresiv
în greutate și caracteristici ale sindromului metabolic .
Acest fenotip a fost asociat cu un repertoriu modificat de celule T din țesutul adipos și ar putea fi complet prevenite prin depleția celulelor T in vivo.
Un efect similar celui al perf-DCs pe celulele T inflamatorii a fost, de asemenea, găsit într-un model bine definit de scleroză multiplă, encefalomielita
autoimună experimentală (EAE).
Perf-DCs reprezintă, probabil, o subpopulație de celule de reglementare critice pentru protecția împotriva sindromului metabolic
și autoimunitate. Perforinei pozitive Celulele dendritice Planșa un rol imuno de reglementare în sindromul metabolic și autoimunitate.
Reisner și colab 2015
Zlotnikov-Klionsky et al., 2015, Immunity
43, 1–12
October 20, 2015 ª2015 Elsevier Inc.
http://dx.doi.org/10.1016/j.immuni.2015.08.015
 IN VIITOR
• Vor prelua imunologii si adipocitul ???
•Vom trata comorbiditatile SM cu terapii
biologice?
•Vom utiliza in SM inhibitori de TNF Alfa???
•O noua generatie de vaccinuri va ocoli
inflamatia care este conditie a eficientei?
 TIMPUL OFERA SANSE
“ Pentru a fi real si impactant, trebuie să exişti
nu în conştiinţa ta, care e aşa de nesigură, ci în
conştiinţa altui om.
Şi nu pur şi simplu a unui om, ci a celui pentru
care e important să ştie că tu exişti. «
(Mihail Siskin-
SCRISOAREA)