Title ULOGA VIRUSNIH INFEKCIJA U RAZVOJU REZISTENCIJE
NA INZULIN I ŠEĆERNE BOLESTI TIPA 2 U DEBLJINI Title (english) THE ROLE OF VIRAL INFECTIONS IN THE DEVELOPMENT
OF INSULIN RESISTANCE AND DIABETES MELLITUS
TYPE 2 IN OBESITY Author Marko Šestan Mentor Bojan Polić (mentor)Committee member Astrid Krmpotić (predsjednik povjerenstva)Committee member Alenka Gagro (član povjerenstva)Committee member Sanja Klobučar-Majanović (član povjerenstva)Granter University of Rijeka Defense date and country 2018-07-09, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Universal decimal classificationUDC ) 61 - Medical sciences ThesaurusMESH - Medical Subject Headings )
Diabetes Mellitus, Type 2
Obesity
Infection
Insulin Resistance
CD8-Positive T-Lymphocytes
Abstract Cilj istraživanja: Šećerna bolest tipa 2 (T2DM) je kronični metabolički poremećaj koji
je povezan s pretilošću i karakteriziran je s povišenim razinama glukoze u krvi,
inzulinskom rezistencijom (IR) u perifernim tkivima i kroničnom sistemskom upalom
niskog intenziteta. Prospektivne kliničke studije pokazuju da je razvoj T2DM-a povezan
s naglim pogoršanjem metaboličkih parametara u predijabetičnih osoba. No, čimbenici
koji uzrokuju navedeno pogoršanje su uglavnom nepoznati. Stoga je glavni cilj ovoga
istraživanja bio ispitati utječu li i kako virusne infekcije na kontrolu glikemije u
predijabetesu.
Materijali i metode: Kako bih istražio utječu li virusne infekcije na homeostazu
glukoze, u suradnji s KBC-om Rijeka uspostavio sam prospektivnu studiju u kojoj smo
mršavim i pretilim euglikemičnim pacijentima koji su bolovali od akutnih respiratornih
infekcija odredili razine glukoze i inzulina u krvi natašte u periodu akutne infekcije, te 3
mjeseca kasnije. Kako bih podrobnije istražio mehanizam pogoršanja metaboličkih
parametara u virusnoj infekciji kod pretilih subjekata, upotrijebio sam mišji model
dijetom inducirane pretilosti koji dovodi do razvoja T2DM. U predijabetičnoj fazi (6
tjedana od početka visokokalorijske dijete) miševe sam inficirao s mišjim
citomegalovirusom ili virusom limfocitnog koriomeningitisa. U tom modelu neutralizirao
sam citokine monoklonskim protutijelima ili koristio genetski modificirane životinje
kojima nedostaju geni čiji su produkti citokini (Ifng-/-) ili njihovi receptori (IFNgR1-/-,
TNFRp55-/-). Kako bih istražio na koje stanice bitne za homeostazu glukoze IFNg ima
najveći utjecaj, koristio sam mišji model specifične delecije IFNgR1 na adipocitima,
hepatocitima i skeletnim mišićnim stanicama.
Rezultati: Virusom potaknuti IFNg uzrokuje IR-u u skeletnom mišičju smanjenjem
izražaja inzulinskog receptora. Tako potaknuta selektivna IR-a uzrokuje
kompenzatornu hiperinzulinemiju s ciljem prevencije hiperglikemije. Hiperinzulinemija
je u funkciji imunosnog odgovora jer pojačava antivirusno djelovanje CD8+ limfocita T.
Kada je sistemska inzulinska osjetljivost dodatno smanjena, kao što je to u
predijabetičnih pretilih subjekata radi povećane IR-e jetre, infekcija nadvlada
kompenzatornu sposobnost endokrinog sustava i dovodi do nastanka intolerancije na
glukozu i razvoja T2DM-a.
Zaključak: Virusom potaknuta IR-a u skeletnim mišićima uzrokuje kompenzatornu
hiperinzulinemiju s ciljem pojačanja anti-virusnog imunosnog odgovora. Međutim, taj
mehanizam u pretilosti zbog povećane IR-e jetre dovodi do gubitka homeostaze
glukoze i nagle progresije iz predijabetesa u dijabetes.
Abstract (english) Objectives: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder mostly
associated with obesity and characterized by high blood glucose levels, insulin
resistance (IR) in peripheral tissues and chronic systemic low-grade inflammation.
Prospective clinical studies show that development of T2DM is often associated with
an abrupt increase in blood glucose levels after a stable pre-diabetic phase. However,
factors which induce this aggravation are largely unknown. The aim of this study was
to investigate whether and how a viral infection influence glucose homeostasis in prediabetic
obese subjects.
Material and methods: To investigate whether infection impacts glucose
homeostasis, in collaboration with Clinical hospital Rijeka a small prospective human
study was setup in which lean and overweight/obese patients were analyzed for fasting
plasma insulin and glucose levels at the time of diagnosis of an acute respiratory
infection and 3 months later. In parallel, C57BL/6J mice were exposed to diet induced
obesity and subjected to infection with mouse cytomegalovirus (MCMV) and
Lymphocytic choriomeningitis virus (LCMV) at the pre-diabetic phase (6 weeks after
start of high fat diet - HFD). To gain insight in the mechanism underlying virus-induced
progression of T2DM, cytokines were neutralized by antibodies or appropriate
knockout mice for genes encoding cytokines (Ifng-/-) or their receptors (IFNgR1,
TNFRp55) were used. To investigate which cell types important for glucose
homeostasis are mostly affected by IFNg, mouse models for specific ablation of IFNgR1
on adipocytes, hepatocytes and skeletal muscle cells were used.
Results: Virally induced IFNg impairs expression of the insulin receptor in skeletal
muscle, resulting in short-term systemic IR and hyperinsulinemia. Virus induced
muscle specific IR promotes compensatory hyperinsulinemia to prevent
hyperglycemia. The increase of insulin levels boosts anti-viral effector functions of
CD8+ T cells. In mice primed for metabolic dysfunction in diet induced obesity, infection
resulted in loss of glycemic control. Thus, upon pathogen encounter, the immune
system transiently reduces insulin sensitivity of skeletal muscles to induce
hyperinsulinemia and promote antiviral immunity, which derails to glucose intolerance
in obese subjects.
Conclusion: Virus-induced selective IR in skeletal muscle drives hyperinsulinemia to
boost antiviral immune response in lean subjects. However, it derails glycemic control
in obesity, causing rapid progression from pre-diabetes to T2DM.
Keywords
CD8+ limfociti T
IFNg
Infekcija
Inzulinska rezistencija
Inzulinski receptor
Skeletno mišičje
Šećerna bolest tipa 2.
Keywords (english)
CD8+ T cells
Diabetes mellitus type 2
IFNg
Infection
Insulin receptor
Insulin resistance
Skeletal muscle
Language croatian URN:NBN urn:nbn:hr:184:292148 Project Number: IP-2016-06-9306 Study programme Title: Biomedicine Postgraduate (doctoral) study programme Type of resource Text File origin Born digital Access conditions Access restricted to students and staff of home institution Terms of use Created on 2019-01-17 17:47:37
